Mechanical Behavior of Lithium-Ion Battery Separators under Uniaxial and Biaxial Loading Conditions.

The mechanical integrity of two commercially available lithium-ion battery separators was investigated under uniaxial and biaxial loading conditions. Two dry-processed microporous films with polypropylene (PP)/polyethylene (PE)/polypropylene (PP) compositions were studied: Celgard H2010 Trilayer and Celgard Q20S1HX Ceramic-Coated Trilayer. The uniaxial tests were carried out along the machine direction (MD), transverse direction (TD), and diagonal direction (DD). In order to generate a state of in-plane biaxial tension, a pneumatic bulge test setup was prioritized over the commonly performed punch test in an attempt to eliminate the effects of contact friction. The biaxial flow stress-strain behavior of the membranes was deduced via the Panknin-Kruglov method coupled with a 3D Digital Image Correlation (DIC) technique. The findings demonstrate a high degree of in-plane anisotropy in both membranes. The ceramic coating was found to negatively affect the mechanical performance of the trilayer microporous separator, compromising its strength and stretchability, while preserving its failure mode. Derived from experimentally calibrated constitutive models, a finite element model was developed using the explicit solver OpenRadioss. The numerical model was capable of predicting the biaxial deformation of the semicrystalline membranes up until failure, showing a fairly good correlation with the experimental observations.

A statistical model of the rate-dependent fracture behavior of dental polymer-based biomaterials.

An insight into the fracture behavior of dental polymer-based biomaterials is important to reduce safety hazards for patients. The crack-driven fracture process of polymers is largely stochastic and often dependent on the loading rate. Therefore, in this study, a statistical model was developed based on three-point bending tests on dental polymethyl methacrylate at different loading rates. The fracture strains were investigated (two-parameter Weibull distribution (2PW)) and the rate-dependency of the 2PW parameters were examined (Cramér-von Mises test (CvM)), arriving at the conclusion that there could be a limiting distribution for both quasi-static and dynamic failure. Based on these findings, a phenomenological model based on exponential functions was developed, which would further facilitate the determination of the failure probability of the material at a certain strain with a given strain rate. The model can be integrated into finite element solvers to consider the stochastic fracture behavior in simulations.

Tablets Made from Paper-An Industrially Feasible Approach.

Many orally administrated drugs exhibit poor bioavailability due to their limited solubility. The smartFilm technology is an innovative approach to improve the drug aqueous solubility, where the drug is embedded within the matrix of cellulose-based paper in an amorphous state, hence increasing its solubility. Despite its proven effectiveness, smartFilms, i.e., pieces of paper, exhibit limited flowability and are not easy to swallow, and thus oral administration is not convenient. In addition, there is a lack of knowledge of their mechanical behavior under compression. This study aimed to transform unloaded smartFilms, i.e., paper, into a flowable physical form and investigated its mechanical behavior when compressed. Granules made of paper were prepared via wet granulation and were compressed into tablets. The influence of using different amounts and forms of sucrose, as a binder, on the pharmaceutical properties of the produced granules and tablets was studied and the most suitable composition was identified by using instrumented die experiments. For this, the Poisson's ratio and Young's modulus were determined for different compaction force levels and the deformation behavior was estimated with the Heckel mathematical model. All granule batches showed good flowability with angle of repose values between 25-35°. Granule batches with ≤30% dry sucrose content produced tablets that fulfilled the European Pharmacopeia requirements, and the compaction behavior of the granules was found to be comparable to the behavior of classical binders and compression enhancers. Paper can be transferred into granules. These granules can be used as suitable intermediate products for the production of tablets made of paper in large, industrial scale.

Paired Donor and Recipient Immunophenotyping in Allogeneic Hematopoietic Stem Cell Transplantation: A Cellular Network Approach.

