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Abstract Background Despite advances in total knee arthroplasty, many patients are still unsatisfied with the functional outcome. Multibody simulations enable a more efficient exploration of independent variables compared to experimental studies. However, to what extent numerical models can fully reproduce knee joint kinematics is still unclear. Hence, models must be validated with different test scenarios before being applied to biomechanical questions. Methods In our feasibility study, we analyzed a human knee specimen on a six degree of freedom joint simulator, applying a passive flexion and different laxity tests with sequential states of ligament resection while recording the joint kinematics. Simultaneously, we generated a subject-specific multibody model of the native tibiofemoral joint considering ligaments and contact between articulating cartilage surfaces. Results Our experimental data on the sequential states of ligament resection aligned well with the literature. The model-based knee joint kinematics during passive flexion showed good agreement with the experiment, with root-mean-square errors of less than 1.61 mm for translations and 2.1° for knee joint rotations. During laxity tests, the experiment measured up to 8 mm of anteroposterior laxity, while the numerical model allowed less than 3 mm. Conclusion Although the multibody model showed good agreement to the experimental kinematics during passive flexion, the validation showed that ligament parameters used in this feasibility study are too stiff to replicate experimental laxity tests correctly. Hence, more precise subject-specific ligament parameters have to be identified in the future through model optimization.

Background and objective: The primary cilium is a small protrusion found on most mammalian cells. It acts as a cellular antenna, being involved in various cell signaling pathways. The length of the primary cilium affects its function. To study the impact of physical or chemical stimuli on cilia, their lengths must be determined easily and reproducibly. Methods: We have developed and evaluated an open-source R package called detectCilia to detect and measure primary cilia automatically. As a case study to demonstrate the capability of our tool, we compared the influence of 4 different cell culture media compositions on the lengths of primary cilia in human chondrocytes. These media compositions include (1) insulin-transferrin-selenium (ITS); (2) ITS and dexamethasone (Dexa); (3) ITS, Dexa, insulin-like growth factor 1 (IGF-1), and transforming growth factor beta 1 (TGF-β1); and (4) fetal bovine serum (FBS). Results: The assessment of detectCilia included a comparison with 2 similar tools: ACDC (Automated Cilia Detection in Cells) and CiliaQ. Several differences and advantages of our package make it a valuable addition to these tools. In the case study, we have observed variations in the ciliary lengths associated with using different media compositions. Conclusions: We conclude that detectCilia can automatically and reproducibly detect and measure primary cilia in confocal microscopy images with low false-positive rates without requiring extensive user interaction.

The current reconstructive surgical procedures implemented after the resection of extended bone segments are associated with high complication rates and long-term treatments. By transplanting an autologous, vascularized and stabilized bone segment, these challenges can be managed. Thus, we propose a novel procedure to expand the currently available autologous bone grafts to the dimensions of the recipient bone using an implantable device. The objective of the present study was to characterize the feasibility of developing an implant prototype for fibula expansion in an in vitro model using a porcine fibula. A balloon catheter, as the part of the implant responsible for expansion, was proven to expand while being periodically filled with sodium chloride. Therefore, the expansion of the balloon catheter was analyzed in an experimental test setup with a 3D-printed porcine fibula with a closure film simulating callus formation to simulate the in vivo situation. Our experimental testing proved the successful expansion of the porcine fibula by the balloon catheter. Hence, the feasibility of the concept for subsequent animal testing was confirmed.

IntroductionThe release of mature interleukin (IL-) 1β from osteoblasts in response to danger signals is tightly regulated by the nucleotide-binding oligomerization domain leucine-rich repeat and pyrin-containing protein 3 (NLRP3) inflammasome. These danger signals include wear products resulting from aseptic loosening of joint arthroplasty. However, inflammasome activation requires two different signals: a nuclear factor-kappa B (NF-κB)-activating priming signal and an actual inflammasome-activating signal. Since human osteoblasts react to wear particles via Toll-like receptors (TLR), particles may represent an inflammasome activator that can induce both signals.MethodsTemporal gene expression profiles of TLRs and associated intracellular signaling pathways were determined to investigate the period when human osteoblasts take up metallic wear particles after initial contact and initiate a molecular response. For this purpose, human osteoblasts were treated with metallic particles derived from cobalt-chromium alloy (CoCr), lipopolysaccharides (LPS), and tumor necrosis factor-alpha (TNF) alone or in combination for incubation times ranging from one hour to three days. Shortly after adding the particles, their uptake was observed by the change in cell morphology and spectral data.ResultsExposure of osteoblasts to particles alone increased NLRP3 inflammasome-associated genes. The response was not significantly enhanced when cells were treated with CoCr + LPS or CoCr + TNF, whereas inflammation markers were induced. Despite an increase in genes related to the NLRP3 inflammasome, the release of IL-1β was unaffected after contact with CoCr particles.DiscussionAlthough CoCr particles affect the expression of NLRP3 inflammasome-associated genes, a single stimulus was not sufficient to prime and activate the inflammasome. TNF was able to prime the NLRP3 inflammasome of human osteoblasts.

Abstract High hydrostatic pressure specifically devitalizes cells and tissues without major changes in their molecular structure. Hence, high hydrostatic pressure may enhance the development of whole-cell anti-tumor vaccines, representing tumor heterogeneity and thus (neo-) antigen diversity. Moreover, safe devitalization of tumor-infiltrated supporting tissue may facilitate reimplantation for functional reconstruction. However, precise high hydrostatic pressure thresholds for safe cancer cell killing are unknown. Here, we show that high hydrostatic pressure of at least 315 MPa is necessary to safely devitalize head and neck squamous cell cancer. A pressure of 210 MPa, which has been used frequently in cancer vaccine preparation, resulted in partial devitalization with 27% live cells in flow cytometry and 4% remaining autofluorescence in cell culture after one week. The remaining cells could form vital tumors in the chorioallantoic membrane assay. In contrast, 315 MPa killed all cells in vitro and prevented tumor outgrowth in ovo. The effectiveness of 315 MPa was attributed to the induction of DNA double-strand breaks, independent of apoptosis, autophagy, or methuosis. Furthermore, 315 MPa continued to induce immunogenic cell death. Our results demonstrate that 315 MPa of high hydrostatic pressure induces safe and sustained devitalization of head and neck cancer cells and tissues. Because of the heterogeneity in pressure resistance, we propose our approach as a starting point for determining the precise thresholds for other cancer entities. Further studies on head and neck cancer should focus on immunological co-cultures, combinations of immune checkpoint inhibition, and accurate anatomical reconstruction with pressure-treated autografts.

Accurate detection of implant loosening is crucial for early intervention in total hip replacements, but current imaging methods lack sensitivity and specificity. Vibration methods, already successful in dentistry, represent a promising approach. In order to detect loosening of the total hip replacement, excitation and measurement should be performed intracorporeally to minimize the influence of soft tissue on damping of the signals. However, only implants with a single sensor intracorporeally integrated into the implant for detecting vibrations have been presented in the literature. Considering different mode shapes, the sensor’s position on the implant is assumed to influence the signals. In the work at hand, the influence of the position of the sensor on the recording of the vibrations on the implant was investigated. For this purpose, a simplified test setup was created with a titanium rod implanted in a cylinder of artificial cancellous bone. Mechanical stimulation via an exciter attached to the rod was recorded by three accelerometers at varying positions along the titanium rod. Three states of peri-implant loosening within the bone stock were simulated by extracting the bone material around the titanium rod, and different markers were analyzed to distinguish between these states of loosening. In addition, a modal analysis was performed using the finite element method to analyze the mode shapes. Distinct differences in the signals recorded by the acceleration sensors within defects highlight the influence of sensor position on mode detection and natural frequencies. Thus, using multiple sensors could be advantageous in accurately detecting all modes and determining the implant loosening state more precisely.

