Schedule of ELAINE Colloquia
Dr. Christian Kuttner, Nature Communications, Berlin
How to publish in Nature
Prof. Dr. Sara Marceglia, Università degli Studi di Trieste
Prof. Dr. Christine Selhuber-Unkel, Universität Heidelberg
3D hydrogel microstructures for controlling cells
Prof. Dr. Oliver Friedrich, Friedrich-Alexander-Universität Erlangen-Nürnberg
Dr. Sahba Mobini, Instituto de Micro y Nanotecnología, Madrid
In vitro Electrical Stimulation: Advancements and Obstacles
The three classic pillars of tissue engineering (TE) - cell, matrix, and signalling- are evolving rapidly since novel cell sources, advanced biomaterials, and innovative fabrication techniques are emerging. In addition, pivotal discoveries shed light on the crucial role of biophysical (mechanical, electrical, and architectural) cues, beside biochemical signalling, in developing functional TE products for in vivo and in vitro applications. Like mechanobiology, electrobiology is becoming significant to the field of TE and regenerative medicine. Traditionally, electrical properties of the cells were only considered in the context of electroactive cells (e.g., neurons) and research was highly focused on action potential. However, recently the significant role of low intensity currents and plasma membrane voltage in governing several vital biological functions of cells and tissues has become evident. The use of exogenous electrical stimulation (ES) as a tool for manipulating cells and tissues has drawn attention of several researchers in the fields of biology and biomedical engineering. Currently, ES is applied via different protocols (intensity, frequency, duration, shape of signal) and devices for various clinical and research applications. To what extend is ES effective in tissue regeneration, which protocols are effective and why, and which general biological mechanisms are triggered by ES, are the main remaining questions. In this seminar, I am going to review the role of electrobiology in tissue engineering and focus on recent progress and open questions. I will also discuss possible strategies to address the remaining challenges. Moreover, I will elaborate on future directions and novel ideas for utilizing ES in TE and regenerative medicine.
J.-Prof. Dr. Stefan Simm, Universitätsmedizin Greifswald
Explainable AI in combination with Deep Neural Networks in biomedical research
Explainable Artificial Intelligence (XAI) becomes more and more important, especially in the life sciences, where it is urgent to understand the selection criteria and single decision-making steps to overcome black box systems. XAI in combination with Deep Neural Networks allows the prevention of "Clever Hans" predictors as well as supports clinicians and experimentalists with additional information during the training and validation of huge datasets. Convolutional neural nets (CNNs) are already well established in image classification and the addition of explainable components like layerwise relevance propagation (LRP) allows the extraction of important features from the classifier to make the decision. Especially in high-throughput methods like sequencing (Omics) and cytometry imaging (RT-DC) XAI can be useful to recognize motifs and patterns for classification. On single-cell imaging and bulk/single-cell sequencing, such approaches can be used to detect important biomarkers for disease diagnosis and identify confounder effects from environmental and physical parameters like gender, age, or BMI. In both cases, different neural network architectures with explainable components can be used to expand the knowledge in cardiovascular diseases or the detection of risk factors on a molecular level for specific diseases based on minimal-invasive procedures.
Prof. Dr. Mihaela Delcea, Universität Greifswald
Biophysical insights into the dynamics of cells and the impact on biomedical research
The study of cellular processes (e.g. activation, migration, mechanics) is very relevant for biomedical research as it may allow elucidation of diseases’ mechanisms.
Living cells and tissues are sensitive to micro- and nanoscale topographic patterns, including extracellular matrix structures. We reported on the effect of 3D micropillars as ideal scaffolds in tissue engineering on the mechanobiology (i.e. cell stiffness, cell beating frequency, and cytoskeleton organization) on healthy and diseased human induced pluripotent stem cell-derived cardiomyocytes.
Although the strength of a blood thrombus has likely major biological importance, little is known about the mechanisms underlying the interaction among blood platelets during activation and aggregation processes. We filled this gap by measuring adhesion forces between platelets at different activation states. Our studies pave the way for testing and improving new materials' biocompatibility and assessing platelet defects' mechanical characteristics.
