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Fibre metal laminates (FMLs) consisting of layers made of PA6 polyamide prepregs reinforced with glass and carbon fibres and an aluminium alloy core are the new variant of the other types used by aerospace FML materials such as GLARE or CARALL. By using a thermoplastic matrix, they can be shaped by stamping processes, which allows for a more efficient production process than classical laminating methods such as vacuum bagging. In addition to the improved impact energy absorption efficiency, the metallic core can be utilised to effectively bond the composite part to adjacent metallic structures. This article presents the influence of the material configuration of fibre-metal laminates consisting of continuous fibre-reinforced thermoplastic outer layers integrated with a layer of metallic aluminium alloy inserts—a number of layers, type and direction of reinforcing fibres—on the static and fatigue flexural properties. In this study, eight laminate configurations were prepared using a one-step variothermal consolidation process. The results showed that in the three-point flexural fatigue test, the samples exceeded 106 cycles at stresses

Ultra light, highly porous materials arranged as a sandwich structure with thermoplastic fiber reinforced composites (TP-FRC) as a cover layer have very good physical and mechanical properties. An essential prerequisite for the production of hybrid material composites is therefore the provision of material compatible and cost effective manufacturing processes. The lightweight potential of such a syntactic core composite sandwich (SCCS) with thermoplastic and expanded glass granules was examined with the aim of a mass production. After developing a manufacturing strategy, various samples are prepared and their mechanical properties are evaluated by performing bending tests and examination of micrographs.

Large-scale curved structures such as wind turbine wings usually require a special and cost intensive transport to the installation destination. These transport and installation costs can be reduced by a flat transport condition and the possibility of layering several structural components. For this reason, the focus at the Department of Lightweight Structures and Polymer Technology at TU Chemnitz was on a novel active material composite, which enables resource-efficient mass production and has a new component architecture. The large-volume multidimensional curvature of the active structure could be achieved by using a shape memory polymer (SMP). The associated reduction of the specific investment costs, the use of materials and the possibility of an integrative design, can contribute to the fact that, for example, the small wind turbines will become an economically viable investment in the future. The active structure influencing was represented by means of a finite element simulation (FEM) for different material composites and could be verified by generic demonstrators regarding its validity.