Proximal femur fracture risk depends on subject-specific factors such as bone mineral density and morphological parameters. Here, we aim to analyze the dependency of the femoral strength on sixteen morphological parameters. Therefore, finite-element analyses of 20 human femurs during stumbling and lateral falls on the hip were conducted. Pearson correlation coefficients were calculated and morphological parameters with significant correlations were examined in principal component analysis and linear regression analysis. The dependency of the fracture strength on morphological parameters was more pronounced during lateral falls on the hip compared to stumbling. Significant correlations were observed between the neck shaft angle (r = −0.474), neck diameter (r = 0.507), the true distance between the femoral head center and femoral shaft axis (r = 0.459), and its projected distance on the frontal plane (r = 0.511), greater trochanter height (r = 0.497), and distance between the femoral head center and a plane parallel to the frontal plane containing the projection of the femoral head center to the femoral neck axis (r = 0.669). Principal component analysis was strongly weighted by parameters defining the lever arm during a lateral fall as well as the loaded cross-section in the femoral neck.

A three-dimensional (3D) understanding of muscle attachment footprints became increasingly relevant for musculoskeletal modeling. The established method to project attachments as points ignores patient-specific individuality. Research focuses on investigating certain muscle groups rather than comprehensively studying all muscles spanning a joint. Therefore, we present a reliable method to study several muscle attachments in order to reconstruct the attachment sites in 3D based on CT imaging for future applications in musculoskeletal modeling. For the present feasibility study, 23 knee-related muscle attachments were CT-scanned postmortem from four nonadipose male specimens. For this, the specific muscle attachments were dissected and marked with a barium sulfate containing paint (60 g BaSO4 in 30 mL water and 10 mL acrylic paint). Subsequently, bone geometries and muscle attachments were reconstructed and evaluated from CT datasets. Bone morphology and footprint variations were studied. Exemplarily, variations were high for pes anserinus insertions (mean 56%) and the origins of M. biceps femoris (mean 54%). In contrast, the origins of the vastus muscles as well as the insertion of the Achilles tendon showed low variation (mean 9% and 13%, respectively). Most attachment sites showed variation exceeding the individuality of bone morphology. In summary, the present data were consistent with the few published studies of specific muscle footprints. Our data shed light on the high variability of muscle attachments, which need to be addressed when studying muscle forces and movements through musculoskeletal modeling. This is the first step to achieving a more profound understanding of muscle morphology to be utilized in numerical simulations.

This study deals with synthetic biomaterials that are biocompatible and mechanically stable to serve as a potential bone graft for improved mandibular reconstruction. To fabricate novel hybrid scaffolds containing beta-tricalcium phosphate (β-TCP) and zirconia (ZrO2), 3D printing was combined with Freeze Foaming to achieve a certain porosity, mimicking cancellous bone. The aim was to characterize the differentiation capacity of human pre-osteoblasts on the hybrid scaffolds. Although a good biocompatibility was demonstrated for the tested components of the hybrid scaffold, pure β-TCP foams showed the best results regarding osteogenic differentiation and pro-inflammatory processes. To enhance the osteoinductive properties of the β-TCP foam, the structures were also biofunctionalized with bone morphogenic protein 2 (BMP–2) and its effect was analyzed either on single cell cultures of pre-osteoblasts or pre-osteoblasts directly co-cultured with human peripheral blood mononuclear cells (PBMCs). The latter served to analyze the induction of bone remodelling processes. The immobilization of BMP-2 on scaffolds and its biological accessibility could be demonstrated, however, the biofunctionalization did not result in an enhanced differentiation capacity and bone remodeling processes of either pre-osteoblasts or directly co-cultured pre-osteoblasts and PBMCs.

Abstract Purpose Refixation of acute anterior cruciate ligament (ACL) tears represents an increasingly popular treatment option. Systematic evaluations of various suture technique parameters are still pending. We therefore aimed to evaluate the mechanical pull‐out outcomes of various suture methods for optimization of ACL refixation. Methods Sixty fresh knees from mature domestic pigs were dissected and the femoral attachment of the ACL was peeled off. The 60 knees were divided in 10 groups and sutured as follows: (A) one suture (1, 2, 4 and 6 passes), (B) two sutures (2, 4 and 6 passes each; sutures knotted together as a loop) and (C) two sutures (2, 4 and 6 passes each, sutures knotted separately). The pull‐out test was conducted using a validated electrodynamic testing machine. First occurrence of failure, maximum pull‐out load and stiffness were measured. Suture failure was defined as pull‐out of the ACL. Results Two‐point fixation, using two sutures, with at least two passes, showed the most favourable biomechanical stability. The maximum pull‐out load was significantly higher with two sutures (529.5 N) used compared to one (310.4 N), p

Abstract Background The rising number of total hip and knee arthroplasties and the decreasing availability of physiotherapists require clinically and economically effective rehabilitation approaches. Therefore, the present pilot study investigated the effect of a novel digital-assisted individualized group rehabilitation program on clinical and functional outcomes after total hip and knee arthroplasty. Methods In this randomized controlled pilot study, 26 patients undergoing total knee or hip replacement were randomly assigned to either the intervention group (IG, novel digital-assisted group therapy) or the control group (CG, standard postoperative physiotherapy currently carried out in Germany). The IG received the novel digital-assisted group therapy twice per week for a six-months period, while the CG received individual outpatient therapy depending on the prescription of the supervising physician. The number of therapy sessions was recorded. Moreover, subjective outcomes (EuroQol-5Dimensions (EQ-5D) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)), functional outcome (30 s sit to stand test and timed up and go test (TUG)), as well as gait parameters were quantified preoperatively as well as at three and six months after surgery. Data were analyzed using an analysis of covariance with baseline-adjustment. Results No patient-reported falls, pain, and hospital readmissions were recorded. On average, the IG received more therapy sessions. The clinical and functional outcomes were mainly not significantly different between groups at three- and six-months follow-up, but medium to large effect sizes for the differences in quality of life (EQ-5D) as well as pain, stiffness, and physical function (WOMAC), and TUG performance were observed in favor of the IG. However, the IG showed a higher variability of gait velocity after total joint replacement. Conclusion The digital-assisted rehabilitation had positive effects on quality of life, pain, stiffness, physical function, and TUG performance. Nevertheless, the therapy concept may be improved by adding exercises focusing on gait performance to reduce gait variability. The results indicate that the digital-assisted therapy concept is effective and safe. Therefore, a consecutive full-scaled randomized controlled clinical trial is recommended. Trial registration This study was retrospectively registered on 14/02/2022 in the German Clinical Trial Register (DRKS00027960).

Resultant hip joint forces can currently only be recorded in situ in a laboratory setting using instrumented total hip replacements (THRs) equipped with strain gauges. However, permanent recording is important for monitoring the structural condition of the implant, for therapeutic purposes, for self-reflection, and for research into managing the predicted increasing number of THRs worldwide. Therefore, this study aims to investigate whether a recently proposed THR with an integrated piezoelectric element represents a new possibility for the permanent recording of hip joint forces and the physical activities of the patient. Hip joint forces from nine different daily activities were obtained from the OrthoLoad database and applied to a total hip stem equipped with a piezoelectric element using a uniaxial testing machine. The forces acting on the piezoelectric element were calculated from the generated voltages. The correlation between the calculated forces on the piezoelectric element and the applied forces was investigated, and the regression equations were determined. In addition, the voltage outputs were used to predict the activity with a random forest classifier. The coefficient of determination between the applied maximum forces on the implant and the calculated maximum forces on the piezoelectric element was R2 = 0.97 (p < 0.01). The maximum forces on the THR could be determined via activity-independent determinations with a deviation of 2.49 ± 13.16% and activity-dependent calculation with 0.87 ± 7.28% deviation. The activities could be correctly predicted using the classification model with 95% accuracy. Hence, piezoelectric elements integrated into a total hip stem represent a promising sensor option for the energy-autonomous detection of joint forces and physical activities.