Success and complications of allogeneic hematopoietic stem cell transplantation (alloHSCT) are closely connected to the transferred graft and immune reconstitution post alloHSCT. Due to the variety of immune cells and their distinct roles, a broad evaluation of the immune cellular network is warranted in mobilization and reconstitution studies in alloHSCT. Here, we propose a comprehensive phenotypic analysis of 26 immune cell subsets with multicolor flow cytometry from only 100µl whole blood per time point. Using this approach, we provide an extensive longitudinal analysis of almost 200 time points from 21 donor-recipient pairs. We observe a broad mobilization of innate and adaptive immune cell subsets after granulocyte-colony stimulating factor (G-CSF) treatment of healthy donors. Our data suggest that the relative quantitative immune cell subset composition in recipients approaches that of healthy donors from day +180 post alloHSCT onwards. Correlation of donor and recipient cell counts reveals distinct association patterns for different immune cell subsets and hierarchical clustering of recipient cell counts identifies distinct reconstitution groups in the first month after transplantation. We suggest our comprehensive immune subset analysis as a feasible and time efficient approach for a broad immune assessment for future clinical studies in the context of alloHSCT. This comprehensive cell composition assessment can be a critical step towards personalized graft composition strategies and individualized therapy management in areas such as GvHD prophylaxis in the highly complex immunological setting of alloHSCT.

Flow cytometry can reliably capture gut microbial composition in healthy adults as well as dysbiosis dynamics in patients with aggressive B-cell non-Hodgkin lymphoma.

Modulation of commensal gut microbiota is increasingly recognized as a promising strategy to reduce mortality in patients with malignant diseases, but monitoring for dysbiosis is generally not routine clinical practice due to equipment, expertise and funding required for sequencing analysis. A low-threshold alternative is microbial diversity profiling by single-cell flow cytometry (FCM), which we compared to 16S rRNA sequencing in human fecal samples and employed to characterize longitudinal changes in the microbiome composition of patients with aggressive B-cell non-Hodgkin lymphoma undergoing chemoimmunotherapy. Diversity measures obtained from both methods were correlated and captured identical trends in microbial community structures, finding no difference in patients' pretreatment alpha or beta diversity compared to healthy controls and a significant and progressive loss of alpha diversity during chemoimmunotherapy. Our results highlight the potential of FCM-based microbiome profiling as a reliable and accessible diagnostic tool that can provide novel insights into cancer therapy-associated dysbiosis dynamics.

Finite element simulation of fixed dental prostheses made from PMMA -Part II: Material modeling and nonlinear finite element analysis.

Material characteristics can change significantly with increasing chewing velocity. As these in-vitro examinations are very time-consuming and cost-intensive, the application of finite element analysis (FEA) offers a suitable alternative for predicting the material behavior of complex specimen geometries under clinically relevant loads. Although FEA is applied within numerous dental investigations, there are only few studies available in which a nonlinear FEA is validated with real experiments. Therefore, the aim of the present study was to predict the mechanical behavior of a clinically close three-unit temporary bridge composed of polymethyl methacrylate (PMMA) in the left upper jaw with nonlinear FEA and to verify the prediction through validation experiments. In conclusion, simplifying assumptions of linear elastic material properties for polymeric materials should be avoided in FEA studies, because rate dependencies, stress relaxation and plastic flow are not considered. Additionally, precise preliminary investigations for material characterization are necessary.

Finite element simulation of fixed dental prostheses made from PMMA -Part I: Experimental investigation under quasi-static loading and chewing velocities.

Material properties are of high clinical relevance, even though in vitro laboratory setups may differ from clinical conditions. Therefore, the aim of the present study was to investigate the fracture behavior of three-unit bridge restoration (Telio CAD) with different test velocities (1.0 mm/min International Organization for Standardization (ISO) standard speed/ 130 mm/s mean chewing velocity) and to provide crucial validation experiments for the upcoming Part 2 of our study, in which FEA on such temporary restorations will be conducted. Local strains were detected using digital image correlation (DIC). The material exhibited significantly different responses at different test velocities, and the forces at fracture were found to be much smaller at chewing velocity (130 mm/s) than in the quasi-static test. Overall, the results of the present study show that characteristics pertaining to material behavior can change significantly with increasing chewing velocity, and that fracture forces decrease with increasing test velocity.