In my talk I will also refer to the dynamics of neutrophils that are engaged in NET-osis (i.e. formation of neutrophil extracellular traps) - a suicidal pathway to trap pathogens and limit their spread during infection. Neutrophil labeling, imaging, and tracking will be also highlighted.
Prof. Dr. Bikramjit Basu, Indian Institute of Science, Bangalore, India
Biophysical stimulation of stem cells on functional biomaterials: in vitro and in silico studies
Biomaterials science and biomedical engineering have sustained as one among frontier and growing areas of research and innovation within the engineering science community in the world; considering the number of scientific discoveries and their societal impact. Against this backdrop, I shall first mention the Indian landscape of research on Biomaterials Science and the recent efforts towards indigenous manufacturing of biomaterial implants in India.
While introducing the fundamental concepts, it will be emphasized that the phenomenological interaction of a biological cell with a synthetic material is influenced by several factors, e.g. elastic stiffness, surface topography and wettability. In this context, the results of the plethora of in vitro studies to validate a strikingly different approach, involving the intermittent delivery of electric or magnetic field stimulation to manipulate cell functionality on electroconductive or magnetoactive biomaterials, will be discussed. It will be argued how the electric stimuli can potentially restrict the cell proliferation, leading to early onset of stem cell differentiation.
In an effort to rationalize the outcome of in vitro studies, the theoretical concept based on the analytical solution of the Poisson’s equations with appropriate boundary conditions will be described. The outcome of such in silico study will unravel the significance of substrate conductivity in synergy with electric field parameters towards modulation of bioelectric stress field, which has major ramification on cellular deformation and cell fate processes. Towards the end, the results of our recent molecular dynamics (MD) study to probe into the influence of electric field on protein adsorption (on bioceramic) and adsorbed protein-cell surface receptor interaction will be presented.
The seminar will close with the mention of many unanswered questions and potential collaboration opportunities.
PD Dr. med. Christoph van Riesen, Universitätsmedizin Göttingen
Probing and manipulating dysfunctional circuits in Parkinson´s disease
In Parkinson´s disease a chronic progressive loss of dopaminergic neurons in the brain leads to debilitating motor symptoms in the form of akinesia, rigidity (increased muscle tone) and tremor. Currently, only symptomatic treatments are available that do not slow the underlying degenerative disease. For this reason, there is an urgent need to better understand the underlying disease process and to develop individualized neuromodulatory treatments.
Cumulative evidence shows that the motor impairment in PD is closely linked to increased oscillatory synchrony in the cortico-basal ganglia-thalamic loop. These enhanced beta oscillations correlate with the severity of motor impairment and are suppressed by symptomatic treatments such as levodopa and deep brain stimulation. It has been hypothesized that beta oscillations might mediate akinesia and rigidity. However, the pathophysiological significance of these findings is still at debate.
Medication induced dyskinesias are a frequent complication of long-term dopaminergic treatment in PD. Only recently, it was shown that increased narrow band gamma oscillations are related to these hyperkinesia.
Derived from above findings, beta and gamma oscillations are being tested in laboratories worldwide as feedback biomarkers for adaptive closed loop deep brain stimulation.
In my talk, I will review the evidence on the significance of increased beta and gamma oscillations in the pathophysiology of PD using data from my own and other labs. Furthermore, I will discuss how and if beta and gamma oscillations can be used to improve neuromodulation by deep brain stimulation.
Prof. Dr. Sarah Cartmell, The University of Manchester
Electrical Stimulating Regimes to Influence Stem Cell Proliferation and Differentiation for Tissue Engineering
The growth of new bone tissue in vitro requires a variety of different factors that need to be controlled and optimised. One of these factors that has previously not been considered for bone tissue engineering is electrical stimuli. Given that bone is piezoelectric in nature, it is feasible to assume that local electrical regimes have an effect on osteogenesis. There are clinical products currently on the market that deliver electrical currents locally via a cathode to fracture sites. These products demonstrate significant clinical improvements in bone repair.