Background: To predict worsening heart failure hospitalizations (WHFHs), the HeartInsight multiparametric algorithm calculates a heart failure (HF) Score based on temporal trends of physiologic parameters obtained through automatic daily remote monitoring of implantable cardioverter-defibrillators (ICDs)., Objective: We studied the association of the baseline HF Score, determined at algorithm activation, with long-term patient outcomes., Methods: Data from 9 clinical trials were pooled, including 1841 ICD patients with a preimplantation ejection fraction ≤35%, New York Heart Association class II/III, and no long-standing atrial fibrillation. The primary end point was a composite of death or WHFH., Results: After a median follow-up of 631 days (interquartile range, 385-865 days), there were 243 WHFHs in 173 patients (9.4%) and 122 deaths (6.6%), 52 of which (42.6%) were cardiovascular. The primary end point occurred in 265 patients (14.4%). A multivariable time-to-first-event analysis showed that a high baseline HF Score (>23, as determined by a time-dependent receiver operating characteristics curve analysis) was significantly associated with the occurrence of the primary end point (adjusted hazard ratio [HR], 2.05; 95% confidence interval [CI], 1.54-2.71; P < .0001), all-cause death (HR, 2.37; CI, 1.56-3.58; P < .0001), cardiovascular death (HR, 2.19; CI, 1.14-4.22; P = .019), and WHFH (HR, 1.91; CI, 1.35-2.71; P = .0003). In a hierarchical event analysis of all-cause death as the outcome with highest priority and WHFHs as repeated event outcomes, the win ratio was 2.47 (CI, 1.89-3.24; P < .0001)., Conclusion: Based on a retrospective analysis of clinical trial data with adjudicated events, baseline HF Score derived from device-monitored variables was able to stratify patients at higher long-term risk of death or WHFH., Competing Interests: Disclosures G.B. received speaker’s fee from Abbott, Biotronik, Boston Scientific, Medtronic, and MicroPort. A.B. received consultant fees and/or grant support from Abbott, Biotronik, and Boston Scientific. M.S. received grant support from Abbott, Biotronik, Boston Scientific, and Medtronic., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Aims: To predict worsening heart failure hospitalizations (WHFHs) in patients with implantable defibrillators and remote monitoring, the HeartInsight algorithm (Biotronik, Berlin, Germany) calculates a heart failure (HF) score combining seven physiologic parameters: 24 h heart rate (HR), nocturnal HR, HR variability, atrial tachyarrhythmia, ventricular extrasystoles, patient activity, and thoracic impedance. We compared temporal trends of the HF score and its components 12 weeks before a WHFH with 12-week trends in patients without WHFH, to assess whether trends indicate deteriorating HF regardless of alert status., Methods and Results: Data from nine clinical trials were pooled, including 2050 patients with a defibrillator capable of atrial sensing, ejection fraction ≤ 35%, NYHA class II/III, no long-standing atrial fibrillation, and 369 WHFH from 259 patients. The mean HF score was higher in the WHFH group than in the no WHFH group (42.3 ± 26.1 vs. 30.7 ± 20.6, P < 0.001) already at the beginning of 12 weeks. The mean HF score further increased to 51.6 ± 26.8 until WHFH (+22% vs. no WHFH group, P = 0.003). As compared to the no WHFH group, the algorithm components either were already higher 12 weeks before WHFH (24 h HR, HR variability, thoracic impedance) or significantly increased until WHFH (nocturnal HR, atrial tachyarrhythmia, ventricular extrasystoles, patient activity)., Conclusion: The HF score was significantly higher at, and further increased during 12 weeks before WHFH, as compared to the no WHFH group, with seven components showing different behaviour and contribution. Temporal trends of HF score may serve as a quantitative estimate of HF condition and evolution prior to WHFH., Competing Interests: Conflict of interest: G.L.B. received speaker’s fee from Abbott, Biotronik, Boston Scientific, Medtronic, and Microport. A.B. received consultant fees and/or grant support from Abbott, Biotronik, and Boston Scientific. A.G. and D.G. are employees of Biotronik Italy. T.T. is employee of Biotronik SE & Co. KG, Berlin, Germany. L.G.-M. received fees for lectures and/or consulting from Novartis, Microport, Boston Scientific, and Medtronic outside the submitted work. Lille University Hospital Center received grants from BMS, Abbott, Biotronik, Boston Scientific, Microport, and Medtronic outside the submitted work. All remaining authors have declared no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: To allow timely initiation of anticoagulation therapy for the prevention of stroke, the European guidelines on atrial fibrillation (AF) recommend remote monitoring (RM) of device-detected atrial high-rate episodes (AHREs) and progression of arrhythmia duration along pre-specified strata (6 min…<1 h, 1 h…<24 h, ≥ 24 h). We used the MATRIX registry data to assess the capability of a single-lead implantable cardioverter-defibrillator (ICD) with atrial sensing dipole (DX ICD system) to follow this recommendation in patients with standard indication for single-chamber ICD., Methods and Results: In 1841 DX ICD patients with daily automatic RM transmissions, electrograms of first device-detected AHREs per patient in each duration stratum were adjudicated, and the corresponding positive predictive values (PPVs) for the detections to be true atrial arrhythmia were calculated. Moreover, the incidence and progression of new-onset AF was assessed in 1451 patients with no AF history. A total of 610 AHREs ≥6 min were adjudicated. The PPV was 95.1% (271 of 285) for episodes 6min…<1 h, 99.6% (253/254) for episodes 1 h…<24 h, 100% (71/71) for episodes ≥24 h, or 97.5% for all episodes (595/610). The incidence of new-onset AF was 8.2% (119/1451), and in 31.1% of them (37/119), new-onset AF progressed to a higher duration stratum. Nearly 80% of new-onset AF patients had high CHA2DS2-VASc stroke risk, and 70% were not on anticoagulation therapy. Age was the only significant predictor of new-onset AF., Conclusion: A 99.7% detection accuracy for AHRE ≥1 h in patients with DX ICD systems in combination with daily RM allows a reliable guideline-recommended screening for subclinical AF and monitoring of AF-duration progression., Competing Interests: Conflict of interest: D.T. is a consultant of Boston Scientific and has received research grants from Biotronik and Boston Scientific. M.A. has received speaker fees and conducts research sponsored by Biotronik. J.M. is an investigator in the Bio|Stream.HF study sponsored by Biotronik. I.D. has received speaker fees from Biotronik and Boston Scientific and conducts research sponsored by Abbott, Biotronik, Boston Scientific, and Medtronic. T.T. is an employee of Biotronik. The other authors declare no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Sensing malfunction and misinterpretation of intracardiac electrograms (IEGMs) in patients with implantable cardioverter defibrillators (ICDs) may lead to inadequate device activity such as inappropriate shock delivery or unnecessary mode-switching. Remote monitoring has the potential for early detection of sensing malfunction or misclassification and may thus prevent adverse device activity. Therefore, the authors analyzed the amount, nature, and distribution of misclassification in current ICD and cardiac resynchronization therapy defibrillator technology using the device transmissions of the IN-TIME study population., Methods: All transmitted tachyarrhythmic episodes in the 664 IN-TIME patients, comprising 2214 device-classified atrial fibrillation (DC-AF) episodes lasting ≥ 30 s and 1330 device-classified ventricular tachycardia or fibrillation (DC-VT/VF) episodes, were manually analyzed by two experienced cardiologists., Results: After evaluation of all DC-VT/VF episodes, a total of 300 VT/VF events (23.1%) were false-positive, with supraventricular tachycardia being the most frequent cause (51.7%), followed by atrial fibrillation (21.3%) and T‑wave oversensing (21.0%). A total of 15 patients with false-positive DC-VT/VF received inappropriate shocks. According to the inclusion criteria, 616 IEGMs with DC-AF were assessed. A total of 19.7% were false-positive AF episodes and R‑wave oversensing was the most common reason (55.9%)., Conclusions: Remote monitoring offers the opportunity of early detection of signal misclassification and thus early prevention of adverse device reaction, such as inappropriate shock delivery or mode-switching with intermittent loss of atrioventricular synchrony, by correcting the underlying causes., (© 2021. Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Aims: There have been no published studies on the safety of magnetic resonance imaging (MRI) at 3 Tesla (3 T) in patients with MRI-conditional implantable cardioverter-defibrillators (ICDs). The aim of this study was to assess clinical safety of the Biotronik ProMRI ICD system during non-diagnostic head and lower lumbar scans under 3 T MRI conditions., Methods and Results: The study enrolled 129 patients at 12 sites in Australia, Singapore, and Europe. Predefined head and lower lumbar MR scans (total duration ≈30 min) were performed in 112 patients. Three primary endpoints were evaluated from the pre-MRI to the 1-month post-MRI visit: (i) freedom from serious adverse device effects (SADEs) related to MRI (hypothesized to be >90%); (ii) pacing threshold invariance for all leads (geometric mean of the patient-wise ratios for 1 month vs. pre-MRI was hypothesized to be <1.07); and (iii) sensing amplitude invariance (geometric mean of the ratios was hypothesized to be >0.993). No MRI-related SADE occurred (SADE-free rate 100%, 95% confidence interval 95.98-100%). Pacing threshold and sensing amplitudes fulfilled the invariance hypotheses with high statistical significance (P < 0.0013). No threshold increase >0.5 V or sensing amplitude decrease by >50% was observed (secondary endpoints). Lead impedances, battery capacity, and detection and treatment of arrhythmias by ICDs were not affected by MRI scans., Conclusion: The head and lower lumbar scans under specific 3 T MRI conditions were safe in the investigated MR-conditional ICD systems. There was no evidence of harm to the patients or any negative influence of the MRI scan on the implanted systems., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)