Is the assumption of linear elasticity within prosthodontics valid for polymers? -An exemplary study of possible problems.

As shown in previous studies within other scientific fields, the material behavior of polymethyl methacrylate (PMMA) is viscoelastic-viscoplastic. However, in dental biomaterial science it is mostly considered as linear elastic or elastic-plastic. The aim of the present study was to evaluate, whether the assumption of elastic or elastic-plastic material behavior for PMMA is a practicable simplification or a potential source of error, especially considering clinical loading conditions. Telio-CAD was tested in three-point bending tests with different test velocities to examine the material behavior at different initial loading rates. Additionally, a dynamic-mechanical-thermal-analysis at different frequencies and temperatures was used. Here, a significant influence of loading rate and temperature as well as stress relaxation and creep were observed. To describe the rate-dependency of the elastic modulus, a new model was created, from which the elastic modulus can be calculated with a given strain rate. This model was validated using linear elastic finite element analysis.

Lung-Seeking Metastases.

Metastases from different cancer types most often affect the lung parenchyma. Moreover, the lungs are among the most frequent sites of growth of metastatic masses of uncertain/unknown lineage of origin. Thus, with regards to pulmonary neoplastic parenchymal nodules, the critical issue is to determine if they are IN the lung or OF the lung. In this review, we highlight the clinical, instrumental and molecular features which characterize lung metastases, mainly focusing on recently advancing and emerging concepts regarding the metastatic niche, inflammation, angiogenesis, immune modulation and gene expression. A novel issue is related to the analysis of biomechanical forces which cooperate in the expansion of tumor masses in the lungs. We here aim to analyze the biological, genetic and pathological features of metastatic lesions to the lungs, here referred to as site of metastatic growth. This point should be a crucial part of the algorithm for a proper diagnostic and therapeutic approach in the era of personalized medicine.

Erratum: Stella, G.M. et al. Brain Metastases from Lung Cancer: Is MET an Actionable Target? Cancers 2019, 11, 271.

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

Brain Metastases from Lung Cancer: Is MET an Actionable Target?

The process of metastatic dissemination begins when malignant cells start to migrate and leave the primary mass. It is now known that neoplastic progression is associated with a combination of genetic and epigenetic events. Cancer is a genetic disease and this pathogenic concept is the basis for a new classification of tumours, based precisely on the presence of definite genetic lesions to which the clones are addicted. Regarding the scatter factor receptors MET and Recepteur d'Origin Nantais (RON), it is recognised that MET is an oncogene necessary for a narrow subset of tumours (MET-addicted) while it works as an adjuvant metastogene for many others. This notion highlights that the anti-MET therapy can be effective as the first line of intervention in only a few MET-addicted cases, while it is certainly more relevant to block MET in cases of advanced neoplasia that exploit the activation of the invasive growth program to promote dissemination in other body parts. Few data are instead related to the role played by RON, a receptor homologous to MET. We have already demonstrated an implication of MET and RON genes in brain metastases from lung cancer. On this basis, the aim of this work is to recapitulate and dissect the molecular basis of metastatic brain dissemination from lung cancer. The latter is among the big killers and frequently gives rise to brain metastases, most often discovered at diagnosis. Molecular mechanisms leading to tumour spread to the brain are mostly unknown and in turn these tragic cases are still lacking effective therapies. Based on previously published data from our group, we aim to summarise and analyse the pathogenic mechanisms leading to activation of the scatter factor receptor in brain metastatic lesions of lung primaries, from the point of view of replacing the currently used empirical treatment with a more targeted approach.

"Metastatic Cancer of Unknown Primary" or "Primary Metastatic Cancer"?