We have recently designed a variety of different bioreactors to both house the developing tissue and also control the applied electrical stimuli in either capacitive or direct contact methods to in vitro cultures. These bioreactors have enabled us to assess the potential use of this stimuli for in vitro bone tissue engineering purposes. It has also allowed us to further study the mechanism by which the activity of primary human mesenchymal stem cells are altered both in terms of cell proliferation and differentiation. A novel finding of the importance of the faradic by product of H2O2 proximal to the cathode as result of the direct electrical stimulus will be presented and its subsequent role in influencing primary mesenchymal stem cell proliferation. The morphology of primary cilia on these cells after electrical stimulation has been applied will also be discussed, in addition to the effect of varying electrical regime on cell response. The use of conducting polymers and piezoelectric materials to apply electrical regimes to the cells will be discussed.
During the presentation I will briefly introduce a new tendon repair product that has been developed and subsequent spin off company that has been set up in 2021.
As part of the Women in STEM presentation invite I will also go through some of my career decisions and give some key tips that I have found helpful throughout my career.
Prof. Dr. Friedemann Reinhard, Universität Rostock
Upcoming quantum and classical sensors for tissue conductivity and electric activity
I will review ongoing efforts of my group and others to detect and image electric signals in living matter. This will include diamond quantum sensors, which can image the magnetic stray field of action potentials as well as tissue conductivity with microscopic resolution. I will also discuss an ongoing effort of our lab to image action potentials in a label-free way by searching for intrinsic optical signals accompanying neural activity.
Dr. Markus Becker, INP Greifswald
Electronic laboratory notebooks and other tools for user-friendly research data management workflows with examples from plasma technology
The need to implement the FAIR data principles and structured research data management in our research workflows is growing. On the one hand, this is due to pressure, e.g. from research funders and publishers. But on the other hand, it is particularly because the advantages thus achieved in the use of data-driven research methods are becoming increasingly obvious. In my presentation I will introduce practical tools and workflows that aim to integrate research data management into the everyday work of scientists and to take the FAIR principles into account as early as possible in the life cycle of research data, avoiding additional work for the researcher as far as possible. While my examples are from practical implementation for plasma technology research, the approaches are generally applicable to any research area involving different research methods and domains.
Prof. Dr. Derek Groen, Brunel University London
Uncertainty Quantification and Multiscale Simulation using the SEAVEA (or VECMA) toolkit
PD Dr. Haidar Dafsari, Uniklinik Köln
Non-motor effects of deep brain stimulation in Parkinson's disease
Deep brain stimulation is a well-established and safe treatment option for patients with advanced Parkinson's disease, improving quality of life, motor and non-motor symptoms.
This talk will present current research on the non-motor effects of deep brain stimulation in Parkinson's disease and highlight the opportunities and challenges of this therapy for a personalized treatment of patients.
Prof. Dr. Michael Levin, Tufts University - virtual lecture:
Instruct growth and form: from pre-neural mechanisms to electroceuticals for regenerative medicine
Embryos and regenerating systems produce very complex, robust anatomical structures and stop growth and remodeling when those structures are complete. One of the most remarkable things about morphogenesis is that it is not simply a feed-forward emergent process, but one that has massive plasticity: even when disrupted by manipulations such as damage or changing the sizes of cells, the system often manages to achieve its morphogenetic goal. How do cell collectives know what to build and when to stop? In this talk, I will highlight some important knowledge gaps about this process of anatomical homeostasis that remain despite progress in molecular genetics. I will then offer a perspective on morphogenesis as an example of a goal-directed collective intelligence that solves problems in morphospace and physiological space. We have been pursuing the hypothesis that an ancient, pre-neural bioelectric communication system among somatic cells enables them to cooperate toward anatomical outcomes. I will show examples of our work to read and write the bioelectric information that instructs growth and form. I will show how new biophysical and computational tools are enabling increased control over large-scale morphogenesis in the context of birth defects, regeneration, and cancer. Ion channel drugs thus form a class of "electroceuticals" for new applications in regenerative medicine.