The function of caveolae, small invaginations of the plasma membrane, remains a matter of debate. We discuss endocytosis and compartmentalization of metabolic and signaling pathways. Caveolin 3 (CAV3) and polymerase I and transcript release factor (PTRF) are important proteins that ensure shaping of caveolae in muscle cells. We investigated caveolae morphologically by electron microscopy in myotubes obtained from patients with CAV3 mutations and performed functional analyses in fibroblasts from a patient with a mutation in PTRF. Despite the complete clinical picture of a caveolinopathy, we found that caveolae in the CAV3-deficient myotubes were normal in shape and number. Furthermore, we found a difference in uptake of cholera toxin B between PTRF-deficient fibroblasts devoid of caveolae and normal fibroblasts. However, after caveolae were rescued by transfection of PTRF, cholera toxin B uptake did not normalize. We conclude that the presence of caveolae as an anatomic structure is not sufficient to ensure their proper function. Alternatively, the functional properties assigned to caveolae might be mediated by different mechanisms that have yet to be resolved., (Copyright © 2015 the American Physiological Society.)

GDF8, or myostatin, is a member of the TGF-β superfamily of secreted polypeptide growth factors. GDF8 is a potent negative regulator of myogenesis both in vivo and in vitro. We found that GDF8 signaling was inhibited by the small molecule ATP competitive inhibitors dorsomorphin and LDN-193189. These compounds were previously shown to be potent inhibitors of BMP signaling by binding to the BMP type I receptors ALK1/2/3/6. We present the crystal structure of the type II receptor ActRIIA with dorsomorphin and demonstrate that dorsomorphin or LDN-193189 target GDF8 induced Smad2/3 signaling and repression of myogenic transcription factors. As a result, both inhibitors rescued myogenesis in myoblasts treated with GDF8. As revealed by quantitative live cell microscopy, treatment with dorsomorphin or LDN-193189 promoted the contractile activity of myotubular networks in vitro. We therefore suggest these inhibitors as suitable tools to promote functional myogenesis., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

Combining the biological specificity of fluorescence microscopy with topographical features revealed by atomic force microscopy (AFM) provides new insights into cell biology. However, the lack of systematic alignment capabilities especially in scanning-tip AFM has limited the combined application approach as AFM drift leads to increasing image mismatch over time. We present an alignment correction method using the cantilever tip as a reference landmark. Since the precise tip position is known in both the fluorescence and AFM images, exact re-alignment becomes possible. We used beads to demonstrate the validity of the method in a complex artificial sample. We then extended this method to biological samples to depict membrane structures in fixed and living human fibroblasts. We were able to map nanoscale membrane structures, such as clathrin-coated pits, to their respective fluorescent spots. Reliable alignment between fluorescence signals and topographic structures opens possibilities to assess key biological processes at the cell surface such as endocytosis and exocytosis.

Skeletal muscle is continually subjected to microinjuries that must be repaired to maintain structure and function. Fluorescent dye influx after laser injury of muscle fibers is a commonly used assay to study membrane repair. This approach reveals that initial resealing only takes a few seconds. However, by this method the process of membrane repair can only be studied in part and is therefore poorly understood. We investigated membrane repair by visualizing endogenous and GFP-tagged repair proteins after laser wounding. We demonstrate that membrane repair and remodeling after injury is not a quick event but requires more than 20 min. The endogenous repair protein dysferlin becomes visible at the injury site after 20 seconds but accumulates further for at least 30 min. Annexin A1 and F-actin are also enriched at the wounding area. We identified a new participant in the membrane repair process, the ATPase EHD2. We show, that EHD2, but not EHD1 or mutant EHD2, accumulates at the site of injury in human myotubes and at a peculiar structure that develops during membrane remodeling, the repair dome. In conclusion, we established an approach to visualize membrane repair that allows a new understanding of the spatial and temporal events involved., (© 2012 John Wiley & Sons A/S.)