Cancer of unknown primary (CUP) is an umbrella term used to classify a heterogeneous group of metastatic cancers based on the absence of an identifiable primary tumor. Clinically, CUPs are characterized by a set of distinct features comprising early metastatic dissemination in an atypical pattern, an aggressive clinical course, poor response to empiric chemotherapy and, consequently, a short life expectancy. Two opposing strategies to change the dismal prognosis for the better are pursued. On the one hand, following the traditional tissue-gnostic approach, more and more sophisticated tissue-of-origin (TOO) classifier assays are employed to push identification of the putative primary to its limits with the clear intent of allowing tumor-site specific treatment. However, robust evidence supporting its routine clinical use is still lacking, notably with two recent randomized clinical trials failing to show a patient benefit of TOO-prediction based site-specific treatment over empiric chemotherapy in CUP. On the other hand, with regards to a tissue-agnostic strategy, precision medicine approaches targeting actionable genomic alterations have already transformed the treatment for many known tumor types. Yet, an unmet need remains for well-designed clinical trials to scrutinize its potential role in CUP beyond anecdotal case reports. In the absence of practice changing results, we believe that the emphasis on finding the presumed unknown primary tumor at all costs, implicit in the term CUP, has biased recent research in the field. Focusing on the distinct clinical features shared by all CUPs, we advocate adopting the term primary metastatic cancer (PMC) to denominate a distinct cancer entity instead. In our view, PMC should be considered the archetype of metastatic disease and as such, despite accounting for a mere 2-3% of malignancies, unraveling the mechanisms at play goes beyond improving the prognosis of patients with PMC and promises to greatly enhance our understanding of the metastatic process and carcinogenesis across all cancer types.

Passive magnetic shielding in MRI-Linac systems.

Passive magnetic shielding refers to the use of ferromagnetic materials to redirect magnetic field lines away from vulnerable regions. An application of particular interest to the medical physics community is shielding in MRI systems, especially integrated MRI-linear accelerator (MRI-Linac) systems. In these systems, the goal is not only to minimize the magnetic field in some volume, but also to minimize the impact of the shield on the magnetic fields within the imaging volume of the MRI scanner. In this work, finite element modelling was used to assess the shielding of a side coupled 6 MV linac and resultant heterogeneity induced within the 30 cm diameter of spherical volume (DSV) of a novel 1 Tesla split bore MRI magnet. A number of different shield parameters were investigated; distance between shield and magnet, shield shape, shield thickness, shield length, openings in the shield, number of concentric layers, spacing between each layer, and shield material. Both the in-line and perpendicular MRI-Linac configurations were studied. By modifying the shield shape around the linac from the starting design of an open ended cylinder, the shielding effect was boosted by approximately 70% whilst the impact on the magnet was simultaneously reduced by approximately 10%. Openings in the shield for the RF port and beam exit were substantial sources of field leakage; however it was demonstrated that shielding could be added around these openings to compensate for this leakage. Layering multiple concentric shield shells was highly effective in the perpendicular configuration, but less so for the in-line configuration. Cautious use of high permeability materials such as Mu-metal can greatly increase the shielding performance in some scenarios. In the perpendicular configuration, magnetic shielding was more effective and the impact on the magnet lower compared with the in-line configuration.

Magnetization curves of sintered heavy tungsten alloys for applications in MRI-guided radiotherapy.