The AMTI VIVO™ six degree of freedom joint simulator allows reproducible preclinical testing of joint endoprostheses under specific kinematic and loading conditions. When testing total knee endoprosthesis, the articulating femoral and tibial components are each mounted on an actuator with two and four degrees of freedom, respectively. To approximate realistic physiological conditions with respect to soft tissues, the joint simulator features an integrated virtual ligament model that calculates the restoring forces of the ligament apparatus to be applied by the actuators. During joint motion, the locations of the ligament insertion points are calculated depending on both actuators’ coordinates. In the present study, we demonstrate that unintended elastic deformations of the actuators due to the specifically high contact forces in the artificial knee joint have a considerable impact on the calculated ligament forces. This study aims to investigate the effect of this structural compliance on experimental results. While the built-in algorithm for calculating the ligament forces cannot be altered by the user, a reduction of the ligament force deviations due to the elastic deformations could be achieved by preloading the articulating implant components in the reference configuration. As a proof of concept, a knee flexion motion with varying ligament conditions was simulated on the VIVO simulator and compared to data derived from a musculoskeletal multibody model of a total knee endoprosthesis.

Aseptic implant loosening after a total joint replacement is partially influenced by material-specific factors when cobalt–chromium alloys are used, including osteolysis induced by wear and corrosion products and stress shielding. Here, we aim to characterize a hybrid material consisting of alumina-toughened zirconia (ATZ) ceramics and additively manufactured Ti-35Nb-6Ta (TiNbTa) alloys, which are joined by a glass solder. The structure of the joint, the static and fatigue shear strength, the influence of accelerated aging, and the cytotoxicity with human osteoblasts are characterized. Furthermore, the biomechanical properties of the functional demonstrators of a femoral component for total knee replacements are evaluated. The TiNbTa-ATZ specimens showed a homogenous joint with statistically distributed micro-pores and a slight accumulation of Al-rich compounds at the glass solder–TiNbTa interface. Shear strengths of 26.4 ± 4.2 MPa and 38.2 ± 14.4 MPa were achieved for the TiNbTa-ATZ and Ti-ATZ specimens, respectively, and they were not significantly affected by the titanium material used, nor by accelerated aging (p = 0.07). All of the specimens survived 107 cycles of shear loading to 10 MPa. Furthermore, the TiNbTa-ATZ did not impair the proliferation and metabolic activity of the human osteoblasts. Functional demonstrators made of TiNbTa-ATZ provided a maximum bearable extension–flexion moment of 40.7 ± 2.2 Nm. The biomechanical and biological properties of TiNbTa-ATZ demonstrate potential applications for endoprosthetic implants.

Abstract Background Perturbation-based balance training on a treadmill is an emerging method of gait stability training with a characteristic task nature that has had positive and sustained effects on balance recovery strategies and fall reduction. Little is known about the effects produced by shod and barefoot walking. We aimed to investigate which is more appropriate, shod or barefoot walking, for perturbation-based balance training in older adults. Methods Fourteen healthy older adults (age: 68.29 ± 3.41 years; body height: 1.76 ± 0.10 m; body mass: 81.14 ± 14.52 kg) performed normal and trip-like perturbed walking trials, shod and barefoot, on a treadmill of the Gait Real-time Analysis Interactive Lab. The marker trajectories data were processed by Human Body Model software embedded in the Gait Offline Analysis Tool. The outcomes of stride length variability, stride time variability, step width variability, and swing time variability were computed and statistically analyzed by a two-way repeated-measures analysis of variance (ANOVA) based on gait pattern (normal gait versus perturbed recovery gait) and footwear condition (shod versus barefoot). Results Footwear condition effect (p = 0.0310) and gait pattern by footwear condition interaction effect (p = 0.0055) were only observed in swing time variability. Gait pattern effects were detected in all four outcomes of gait variability. Conclusions Swing time variability, independent of gait speed, could be a valid indicator to differentiate between footwear conditions. The lower swing time variability in perturbed recovery gait suggests that barefoot walking may be superior to shod walking for perturbation-based balance training in older adults.

The additive manufacturing of titanium–niobium–tantalum alloys with nominal chemical compositions Ti–xNb–6Ta (x = 20, 27, 35) by means of laser beam powder bed fusion is reported, and their potential as implant materials is elaborated by mechanical and biological characterization. The properties of dense specimens manufactured in different build orientations and of open porous Ti–20Nb–6Ta specimens are evaluated. Compression tests indicate that strength and elasticity are influenced by the chemical composition and build orientation. The minimum elasticity is always observed in the 90° orientation. It is lowest for Ti–20Nb–6Ta (43.2 ± 2.7 GPa) and can be further reduced to 8.1 ± 1.0 GPa for open porous specimens (p < 0.001). Furthermore, human osteoblasts are cultivated for 7 and 14 days on as-printed specimens and their biological response is compared to that of Ti–6Al–4V. Build orientation and cultivation time significantly affect the gene expression profile of osteogenic differentiation markers. Incomplete cell spreading is observed in specimens manufactured in 0° build orientation, whereas widely stretched cells are observed in 90° build orientation, i.e., parallel to the build direction. Compared to Ti–6Al–4V, Ti–Nb–Ta specimens promote improved osteogenesis and reduce the induction of inflammation. Accordingly, Ti–xNb–6Ta alloys have favorable mechanical and biological properties with great potential for application in orthopedic implants.

In biomechanical research, advanced joint simulators such as VIVOTM offer the ability to test artificial joints under realistic kinematics and load conditions. Furthermore, it promises to simplify testing with advanced control approaches and the ability to include virtual ligaments. However, the overall functionality concerning specific test setup conditions, such as the joint lubrication or control algorithm, has not been investigated in-depth so far. Therefore, the aim of this study was to analyse the basic functionality of the VIVOTM joint simulator with six degrees of freedom in order to highlight its capabilities and limitations when testing a total knee endoprostheses using a passive flexion–extension movement. For this, different test setup conditions were investigated, e.g., the control method, repeatability and kinematic reproducibility, waveform frequency, lubrication, and implant embedding. The features offered by the VIVOTM joint simulator are useful for testing joint endoprostheses under realistic loading scenarios. It was found that the results were highly influenced by the varying test setup conditions, although the same mechanical load case was analysed. This study highlights the difficulties encountered when using six degrees of freedom joint simulators, contributes to their understanding, and supports users of advanced joint simulators through functional and tribological analysis of joint endoprostheses.

Abstract Background The lower extremity may play a crucial role in compensating for gait perturbations. The study aimed to explore the mechanism of perturbation compensation by investigating the gait characteristics and lower extremity joint moment effects in young (YS) and older subjects (OS) during the first recovery gait following slipping (slipping_Rec1) and stumbling (stumbling_Rec1). Method An automatic perturbation-triggered program was developed using D-Flow software based on the Gait Real-time Analysis Interactive Lab to induce the two aforementioned perturbations. Marker trajectories and ground reaction forces were recorded from 15 healthy YS (age: 26.53 ± 3.04 years; body height: 1.73 ± 0.07 m; body mass: 66.81 ± 11.44 kg) and 15 healthy OS (age: 68.33 ± 3.29 years; body height: 1.76 ± 0.10 m; body mass: 81.13 ± 13.99 kg). The Human Body Model was used to compute the variables of interest. One-way analysis of variance and independent samples t-test statistical analyses were performed. Results In slipping_Rec1 and stumbling_Rec1, the change in gait pattern was mainly reflected in a significant increase in step width, no alterations in step length and stance/swing ratio were revealed. Based on perturbed task specificity, lower extremity joint moments increased or decreased at specific phases of the gait cycle in both YS and OS in slipping_Rec1 and stumbling_Rec1 compared to normal gait. The two perturbed gaits reflected the respective compensatory requirements for the lower extremity joints, with both sagittal and frontal joint moments producing compensatory effects. The aging effect was not reflected in the gait pattern, but rather in the hip extension moment during the initial stance of slipping_Rec1. Conclusions Slipping appears to be more demanding for gait recovery than stumbling. Gait perturbation compensatory mechanisms for OS should concentrate on ankle strategy in the frontal plane and counter-rotation strategy around the hip.