The objective of this study is to assess the effect of a purge flow on valves of pulsatile heart-assist devices. Clinical applications of these devices are still limited because of frequent thromboembolic complications. These complications often originate at the valves and the unavoidable flow separation regions that are found behind the leaflets. The flow separations cause a long residence time of blood that is considered particularly detrimental. To solve this problem, a valve with a purge flow is proposed. A purge flow is a jet, which is separated from the main blood flow and directed behind the leaflets into the sinus to flush it. Even though the purge flow does not prevent a flow separation, it shortens the residence time of the blood in the sinus. Thus, the purge flow improves the periodic washout of the blood in the region of flow separation. The complex purge flow was investigated in a tri-leaflet valve. The geometrical parameters of the valve were varied systematically. A statistical technique--the Taguchi method--was used to reduce the number of investigated models to 12. The flows through the resulting valve models were numerically simulated and analyzed. The evaluated models with the best results were subsequently investigated experimentally using different methods: hemodynamic tests in a valve tester and flow visualization using the dye washout method. It was shown that the purge flow can effectively wash out the sinus. Therefore, the purge flow valve reduces the potential of a thrombus formation normally associated with the valve., (© 2011, Copyright the Authors. Artificial Organs © 2011, International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.)

Only little is known about how cells coordinately behave to establish functional tissue structure and restore microarchitecture during regeneration. Research in this field is hampered by a lack of techniques that allow quantification of tissue architecture and its development. To bridge this gap, we have established a procedure based on confocal laser scans, image processing, and three-dimensional tissue reconstruction, as well as quantitative mathematical modeling. As a proof of principle, we reconstructed and modeled liver regeneration in mice after damage by CCl(4), a prototypical inducer of pericentral liver damage. We have chosen the regenerating liver as an example because of the tight link between liver architecture and function: the complex microarchitecture formed by hepatocytes and microvessels, i.e. sinusoids, ensures optimal exchange of metabolites between blood and hepatocytes. Our model captures all hepatocytes and sinusoids of a liver lobule during a 16 days regeneration process. The model unambiguously predicted a so-far unrecognized mechanism as essential for liver regeneration, whereby daughter hepatocytes align along the orientation of the closest sinusoid, a process which we named "hepatocyte-sinusoid alignment" (HSA). The simulated tissue architecture was only in agreement with the experimentally obtained data when HSA was included into the model and, moreover, no other likely mechanism could replace it. In order to experimentally validate the model of prediction of HSA, we analyzed the three-dimensional orientation of daughter hepatocytes in relation to the sinusoids. The results of this analysis clearly confirmed the model prediction. We believe our procedure is widely applicable in the systems biology of tissues.

Until today, no ideal heart valve prosthesis for the replacement of a diseased natural valve or for use in ventricular assist devices exists. Valves still cause thromboembolic complications originating from thrombus formations in the valve's stagnant zones. Optimization of valve design involves avoiding stagnation zones and zones of high shear stresses. This requires detailed flow field investigations. Usually, the regions which are more prone to thrombus formation can be estimated using a dye washout experiment. The method allows an assessment of regions with a high or low residence time that may in turn predict regions with a corresponding thrombus risk. This successful experimental method was simulated using numerical methods with a combination of the computational fluid dynamics program FLUENT (Fluent Inc., Lebanon, NH, USA) and of the visualization tool AMIRA (TGS Inc., San Diego, CA, USA). The numerical dye washout visualization was applied to four monoleaflet valves with varying valve housing geometries. The results show a significant difference in the washout processes of the examined valves. The dye washout was characterized by a time course of the gray value averaged over a defined region of interest. Finally, these curves were quantified by a half dye time. The half dye time in the best optimized valve was only 0.2753 s. The same time in the original valve was 0.6834 s. This study shows that the proposed numerical method of dye washout visualization can be used as an additional tool of the flow characterization in artificial organs.

Clinical applications of cardiac assist systems still suffer from thromboembolic complications due to thrombus formation behind the valve's leaflets. Wherever the flow is stagnant such as in the sinus, a thrombus is likely to form. The valve design in this study avoids stagnation zones behind the leaflets by a purge flow during systole. This purge flow is separated from the valve's main flow by a flow divider directing a part of the main flow into the sinus behind the leaflet. The optimization was performed on a monoleaflet valve because of its simple geometry. Relevant geometric parameters were systematically varied. Thirty-two models were designed and numerically investigated. The models with the best results were preselected and investigated in a computer-controlled valve tester. The washout of a dye filled in the sinus was digitally recorded and quantified. The results show that a sinus purge flow minimizes stagnation areas in the sinus and thus may avoid thrombus formation.