PURPOSE: Due to the current interest in MRI-guided radiotherapy, the magnetic properties of the materials commonly used in radiotherapy are becoming increasingly important. In this paper, measurement results for the magnetization (BH) curves of a range of sintered heavy tungsten alloys used in radiation shielding and collimation are presented. METHODS: Sintered heavy tungsten alloys typically contain >90% tungsten and <10% of a combination of iron, nickel, and copper binders. Samples of eight different grades of sintered heavy tungsten alloys with varying binder content were investigated. Using a superconducting quantum interference detector magnetometer, the induced magnetic moment m was measured for each sample as a function of applied external field H0 and the BH curve derived. RESULTS: The iron content of the alloys was found to play a dominant role, directly influencing the magnetization M and thus the nonlinearity of the BH curve. Generally, the saturation magnetization increased with increasing iron content of the alloy. Furthermore, no measurable magnetization was found for all alloys without iron content, despite containing up to 6% of nickel. For two samples from different manufacturers but with identical quoted nominal elemental composition (95% W, 3.5% Ni, 1.5% Fe), a relative difference in the magnetization of 11%-16% was measured. CONCLUSIONS: The measured curves show that the magnetic properties of sintered heavy tungsten alloys strongly depend on the iron content, whereas the addition of nickel in the absence of iron led to no measurable effect. Since a difference in the BH curves for two samples with identical quoted nominal composition from different manufacturers was observed, measuring of the BH curve for each individual batch of heavy tungsten alloys is advisable whenever accurate knowledge of the magnetic properties is crucial. The obtained BH curves can be used in FEM simulations to predict the magnetic impact of sintered heavy tungsten alloys.

Impact of the MLC on the MRI field distortion of a prototype MRI-linac.

PURPOSE: To cope with intrafraction tumor motion, integrated MRI-linac systems for real-time image guidance are currently under development. The multileaf collimator (MLC) is a key component in every state-of-the-art radiotherapy treatment system, allowing for accurate field shaping and tumor tracking. This work quantifies the magnetic impact of a widely used MLC on the MRI field homogeneity for such a modality. METHODS: The finite element method was employed to model a MRI-linac assembly comprised of a 1.0 T split-bore MRI magnet and the key ferromagnetic components of a Varian Millennium 120 MLC, namely, the leaves and motors. Full 3D magnetic field maps of the system were generated. From these field maps, the peak-to-peak distortion within the MRI imaging volume was evaluated over a 30 cm diameter sphere volume (DSV) around the isocenter and compared to a maximum preshim inhomogeneity of 300 µT. Five parametric studies were performed: (1) The source-to-isocenter distance (SID) was varied from 100 to 200 cm, to span the range of a compact system to that with lower magnetic coupling. (2) The MLC model was changed from leaves only to leaves with motors, to determine the contribution to the total distortion caused by MLC leaves and motors separately. (3) The system was configured in the inline or perpendicular orientation, i.e., the linac treatment beam was oriented parallel or perpendicular to the magnetic field direction. (4) The treatment field size was varied from 0 × 0 to 20×20 cm(2), to span the range of clinical treatment fields. (5) The coil currents were scaled linearly to produce magnetic field strengths B0 of 0.5, 1.0, and 1.5 T, to estimate how the MLC impact changes with B0. RESULTS: (1) The MLC-induced MRI field distortion fell continuously with increasing SID. (2) MLC leaves and motors were found to contribute to the distortion in approximately equal measure. (3) Due to faster falloff of the fringe field, the field distortion was generally smaller in the perpendicular beam orientation. The peak-to-peak DSV distortion was below 300 µT at SID≥130 cm (perpendicular) and SID≥140 cm (inline) for the 1.0 T design. (4) The simulation of different treatment fields was identified to cause dynamic changes in the field distribution. However, the estimated residual distortion was below 1.2 mm geometric distortion at SID≥120 cm (perpendicular) and SID≥130 cm (inline) for a 10 mT/m frequency-encoding gradient. (5) Due to magnetic saturation of the MLC materials, the field distortion remained constant at B0>1.0 T. CONCLUSIONS: This work shows that the MRI field distortions caused by the MLC cannot be ignored and must be thoroughly investigated for any MRI-linac system. The numeric distortion values obtained for our 1.0 T magnet may vary for other magnet designs with substantially different fringe fields, however the concept of modest increases in the SID to reduce the distortion to a shimmable level is generally applicable.