Abstract Nowadays, several configurations of total knee arthroplasty (TKA) implants are commercially available whose designs resulted from clinical and biomechanical considerations. Previous research activities led to the development of the so-called medial-pivot (MP) design. However, the actual benefits of the MP, with respect to other prosthesis designs, are still not well understood. The present work compares the impact of two insert geometries, namely the ultra-congruent (UC) and medial-pivot (MP), on the biomechanical behaviour of a bicondylar total knee endoprosthesis. For this purpose, a multibody model of a lower limb was created alternatively integrating the two implants having the insert geometry discretized. Joint dynamics and contact pressure distributions were evaluated by simulating a squat motion. Results showed a similar tibial internal rotation range of about 3.5°, but an early rotation occurs for the MP design. Furthermore, the discretization of the insert geometry allowed to efficiently derive the contact pressure distributions, directly within the multibody simulation framework, reporting peak pressure values of 33 MPa and 20 MPa for the UC and MP, respectively. Clinically, the presented findings confirm the possibility, through a MP design, to achieve a more natural joint kinematics, consequently improving the post-operative patient satisfaction and potentially reducing the occurrence of phenomena leading to the insert loosening.

The present study focused on the investigation of the resorption behavior of high hydrostatic pressure (HHP) treated bone allografts in vitro by analyzing the differentiation and activity of osteoclast precursors. HHP is known to be an efficient method for devitalization of bone grafts and a gentle alternative compared to conventional processing. While bone resorption is part of the physiological fracture healing, highly processed allografts are prone to excessive degradation, which ultimately leads to graft failure. The influence of HHP treatment on the extent of resorption was analyzed in bone blocks cultivated with peripheral blood mononuclear cells (PBMCs). Data on gene and protein expression as well as histological alterations were obtained. The present study showed that an application of 500 MPa led to significant osteoclastic differentiation and activity which was observed already after 8 h of incubation. Whereas a treatment of 250 MPa resulted also in the differentiation of PBMCs, osteoclastic activity was similar to the untreated control. Thus, the pressure level of HHP is crucial for the extent of degradation processes. Based on our results a treatment with 500 MPa might not be suitable for allografts intended for subsequent clinical applications. This study provides a basis for further experiments including in vivo studies which should focus on the equilibrium of bone formation and bone resorption.

Under both physiological (development, regeneration) and pathological conditions (cancer metastasis), cells migrate while sensing environmental cues in the form of mechanical, chemical or electrical stimuli. In the case of bone tissue, osteoblast migration is essential in bone regeneration. Although it is known that osteoblasts respond to exogenous electric fields, the underlying mechanism of electrotactic collective movement of human osteoblasts is unclear. Here, we present a computational model that describes the osteoblast cell migration in a direct current electric field as the motion of a collection of active self-propelled particles and takes into account fluctuations in the direction of single-cell migration, finite-range cell-cell interactions, and the interaction of a cell with the external electric field. By comparing this model with in vitro experiments in which human primary osteoblasts are exposed to a direct current electric field of different field strengths, we show that cell-cell interactions and fluctuations in the migration direction promote anode-directed collective migration of osteoblasts.

Biophysical stimulation by electric fields can promote bone formation in bone defects of critical size. Even though, long-term effects of alternating electric fields on the differentiation of osteoblasts are not fully understood. Human pre-osteoblasts were stimulated over 31 days to gain more information about these cellular processes. An alternating electric field with 0.7 Vrms and 20 Hz at two distances was applied and viability, mineralization, gene expression, and protein release of differentiation factors were analyzed. The viability was enhanced during the first days of stimulation. A higher electric field resulted in upregulation of typical osteogenic markers like osteoprotegerin, osteopontin, and interleukin-6, but no significant changes in mineralization. Upregulation of the osteogenic markers could be detected with a lower electric field after the first days of stimulation. As a significant increase in the mineralized matrix was identified, an enhanced osteogenesis due to low alternating electric fields can be assumed.

Due to advances in surgical procedures and the biocompatibility of materials used in total joint replacement, more and younger patients are undergoing these procedures. Although state-of-the-art joint replacements can last 20 years or longer, wear and corrosion is still a major risk for implant failure, and patients with these implants are exposed for longer to these corrosive products. It is therefore important to investigate the potential effects on the whole organism. Released nanoparticles and ions derived from commonly used metal implants consist, among others, of cobalt, nickel, and chromium. The effect of these metallic products in the process of osteolysis and aseptic implant loosening has already been studied; however, the systemic effect on other cell types, including neurons, remains elusive. To this end, we used human iPSC-derived motoneurons to investigate the effects of metal ions on human neurons. We treated human motoneurons with ion concentrations regularly found in patients, stained them with MitoSOX and propidium iodide, and analyzed them with fluorescence-assisted cell sorting (FACS). We found that upon treatment human motoneurons suffered from the formation of ROS and subsequently died. These effects were most prominent in motoneurons treated with 500 μM of cobalt or nickel, in which we observed significant cell death, whereas chromium showed fewer ROS and no apparent impairment of motoneurons. Our results show that the wear and corrosive products of metal implants at concentrations readily available in peri-implant tissues induced ROS and subsequently cell death in an iPSC-derived motoneuron cell model. We therefore conclude that monitoring of neuronal impairment is important in patients undergoing total joint replacement.

Abstract Orthopaedic and trauma research is a gateway to better health and mobility, reflecting the ever-increasing and complex burden of musculoskeletal diseases and injuries in Germany, Europe and worldwide. Basic science in orthopaedics and traumatology addresses the complete organism down to the molecule among an entire life of musculoskeletal mobility. Reflecting the complex and intertwined underlying mechanisms, cooperative research in this field has discovered important mechanisms on the molecular, cellular and organ levels, which subsequently led to innovative diagnostic and therapeutic strategies that reduced individual suffering as well as the burden on the society. However, research efforts are considerably threatened by economical pressures on clinicians and scientists, growing obstacles for urgently needed translational animal research, and insufficient funding. Although sophisticated science is feasible and realized in ever more individual research groups, a main goal of the multidisciplinary members of the Basic Science Section of the German Society for Orthopaedics and Trauma Surgery is to generate overarching structures and networks to answer to the growing clinical needs. The future of basic science in orthopaedics and traumatology can only be managed by an even more intensified exchange between basic scientists and clinicians while fuelling enthusiasm of talented junior scientists and clinicians. Prioritized future projects will master a broad range of opportunities from artificial intelligence, gene- and nano-technologies to large-scale, multi-centre clinical studies. Like Prometheus in the ancient Greek myth, transferring the elucidating knowledge from basic science to the real (clinical) world will reduce the individual suffering from orthopaedic diseases and trauma as well as their socio-economic impact.

