Charakterisierung funktionaler Nanomaterialien für biomagnetische Sensoren und Atemanalyse

The presented thesis is covering materials aspects for the development of magnetoelectric sensors for biomagnetic sensing and solid state sensors for breath monitoring. The electrophysiological signals of the human body and especially their irregularities provide extremely valuable information about the heart, brain or nerve malfunction in medical diagnostics. Similar and even more detailed information is contained in the generated biomagnetic fields which measurement offers improved diagnostics and treatment of the patients. A new type of room temperature operable magnetoelectric composite sensors is developed in the framework of the CRC1261 Magnetoelectric Sensors: From Composite Materials to Biomagnetic Diagnostics. This thesis focuses on the individual materials structure-property relations and their combination in magnetoelectric composite sensors studied by electron beam based techniques, at lengths scales ranging from micrometers to atomic resolution. The first part of this thesis highlights selected studies on the structural and analytic aspects of single phase materials and their composites using TEM as the primary method of investigation. With respect to the piezoelectric phase, alternatives to AlN have been thoroughly investigated to seek for improvement of specific sensor approaches. In this context, the alloying of Sc into the AlN matrix has been demonstrated to yield high quality films with improved piezoelectric and unprecedented ferroelectric properties grown under the control of deposition parameters. Lead-free titanate films with large piezo-coefficients at the verge of the morphotropic phase boundary as alternative to PZT films have been investigated in terms of crystal symmetry, defect structure and domains of cation ordering. New morphologies of ZnO and GaN semiconductors envisioned for a piezotronic-based sensor approach were subject of in-depth defect and analytical studies describing intrinsic defects and lattice strains upon deposition as well as hollow composite structures. When the dimensions of a materials are reduced, novel exciting properties such as in-plane piezoelectricity can arise in planar transition-metal dichalcogenides. Here, the turbostratic disorder in a few-layered MoSe2 film has been investigated by nanobeam electron diffraction and Fast Fourier Transformations. From the perspective of magnetic materials, the atomic structure of magnetostrictive multilayers of FeCo/TiN showing stability up to elevated temperatures has been analyzed in detail regarding the crystallographic relationship of heteroepitaxy in multilayer composites exhibiting individual layer thicknesses below 1 nm. Further, magnetic hard layers have been investigated in the context of exchange spring concepts and ME composites based on shape memory alloy substrates have been studied regarding structural changes implied by different annealing processes. The second part of this thesis introduces materials aspects and sensor studies on gas detection in the clinical context of breath analysis. The detection of specific vapors in the human breath is of medical relevance, since certain species can be enriched depending on the conditions and processes within the human body. Hence, they can be regarded as biomarkers for the patients condition of health. The selection of suitable materials and the gas measurement working principle are considered and selected studies on solid state sensors with different surface functionalization or targeted application on basis of ZnO or CuO-oxide and Fe-oxide species are presented

AlScN: A III-V semiconductor based ferroelectric

Ferroelectric switching is unambigiously demonstrated for the first time in a III-V semiconductor based material: AlScN -- A discovery which could help to satisfy the urgent demand for thin film ferroelectrics with high performance and good technological compatibility with generic semiconductor technology which arises from a multitude of memory, micro/nano-actuator and emerging applications based on controlling electrical polarization. The appearance of ferroelectricity in AlScN can be related to the continuous distortion of the original wurtzite-type crystal structure towards a layered-hexagonal structure with increasing Sc content and tensile strain, which is expected to be extendable to other III-nitride based solid solutions. Coercive fields which are systematically adjustable by more than 3 MV/cm, high remnant polarizations in excess of 100 \mu C/cm$^2$ which constitute the first experimental estimate of the previously inaccessible spontaneous polarization in a III-nitride based material, an almost ideally square-like hysteresis resulting in excellent piezoelectric linearity over a wide strain interval from -0.3% to +0.4% as well as a paraelectric transition temperature in excess of 600{\deg}C are confirmed. This intriguing combination of properties is to our knowledge as of now unprecedented in the field of polycrystalline ferroelectric thin films and promises to significantly advance the commencing integration of ferroelectric functionality to micro- and nanotechnology, while at the same time providing substantial insight to one of the central open questions of the III-nitride semiconductors - that of their actual spontaneous polarization

On the Impact of the Customer Base on the Added Value through System-Oriented Service Delivery in Industrial Maintenance

Today, during service delivery, providers allocate their delivery resources such that their own delivery-dependent costs are minimal. However, during service delivery, costs arise not only for the provider, but for the customer, too. In industrial maintenance, for example, those costs arise---depending on service delivery---due to longer equipment unavailability. The concept of system-oriented service delivery aims at minimizing the total (customer and provider) delivery-dependent costs within the service system and promises a Pareto improvement over today’s practice. Hence, added value is created. However, so far, we have no understanding of the magnitude of and factors favoring high added value through system-oriented service delivery. Consequently, this work aims at filling this gap and widening knowledge on the added value through system-oriented service delivery. We present a simulation study to elaborate on the added value in dependency of the customer base constellation in an industrial maintenance illustrative scenario