Background: Functional impairment of the knee joint affected by osteoarthritis and loss of muscle strength leads to a significant increase in the number of falls. Nevertheless, little is known about strategies for coping with gait perturbations in patients with knee osteoarthritis (KOA). Thus, this study aimed to examine the compensatory strategies of patients with KOA in response to a backward slip perturbation compared with healthy older adults.Methods: An automated perturbation program was developed by using D-Flow software based on the Gait Real-time Analysis Interactive Lab, and an induced backward slip perturbation was implemented on nine patients with severe KOA (68.89 ± 3.59 years) and 15 age-matched healthy older adults (68.33 ± 3.29 years). Step length, gait speed, range of motion, vertical ground reaction forces, lower extremity joint angles, and joint moments were computed and analyzed.Results: Compared with older adults, patients with KOA had significantly lower step length, gait speed, and vertical ground reaction forces in both normal walking and the first recovery step following backward slip perturbations. Inadequate flexion and extension of joint angles and insufficient generation of joint moments predispose patients with KOA to fall. Hip extension angle and flexion moment, knee range of motion, and vertical ground reaction forces are key monitoring variables.Conclusion: The risk of falls for patients with KOA in response to backward slip perturbations is higher. Patients with KOA should focus not only on quadriceps muscle strength related to knee range of motion but also on improving hip extensor strength and activation through specific exercises. Targeted resistance training and perturbation-based gait training could be better options.

Diabetes-adapted insoles are essential in prevention and rehabilitation of foot ulcers in diabetic foot syndrome. However, their manufacture is labour-intensive and costly. Therefore, the study aims to present an alternative method that allows the individual adjustment of the stiffness of the insoles using the finite element (FE) method and subsequent 3D printing. In the study, 3D gait analysis followed by musculoskeletal modelling was used to determine the boundary conditions of a healthy subject for the FE model. While muscle forces are elaborately implemented in most studies, this FE model presented a more efficient way by using ankle moments and joint reaction forces. The deviation between the simulated plantar peak pressure and the experimentally determined using the Pedar system amounted to 234 kPa in the heel area and 30 kPa in the toe area. The stiffness of the individual insole was adjusted by applying soft insole plugs in areas where high plantar pressures occurred during walking. Three different Young’s moduli were analysed in these areas (0.5 MPa, 1.0 MPa, 1.5 MPa). The computer-based approach to adjust the stiffness of an individual insole revealed a plantar peak pressure reduction by 37% in the heel area and by 119% in the toe area with a Young’s modulus of 0.5 MPa. The presented method could be a valuable tool in the cost-efficient development and engineering of subject-specific 3D-printed insoles for patients with diabetic foot syndrome.

Abstract Background Antibiotic-loaded (particularly gentamicin) bone cement (BC) is widely used in total joint arthroplasty (TJA) to prevent periprosthetic infections (PPIs), but may itself cause implant failure. In light of a complete lack in literature, the objective was to assess the clinical relevance of gentamicin allergy for failure of cemented total knee arthroplasties in 25 out of 250 patients with positive patch test reactions to gentamicin and otherwise unexplained symptoms by evaluating benefits from revision with change to gentamicin-free cement. Methods Fifteen of these 25 patients and their treating orthopaedic surgeons agreed to a re-assessment. They were surveyed regarding interim course of therapy and symptoms, including re-assessment of the Knee Injury and Osteoarthritis Outcome Score (KOOS), and underwent follow-up clinical and radiographic investigations. The initial use of gentamicin-loaded BC was reaffirmed by review of the primary implantation operative reports and respective implant passports. Primary and follow-up KOOS scores were analyzed regarding benefits from revision surgery by comparing nine patients with revision to six without revision. Results Mean follow-up time was 38 months. The entirety of patients experienced an improvement of self-reported symptoms, with revision surgery (i.e., switching to gentamicin-free BC or uncemented total knee arthroplasty) yielding significantly greater improvement (p = 0.031): the nine revised patients reported a significant symptom relief (p = 0.028), contrary to the six unrevised patients (p = 0.14). Interestingly, the decision to proceed with revision surgery was significantly correlated with higher symptom severity (p = 0.05). Conclusion In symptomatic total knee arthroplasty with gentamicin allergy, uncemented revision arthroplasty or change to gentamicin-free BC provides significant symptom relief.

(1) Background: Electrical stimulation is a promising alternative to promote bone fracture healing but with the limitation of tracking the osteogenesis progress in vivo. To overcome this issue, we present an opportunity to combine the electrical stimulation of a commercial titanium implant, which promotes osteogenesis within the fracture, with a real-time readout of the osteogenic progress by impedance sensing. This makes it possible to adjust the electrical stimulation modalities to the individual patient’s fracture healing process. (2) Methods: In detail, osteogenic differentiation of several cell types was monitored under continuous or pulsatile electrical stimulation at 0.7 V AC/20 Hz for at least seven days on a titanium implant by electric cell-substrate impedance sensing (ECIS). For control, chemical induction of osteogenic differentiation was induced. (3) Results: The most significant challenge was to discriminate impedance changes caused by proliferation events from those initiated by osteogenic differentiation. This discrimination was achieved by remodeling the impedance parameter Alpha (α), which increases over time for pulsatile electrically stimulated stem cells. Boosted α-values were accompanied by an increased formation of actin stress fibers and a reduced expression of the focal adhesion kinase in the cell periphery; morphological alterations known to occur during osteogenesis. (4) Conclusions: This work provided the basis for developing an effective fracture therapy device, which can induce osteogenesis on the one hand, and would allow us to monitor the induction process on the other hand.

The piezoelectricity of bone is known to play a crucial role in bone adaptation and remodeling. The application of an external stimulus such as mechanical strain or electric field has the potential to enhance bone formation and implant osseointegration. Therefore, in the present study, the objective is to investigate bone remodeling under electromechanical stimulation as a step towards establishing therapeutic strategies. For the first time, piezoelectric bone remodeling in the human proximal tibia under electro-mechanical loads was analyzed using the finite element method in an open-source framework. The predicted bone density distributions were qualitatively and quantitatively assessed by comparing with the computed tomography (CT) scan and the bone mineral density (BMD) calculated from the CT, respectively. The effect of model parameters such as uniform initial bone density and reference stimulus on the final density distribution was investigated. Results of the parametric study showed that for different values of initial bone density the model predicted similar but not identical final density distribution. It was also shown that higher reference stimulus value yielded lower average bone density at the final time. The present study demonstrates an increase in bone density as a result of electrical stimulation. Thus, to minimize bone loss, for example, due to physical impairment or osteoporosis, mechanical loads during daily physical activities could be partially replaced by therapeutic electrical stimulation.

Aseptic implant loosening is the most common reason for revision surgery after total knee replacement. This is associated with adverse biological reactions to wear debris from the articulating implant components. To predict the amount of wear debris generated in situ, standard wear testing of total knee replacement (TKR) is carried out before its clinical use. However, wear data reported on retrievals of total knee replacement (TKR) revealed significant discrepancies compared with standard wear simulator studies. Therefore, the aim of the present study was to compare the wear patterns on identical posterior-cruciate-retaining TKR designs by analyzing retrieved and experimentally tested implants. The identification and classification of wear patterns were performed using 21 retrieved ultra-high-molecular-weight-polyethylene (UHMW-PE) inserts and four sets of inserts of identical design and material tested in a knee wear simulator. These four sets had undergone different worst-case conditions and a standard test in a wear simulator according to ISO 14243-1. Macroscopic and microscopic examinations of the polyethylene inserts were performed, including the determination of seven modes of wear that correspond to specific wear patterns, the calculation of wear areas, and the classification of the damage over the whole articulating area. Retrieved and standard wear simulator-tested UHMW-PE inserts showed significant differences in wear area and patterns. The total wear areas and the damage score were significantly larger on the retrievals (52.3% versus 23.9%, 32.7 versus 22.7). Furthermore, the range of wear patterns found on the retrievals was not reproducible in the simulator-tested inserts. However, good correspondence was found with the simulator-tested polyethylene inserts under worst-case conditions (third body wear), i.e., deep wear areas could be replicated according to the in vivo situation compared with other wear test scenarios. Based on the findings presented here, standard simulator testing can be used to directly compare different TKR designs but is limited in the prediction of their in situ wear. Preclinical wear testing may be adjusted by worst-case conditions to improve the prediction of in situ performance of total knee implants in the future.

Bone is a highly dynamic tissue characterized mainly by the interactions of osteoblasts and osteoclasts. When the healing ability of bone regeneration is disturbed, targeted biophysical stimulations such as electrical stimulation are applied. In this study the indirect effects of electrically stimulated human osteoblasts on osteoclastogenesis were investigated to better understand detailed cellular interactions. Therefore, two different cell developmental stages were examined: peripheral blood mononuclear cells (PBMCs) as precursors and pre-osteoclasts as differentiated cells. Previously, over a 21-day period, human osteoblasts were stimulated with a low-frequency alternating electric field. The supernatants were collected and used for an indirect co-culture of PBMCs and pre-osteoclasts. The cellular viability and the induction of differentiation and activity were analyzed. Further, the secretion of relevant osteoclastic markers was examined. Supernatants of 7 d and 14 d stimulated osteoblasts led to a decrease in the viability of PBMCs and an increased number of cells containing actin ring structures. Supernatants from osteoblasts stimulated over 7 d induced PBMC differentiation and pre-osteoclastic activation. Furthermore, pre-osteoclasts showed varying mRNA transcripts of MCP-1, ACP5, CA2, and CASP8 when cultivated with media from osteoblasts. Supernatants from day 21 did not influence PBMCs at all but increased the viability of pre-osteoclasts. We could show that different time points of stimulated osteoblasts have varying effects on the cells and that changes can be observed due to the differentiation stages of the cells. Through the effects of the indirect stimulation, it was possible to underline the importance of studying not only osteoblastic differentiation and mineralization behavior under electric stimulation but also analyzing changes in osteoclastogenesis and the activity of osteoclasts.

The reconstruction of critical size bone defects is still clinically challenging. Even though the transplantation of autologous bone is used as gold standard, this therapy is accompanied by donor site morbidities as well as tissue limitations. The alternatively used allografts, which are devitalized due to thermal, chemical or physical processing, often lose their matrix integrity and have diminished biomechanical properties. High Hydrostatic Pressure (HHP) may represent a gentle alternative to already existing methods since HHP treated human osteoblasts undergo cell death and HHP treated bone cylinders maintain their mechanical properties. The aim of this study was to determine the biological effects caused by HHP treatment regarding protein/matrix integrity and type of cell death in trabecular bone cylinders. Therefore, different pressure protocols (250 and 300 MPa for 10, 20 and 30 min) and end point analysis such as quantification of DNA-fragmentation, gene expression, SDS-PAGE, FESEM analysis and histological staining were performed. While both protein and matrix integrity was preserved, molecular biological methods showed an apoptotic differentiation of cell death for lower pressures and shorter applications (250 MPa for 10 and 20 min) and necrotic differentiation for higher pressures and longer applications (300 MPa for 30 min). This study serves as a basis for further investigation as it shows that HHP successfully devitalizes trabecular bone cylinders.

Background: Continuous passive motion (CPM) is frequently used during rehabilitation following total knee arthroplasty (TKA). Low-load resistance training (LLRT) using continuous active motion (CAM) devices is a promising alternative. We investigated the effectiveness of CPM compared to LLRT using the affected leg (CAMuni) and both legs (CAMbi) in the early post-operative rehabilitation. Hypotheses: (I) LLRT (CAMuni and CAMbi) is superior to CPM, (II) additional training of the unaffected leg (CAMbi) is more effective than unilateral training (CAMuni).Materials and Methods: Eighty-five TKA patients were randomly assigned to three groups, respectively: (i) unilateral CPM of the operated leg; (ii) unilateral CAM of the operated leg (CAMuni); (iii) bilateral alternating CAM (CAMbi). Patients were assessed 1 day before TKA (pre-test), 1 day before discharge (post-test), and 3 months post-operatively (follow-up). Primary outcome: active knee flexion range of motion (ROMFlex). Secondary outcomes: active knee extension ROM (ROMExt), swelling, pain, C-reactive protein, quality of life (Qol), physical activity, timed-up-and-go performance, stair-climbing performance, quadriceps muscle strength. Analyses of covariances were performed (modified intention-to-treat and per-protocol).Results: Hypothesis I: Primary outcome: CAMbi resulted in a higher ROMFlex of 9.0° (95%CI −18.03–0.04°, d = 0.76) and 6.3° (95%CI −14.31–0.99°, d = 0.61) compared to CPM at post-test and follow-up, respectively. Secondary outcomes: At post-test, C-reactive protein was lower in both CAM groups compared with CPM. Knee pain was lower in CAMuni compared to CPM. Improved ROMExt, reduced swelling, better stair-climbing and timed-up-and-go performance were observed for CAMbi compared to CPM. At follow-up, both CAM groups reported higher Qol and CAMbi showed a better timed-up-and-go performance. Hypothesis II: Primary outcome: CAMbi resulted in a higher knee ROMFlex of 6.5° (95%CI −2.16–15.21°, d = 0.56) compared to CAMuni at post-test. Secondary outcomes: At post-test, improved ROMExt, reduced swelling, and better timed-up-and-go performance were observed in CAMbi compared to CAMuni.Conclusions: Additional LLRT of the unaffected leg (CAMbi) seems to be more effective for recovery of function than training of the affected leg only (CAMuni), which may be mediated by positive transfer effects from the unaffected to the affected limb (cross education) and/or preserved neuromuscular function of the trained, unaffected leg.Trial Registration:ClinicalTrials.gov Identifier: NCT02062138.

Abstract Background Device-related infections in orthopaedic and trauma surgery are a devastating complication with substantial impact on morbidity and mortality. Systemic suppressive antibiotic treatment is regarded an integral part of any surgical protocol intended to eradicate the infection. The optimal duration of antimicrobial treatment, however, remains unclear. In a multicenter case-control study, we aimed at analyzing the influence of the duration of antibiotic exposure on reinfection rates 1 year after curative surgery. Methods This investigation was part of a federally funded multidisciplinary network project aiming at reducing the spread of multi-resistant bacteria in the German Baltic region of Pomerania. We herein used hospital chart data from patients treated for infections of total joint arthroplasties or internal fracture fixation devices at three academic referral institutions. Subjects with recurrence of an implant-related infection within 1 year after the last surgical procedure were defined as case group, and patients without recurrence of an implant-related infection as control group. We placed a distinct focus on infection of open reduction and internal fixation (ORIF) constructs. Uni- and multivariate logistic regression analyses were employed for data modelling. Results Of 1279 potentially eligible patients, 269 were included in the overall analysis group, and 84 contributed to an extramedullary fracture-fixation-device sample. By multivariate analysis, male sex (odds ratio [OR] 2.06, 95% confidence interval [CI] 1.08 to 3.94, p = 0.029) and facture fixation device infections (OR 2.05, 95% CI 1.05 to 4.02, p = 0.036) remained independent predictors of reinfection. In the subgroup of infected ORIF constructs, univariate point estimates suggested a nearly 60% reduced odds of reinfection with systemic fluoroquinolones (OR 0.42, 95% CI 0.04 to 2.46) or rifampicin treatment (OR 0.41, 95% CI 0.08 to 2.12) for up to 31 days, although the width of confidence intervals prohibited robust statistical and clinical inferences. Conclusion The optimal duration of systemic antibiotic treatment with surgical concepts of curing wound and device-related orthopaedic infections is still unclear. The risk of reinfection in case of infected extramedullary fracture-fxation devices may be reduced with up to 31 days of systemic fluoroquinolones and rifampicin, although scientific proof needs a randomized trial with about 1400 subjects per group. Concerted efforts are needed to determine which antibiotics must be applied for how long after radical surgical sanitation to guarantee sustainable treatment success.