Learning Variational Models with Unrolling and Bilevel Optimization

In this paper we consider the problem of learning variational models in the context of supervised learning via risk minimization. Our goal is to provide a deeper understanding of the two approaches of learning of variational models via bilevel optimization and via algorithm unrolling. The former considers the variational model as a lower level optimization problem below the risk minimization problem, while the latter replaces the lower level optimization problem by an algorithm that solves said problem approximately. Both approaches are used in practice, but unrolling is much simpler from a computational point of view. To analyze and compare the two approaches, we consider a simple toy model, and compute all risks and the respective estimators explicitly. We show that unrolling can be better than the bilevel optimization approach, but also that the performance of unrolling can depend significantly on further parameters, sometimes in unexpected ways: While the stepsize of the unrolled algorithm matters a lot (and learning the stepsize gives a significant improvement), the number of unrolled iterations plays a minor role

Human vs. supervised machine learning: Who learns patterns faster?

The capabilities of supervised machine learning (SML), especially compared to human abilities, are being discussed in scientific research and in the usage of SML. This study provides an answer to how learning performance differs between humans and machines when there is limited training data. We have designed an experiment in which 44 humans and three different machine learning algorithms identify patterns in labeled training data and have to label instances according to the patterns they find. The results show a high dependency between performance and the underlying patterns of the task. Whereas humans perform relatively similarly across all patterns, machines show large performance differences for the various patterns in our experiment. After seeing 20 instances in the experiment, human performance does not improve anymore, which we relate to theories of cognitive overload. Machines learn slower but can reach the same level or may even outperform humans in 2 of the 4 of used patterns. However, machines need more instances compared to humans for the same results. The performance of machines is comparably lower for the other 2 patterns due to the difficulty of combining input features

Cost and cost effectiveness of long-lasting insecticide-treated bed nets - a model-based analysis

Background: The World Health Organization recommends that national malaria programmes universally distribute long-lasting insecticide-treated bed nets (LLINs). LLINs provide effective insecticide protection for at least three years while conventional nets must be retreated every 6-12 months. LLINs may also promise longer physical durability (lifespan), but at a higher unit price. No prospective data currently available is sufficient to calculate the comparative cost effectiveness of different net types. We thus constructed a model to explore the cost effectiveness of LLINs, asking how a longer lifespan affects the relative cost effectiveness of nets, and if, when and why LLINs might be preferred to conventional insecticide-treated nets. An innovation of our model is that we also considered the replenishment need i.e. loss of nets over time.Methods: We modelled the choice of net over a 10-year period to facilitate the comparison of nets with different lifespan (and/or price) and replenishment need over time. Our base case represents a large-scale programme which achieves high coverage and usage throughout the population by distributing either LLINs or conventional nets through existing health services, and retreats a large proportion of conventional nets regularly at low cost. We identified the determinants of bed net programme cost effectiveness and parameter values for usage rate, delivery and retreatment cost from the literature. One-way sensitivity analysis was conducted to explicitly compare the differential effect of changing parameters such as price, lifespan, usage and replenishment need.Results: If conventional and long-lasting bed nets have the same physical lifespan (3 years), LLINs are more cost effective unless they are priced at more than USD 1.5 above the price of conventional nets. Because a longer lifespan brings delivery cost savings, each one year increase in lifespan can be accompanied by a USD 1 or more increase in price without the cheaper net (of the same type) becoming more cost effective. Distributing replenishment nets each year in addition to the replacement of all nets every 3-4 years increases the number of under-5 deaths averted by 5-14% at a cost of USD 17-25 per additional person protected per annum or USD 1080-1610 per additional under-5 death averted.Conclusions: Our results support the World Health Organization recommendation to distribute only LLINs, while giving guidance on the price thresholds above which this recommendation will no longer hold. Programme planners should be willing to pay a premium for nets which have a longer physical lifespan, and if planners are willing to pay USD 1600 per under-5 death averted, investing in replenishment is cost effective. © 2012 Pulkki-Brännström et al; licensee BioMed Central Ltd

A Data Driven Approach to Support Tailored Clinical Programs for Biosimilar Monoclonal Antibodies