Abstract Background Post-operative limb swelling may negatively affect the outcome of arthroscopic surgery and prolong rehabilitation. The aim of this pilot study was to evaluate the effect of compression stockings versus no compression on post-operative swelling and pain in the early post-operative phase. Methods A single-centre, randomised controlled trial was performed. Patients who underwent minor knee arthroscopy were randomised to wear class II compression stockings (23-32 mmHg) (CS) or no compression stockings (NCS) immediately post-operatively for ten days. All patients received low molecular weight heparin (LMWH) at prophylactic dosage. The primary outcome variable was post-operative swelling of the limb, quantified by using an optical 3D measurement system (Bodytronic© 600). Pain was rated on a visual analogue scale (VAS). From a total of 76 patients assessed, 19 patients were eligible for final analysis. The trial followed the CONSORT criteria, was registered at clinicaltrial.gov and approved by the local ethics committee. Results The circumference at the middle thigh (cF) was significantly different between groups at day 10 (p = 0.032; circumference − 1.35 ± 2.15% (CS) and + 0.79 ± 3.71% (NCS)). Significant differences were also noted around the knee (cD) at day 10 (p = 0.026) and a significant trend at cD and at the mid lower leg (cB1) at day 4. The volume of the thigh was also different with marked difference between days 1 and 4 between the two groups (p = 0.021; volume + 0.54 ± 2.03% (CS) and + 4.17 ± 4.67 (NCS)). Pain was lower in compression group (not statistically significant). Conclusions Post-operative limb swelling can be reduced significantly by wearing compression stockings in the early post-operative phase when compared to not wearing stockings. This may improve the rehabilitation process after arthroscopic surgery. The optimal duration of compression therapy seems to be between three and ten days. Trial registration clinicaltrials.gov (NCT02096562, date of registration 11.11.2013).

Objectives Recently, more accurate description of the femoral geometry has become of interest to engineers and orthopedic surgeons. However, an appropriate database is lacking. Therefore, the aim of this study is to present morphological parameters and their correlations, which are relevant for medical issues such as impingement after total hip replacement, as well as for implant design and the etiology of hip fractures. Methods We investigated 12 well‐known morphological parameters of the femur in 169 healthy human subjects through evaluation of 3D‐reconstructed CT scans. Pearson's coefficients of correlations were calculated using a statistical t‐test method for each pair of parameters. Results The mean, maximum, minimum, median, and standard deviation values are reported for all parameters. Histograms showing the distribution of each morphological parameter are also presented. It is shown that absolute and horizontal offsets, total femur length, and NCVD parameters are normally distributed, but NCDF and NCDS are not. Furthermore, an inter‐correlation matrix was reported to reveal statistical correlations between these parameters. The strongest positive correlation existed between absolute offset (OSA) and horizontal offset (OSH), while the least positive correlation was found between NCDF and total femur length (TFL), and also between NCDS and NCDF. Anteversion angle (ATA) and OSA showed the least negative correlation. However, the strongest negative correlation was found between neck‐shaft angle (NSA) and greater trochanter height (GTH), as well as between OSA and NCVD. Conclusions Comprehending patients’ native bone morphology, including the variations and correlations, is essential for orthopedic surgeons to undertake preoperative planning and surgery as well as to appropriately design medical devices. Thus, more population‐based detailed databases are necessary. We investigated an extensive set of proximal femoral morphology parameters using a statistically standardized method to expand the existing knowledge. The results of our study can be used for diverse medical and biomechanical purposes.

Interleukin (IL-) 6 is a key factor in the inflammatory processes of rheumatoid arthritis. Several biologic agents target the IL-6 signaling pathway, including sarilumab, a monoclonal antibody that blocks the IL-6 receptor and inhibits IL-6-mediated cis- and trans-signaling. A careful analysis of the IL-6 signaling blockade should consider not only inflammatory processes but also the regenerative functions of IL-6. The purpose of this study was to investigate whether inhibition of the IL-6 receptors affects differentiation of human primary osteoblasts (hOB). The effects of sarilumab on viability and the differentiation capacity in unstimulated osteoblasts as well as after stimulation with various IL-6 and sIL6-R concentrations were determined. Sarilumab treatment alone did not affect the differentiation or induction of inflammatory processes in hOB. However, the significant induction of alkaline phosphatase activity which was observed after exogenous IL-6/sIL-6R costimulation at the highest concentrations was reduced back to baseline levels by the addition of sarilumab. The IL-6 receptor blockade also decreased gene expression of mediators required for osteogenesis and bone matrix maintenance. Our results demonstrate that concomitant administration of the IL-6 receptor blocker sarilumab can inhibit IL-6/sIL-6R-induced osteogenic differentiation.

Hydrogels have become an increasingly interesting topic in numerous fields of application. In addition to their use as immobilization matrixes in (bio)catalysis, they are widely used in the medical sector, e.g., in drug delivery systems, contact lenses, biosensors, electrodes, and tissue engineering. Cartilage tissue engineering hydrogels from natural origins, such as collagen, hyaluronic acid, and gelatin, are widely known for their good biocompatibility. However, they often lack stability, reproducibility, and mechanical strength. Synthetic hydrogels, on the other hand, can have the advantage of tunable swelling and mechanical properties, as well as good reproducibility and lower costs. In this study, we investigated the swelling and mechanical properties of synthetic polyelectrolyte hydrogels. The resulting characteristics such as swelling degree, stiffness, stress, as well as stress-relaxation and cyclic loading behavior, were compared to a commercially available biomaterial, the ChondroFiller® liquid, which is already used to treat articular cartilage lesions. Worth mentioning are the observed good reproducibility and high mechanical strength of the synthetic hydrogels. We managed to synthesize hydrogels with a wide range of compressive moduli from 2.5 ± 0.1 to 1708.7 ± 67.7 kPa, which addresses the span of human articular cartilage.

Bone morphogenic protein (BMP-) 2 plays an important role in the regeneration of bone defects by promoting osteogenic differentiation. However, several animal studies have reported adverse side effects of BMP-2, including osteoclast activation, induction of peroxisome proliferator- activated receptor gamma (PPARG)expression, and inflammation. High BMP-2 concentrations are thought to be responsible for these side effects. For this reason, primary pre-osteoblasts were exposed to lower BMP-2 concentrations (1 and 2 µg/mL). Long-term exposure (up to 28 days) was performed to investigate whether this stimulation protocol may promote osteogenic differentiation without causing the side effects mentioned above. The results showed that BMP-2 treatment for 14 or 28 days resulted in increased osteogenesis, through an increase in runt-related transcription factor 2, osterix, alkaline phosphatase, and integrin-binding sialoprotein expression. However, an increase in tumor necrosis factor alpha and receptor activator of nuclear factor kappa-Β ligand protein levels was observed after BMP-2 exposure, indicating also an increased potential for osteoclast activation by osteoblasts. Additionally, morphological changes like intracellular, filled vacuoles could be detected. Enhanced PPARG and perilipin 1 mRNA transcripts and lipid droplets indicated an induced adipogenic differentiation. Overall, the data demonstrate that long-term BMP-2 exposure promotes not only osteogenic differentiation but also adipogenesis and regulates mediators involved in osteoclast activation in vitro.

Purpose: Cementless modular fluted hip stems are commonly used in revision arthroplasty. Nevertheless, there is a wide spectrum of recommendations concerning the minimum bone stock required to enable osseous ingrowth and implant–bone micromotions 100 µm), rotational instability emerged as a mechanism of fixation failure when the implant–bone contact zone was only 5 cm or less. Hence, future studies investigating the implant fixation in the case of femoral bone defects should consider both axial and torsional loading. With regard to the clinical application, our data suggest maintaining 7 cm of diaphyseal implant–bone contact for a safe anchorage of cementless fluted hip revision stems.

Fracture healing and bone regeneration, particularly in the elderly, remains a challenge. There is an ongoing search for methods to activate osteoblasts, and the application of electrical fields is an attractive approach in this context. Although it is known that such electromagnetic fields lead to osteoblast migration and foster mesenchymal osteogenic differentiation, so far the mechanisms of osteoblast activation remain unclear. Possible mechanisms could rely on changes in Ca2+-influx via ion channels, as these are known to modulate osteoblast activity, e.g., via voltage-sensitive, stretch-sensitive, transient-receptor-potential (TRP) channels, or store-operated release. In the present in vitro study, we explored whether electrical fields are able to modulate the expression of voltage-sensitive calcium channels as well as TRP channels in primary human osteoblast cell lines. We show migration speed is significantly increased in stimulated osteoblasts (6.4 ± 2.1 μm/h stimulated, 3.6 ± 1.1 μm/h control), and directed toward the anode. However, within a range of 154–445 V/m, field strength did not correlate with migration velocity. Neither was there a correlation between electric field and voltage-gated calcium channel (Cav3.2 and Cav1.4) expression. However, the expression of TRPM7 significantly correlated positively to electric field strength. TRPM7 channel blockade using NS8593, in turn, did not significantly alter migration speed, nor did blockade of Cav3.2 and Cav1.4 channels using Ni+ or verapamil, respectively, while a general Ca2+-influx block using Mg2+ accelerated migration. Stimulating store-operated Ca2+-release significantly reduced migration speed, while blocking IP3 had only a minor effect (at low and high concentrations of 2-APB, respectively). We conclude that (i) store operated channels negatively modulate migration speed and that (ii) the upregulation of TRPM7 might constitute a compensatory mechanism-which might explain how increasing expression levels at increasing field strengths result in constant migration speeds.

The authors wish to make the following corrections to their paper [...]

The purpose of this computational study was to analyze the effects of different mobile-bearing (MB) total knee replacement (TKR) designs on knee joint biomechanics. A validated musculoskeletal model of the lower right extremity implanted with a cruciate-retaining fixed-bearing TKR undergoing a squat motion was adapted for three different MB TKR design variants: (I) a commercially available TKR design allowing for tibial insert rotation about the tibial tray with end stops to limit the range of rotation, (II) the same design without end stops, and (III) a multidirectional design with an additional translational degree-of-freedom (DoF) and end stops. When modeling the MB interface, two modeling strategies of different joint topologies were deployed: (1) a six DoF joint as a baseline and (2) a combined revolute-prismatic joint (two DoF joint) with end stops in both DoF. Altered knee joint kinematics for the three MB design variants were observed. The commercially available TKR design variant I yielded a deviation in internal-external rotation of the tibial insert relative to the tray up to 5° during knee flexion. Compared to the multidirectional design variant III, the other two variants revealed less femoral anterior-posterior translation by as much as 5 mm. Concerning the modeling strategies, the two DoF joint showed less computation time by 68%, 80%, and 82% for design variants I, II, and III, respectively. However, only slight differences in the knee joint kinematics of the two modeling strategies were recorded. In conclusion, knee joint biomechanics during a squat motion differed for each of the simulated MB design variants. Specific implant design elements, such as the presence of end stops, can impact the postoperative range of knee motion with regard to modeling strategy, and the two DoF joint option tested accurately replicated the results for the simulated designs with a considerably lower computation time than the six DoF joint. The proposed musculoskeletal multibody simulation framework is capable of virtually characterizing the knee joint dynamics for different TKR designs.

Instrumented implants can improve the clinical outcome of total hip replacements (THRs). To overcome the drawbacks of external energy supply and batteries, energy harvesting is a promising approach to power energy-autonomous implants. Therefore, we recently presented a new piezoelectric-based energy harvesting concept for THRs. In this study, the performance of the proposed energy harvesting system was numerically and experimentally investigated. First, we numerically reproduced our previous results for the physiologically based loading situation in a simplified setup. Thereafter, this configuration was experimentally realised by the implantation of a functional model of the energy harvesting concept into an artificial bone segment. Additionally, the piezoelectric element alone was investigated to analyse the predictive power of the numerical model. We measured the generated voltage for a load profile for walking and calculated the power output. The maximum power for the directly loaded piezoelectric element and the functional model were 28.6 and 10.2 µW, respectively. Numerically, 72.7 µW was calculated. The curve progressions were qualitatively in good accordance with the numerical data. The deviations were explained by sensitivity analysis and model simplifications, e.g., material data or lower acting force levels by malalignment and differences between virtual and experimental implantation. The findings verify the feasibility of the proposed energy harvesting concept and form the basis for design optimisations with increased power output.

Skin regeneration is a quite complex process. Epidermal differentiation alone takes about 30 days and is highly regulated. Wounds, especially chronic wounds, affect 2% to 3% of the elderly population and comprise a heterogeneous group of diseases. The prevailing reasons to develop skin wounds include venous and/or arterial circulatory disorders, diabetes, or constant pressure to the skin (decubitus). The hallmarks of modern wound treatment include debridement of dead tissue, disinfection, wound dressings that keep the wound moist but still allow air exchange, and compression bandages. Despite all these efforts there is still a huge treatment resistance and wounds will not heal. This calls for new and more efficient treatment options in combination with novel biocompatible skin scaffolds. Cold atmospheric pressure plasma (CAP) is such an innovative addition to the treatment armamentarium. In one CAP application, antimicrobial effects, wound acidification, enhanced microcirculations and cell stimulation can be achieved. It is evident that CAP treatment, in combination with novel bioengineered, biocompatible and biodegradable electrospun scaffolds, has the potential of fostering wound healing by promoting remodeling and epithelialization along such temporarily applied skin replacement scaffolds.

Presently, total joint replacement (TJR) is a standard procedure in orthopedic surgery. Adequate osseointegration of the implant components still remains a clinical issue. However, active stimulation of bone tissue to enhance bone ongrowth at the implant surfaces has not been widely investigated so far. For the last several years, invasive electromagnetically induced osseotherapy has been employed in clinical practice, e.g., for the treatment of avascular necrosis, femoral neck fractures, and pseudarthrosis. In the present study, the approach of exploiting the electric stimulation effect was transferred to the field of TJR. Therefore, a commercially available total hip stem was instrumented with an electrode on its surface in order to generate an electric field supporting the regeneration of the surrounding bone tissue. The objective was to conduct numerical simulations validated by experimental investigations as a proof of concept for an instrumented electro-stimulative total hip stem. The results revealed that the calculated electric field around a total hip stem fulfills the requirements to stimulate adjacent bone tissue when using clinically applied electric voltages. The derived numerical and experimental data of electric potentials and corresponding electric fields are encouraging for the implementation of active electrical stimulation in uncemented total hip stems to enhance their osseointegration.

Ti6Al4V as a common implant material features good mechanical properties and corrosion resistance. However, untreated, it lacks bioactivity. In contrast, coatings with calcium phosphates (CaP) were shown to improve cell–material interactions in bone tissue engineering. Therefore, this work aimed to investigate how to tailor biomimetic CaP coatings on Ti6Al4V substrates using modified biomimetic calcium phosphate (BCP) coating solutions. Furthermore, the impact of substrate immersion in a 1 M alkaline CaCl2 solution (pH = 10) on subsequent CaP coating formation was examined. CaP coatings were characterized via scanning electron microscopy, x-ray diffraction, energy-dispersive x-ray spectroscopy, and laser-scanning microscope. Biocompatibility of coatings was carried out with primary human osteoblasts analyzing cell morphology, proliferation, collagen type 1, and interleukin 6 and 8 release. Results indicate a successful formation of low crystalline hydroxyapatite (HA) on top of every sample after immersion in each BCP coating solution after 14 days. Furthermore, HA coating promoted cell proliferation and reduced the concentration of interleukins compared to the uncoated surface, assuming increased biocompatibility.