Datos; Anticuerpos monoclonales biosimilaresDades; Anticossos monoclonals biosimilarsData; Biosimilar monoclonal antibodiesBiosimilar monoclonal antibodies (mAbs) have been approved in the European Union since 2013 and have been demonstrated to reduce healthcare costs and to expand patient access. Biosimilarity is mainly established on the basis of demonstrated similarity of relevant quality attributes (QAs), determined by comprehensive physiochemical and functional analyses, and demonstration of bioequivalence. In addition, comparative efficacy/safety studies have been requested for all approved biosimilar mAbs so far, although the European Medicines Agency (EMA) Guidelines state that such confirmatory clinical trials may not be necessary in specific circumstances. In order to evaluate the degree of analytical similarity, how residual uncertainty regarding biosimilarity was resolved, and the value of clinical data, we analyzed the quality and clinical data packages for authorized adalimumab (7 products) and bevacizumab (5 products) biosimilars. The percentage of biosimilar batches meeting the similarity range for QAs, as defined by the biosimilar manufacturer based on a comprehensive characterization of the EU reference product (RP), was determined and clinical data were reviewed. Our analyses show that QAs of approved adalimumab and bevacizumab biosimilars have varying concordance with the EU-RP similarity range. In this study, we found that clinical efficacy data played a limited role in addressing quality concerns. Therefore, we encourage a regulatory review of the standards for clinical data requirements for mAb and fusion protein biosimilars. This study outlines a quality data driven approach for facilitating tailored clinical programs for biosimilars

Regulatory Evaluation of Biosimilars : Refinement of Principles Based on the Scientific Evidence and Clinical Experience

Publisher Copyright: © 2022, The Author(s).The World Health Organization (WHO) guidelines on evaluation of similar biotherapeutic products (SBPs; also called biosimilars) were adopted by the WHO Expert Committee on Biological Standardization (ECBS) in 2009. In 2019, the ECBS considered that a more tailored and potentially reduced clinical data package may be acceptable in cases where this was clearly supported by the available scientific evidence. The goal of this publication is to review the current clinical experience and scientific evidence and to provide an expert perspective for updating the WHO guidelines to provide more flexibility and clarity. As the first step, the relevant guidelines by other regulatory bodies were reviewed in order to identify issues that might help with updating the WHO guidelines. Next, a literature search was conducted for information on the long-term efficacy, safety, and immunogenicity of biosimilars to identify possible long-term problems. Finally, a search for articles concerning the role of clinical studies in the benefit–risk evaluation of biosimilars was conducted. The analysis of other guidelines suggested that the WHO guidelines may need more emphasis on the importance of the state-of-the-art physicochemical and structural comparability exercise and in vitro functional testing. The use of “foreign” reference product will also need clarifications. The value of in vivo toxicological tests in the development of biosimilars is questionable, and the non-clinical part needs revisions accordingly. The concepts of “totality of evidence,” “stepwise development,” and “residual uncertainty” were applied in the evaluation of the clinical sections of the guideline. The review of long-term safety and efficacy demonstrated the robustness of the current biosimilar development concept. The analysis of the roles of different development phases suggested that the large efficacy, safety, and immunogenicity studies are, in most cases, redundant. The residual uncertainty of safety, immunogenicity, and efficacy of biosimilars that has shaped the current regulatory guidelines is now substantially reduced. This will allow the re-evaluation of the non-clinical and clinical requirements of the current WHO main guideline. The shift of the relative impact of the development phases towards physico-chemical and in vitro functional testing will provide a relief to the manufacturers and new challenges to the regulators.Peer reviewe

Al1−xScxN Thin Films at High Temperatures: Sc-Dependent Instability and Anomalous Thermal Expansion

Ferroelectric thin films of wurtzite-type aluminum scandium nitride (Al1-xScxN) are promising candidates for non-volatile memory applications and high-temperature sensors due to their outstanding functional and thermal stability exceeding most other ferroelectric thin film materials. In this work, the thermal expansion along with the temperature stability and its interrelated effects have been investigated for Al1-xScxN thin films on sapphire Al2O3(0001) with Sc concentrations x (x = 0, 0.09, 0.23, 0.32, 0.40) using in situ X-ray diffraction analyses up to 1100 °C. The selected Al1-xScxN thin films were grown with epitaxial and fiber textured microstructures of high crystal quality, dependent on the choice of growth template, e.g., epitaxial on Al2O3(0001) and fiber texture on Mo(110)/AlN(0001)/Si(100). The presented studies expose an anomalous regime of thermal expansion at high temperatures >~600 °C, which is described as an isotropic expansion of a and c lattice parameters during annealing. The collected high-temperature data suggest differentiation of the observed thermal expansion behavior into defect-coupled intrinsic and oxygen-impurity-coupled extrinsic contributions. In our hypothesis, intrinsic effects are denoted to the thermal activation, migration and curing of defect structures in the material, whereas extrinsic effects describe the interaction of available oxygen species with these activated defect structures. Their interaction is the dominant process at high temperatures >800 °C resulting in the stabilization of larger modifications of the unit cell parameters than under exclusion of oxygen. The described phenomena are relevant for manufacturing and operation of new Al1-xScxN-based devices, e.g., in the fields of high-temperature resistant memory or power el. appl