Prof. Dr. Andrea Kühn, Charité Berlin
The role of chronic brain sensing technology for individualized deep brain stimulation therapy
Adaptive deep brain stimulation (aDBS) is a promising concept for feedback-based neurostimulation, with the potential of clinical implementation with the novel, sensing-enabled Percept neurostimulator. We have characterized chronic electrophysiological deep brain recordings during medication and stimulation in patients with Parkinson’s disease and dystonia. In my presentation, I will give an overview on latest findings on biomarkers for motor performance such as beta or theta band activity. Moreover, I will discuss current techniques for chronic brain sensing and its use for therapy optimization in clinical practice.
Annual IRTG Member Meeting - per invitation only
Dr. Florian Wieland, Helmholtz-Zentrum Geesthacht
Usage of synchrotron µCT for the investigation of biomaterials
Dr. Mathis Riehle, University of Glasgow
Cells, drugs and bioengineered constructs to aid peripheral nerve repair
Peripheral nerve injury is common and causes devastating paralysis and sensory loss, with costs to the individual, their families, communities and the health systems. Current Gold Standard surgical management with microsurgical repair fails to address the neurobiology of the injury and recovery is slow and often incomplete with subsequent disability. Therefore developing alternative therapies, that enhance the nerve repair microenvironment remains imperative. Here the development of a bioengineered internally microstructured nerve guidance conduit is demonstrated. How we arrived at the surface features, substrate modifications, growth factors, supporting cells is covered as well as pre-clinical testing. To further improve the device we also briefly introduce acusto-fluidics, electric stimulation and media development to help with translation.
Wed, 17.02.2021: 13:00 IRTG Member Meeting - virtual - per invitation only
Dr. Mathis Riehle, University of Glasgow
- postponed to 24 February 2021
Prof. Dr. Petra Schwille, MPI for Biochemistry, Martinsried
Life without ancestors?
One of the hallmarks of cell theory is the recognition that any life form, consisting of one or more living cells, results from another living cell. Although this insight was a huge step towards making biology a scientific discipline, and freeing the concept of life from metaphysics and speculation, it left us with a fundamental riddle – how did the first cell, how did life as such originate? Using bottom-up synthetic biology of simplistic reconstituted systems, we attempt to identify the fundamental principles of how chemical systems acquire, one by one, the particular features and functions of living systems. Our particular emphasis is on the origin of cell division, and how we could build a minimal system that is able to divide autonomously.
Prof. Dr. Dagmar Waltemath, University of Greifswald
Stay FAIR! Or: How to become a happy scientist
Science is tough, and there's one deadline after another. Contracts are mostly temporary. The publication index is a core measure for success and may correlate with job offers. Quite frustrating. So - what keeps you happy? Is it to think deeply over a topic, the possibility to change the world (a little bit), or your work environment? I believe that happiness in science increases with the positive feedback one gets from fellow researchers. While happiness can be achieved by publishing in top journals, I find it more satisfying to see others reuse one’s work, and to drive science further in a collaborative, friendly yet competitive manner.
In my talk, I will share my experiences and a bit of scientific evidence that collaborative science is good science. My personal stories are based on 10+ years of building, promoting and establishing standards and guidelines for systems medicine and, more recently, medical informatics. I will show you the FAIR principles and sample implementations thereof, elaborate on the work-life balance of the COmputational Modeling in BIology NEtwork (https://co.mbine.org/), and introduce you to two German networks for medical informatics. One was founded in a year-long, coordinated process (https://www.medizininformatik-initiative.de/en/); the other one went online within 2 weeks, driven by passion for virology, data standards, and the will to fight COVID-19 (https://cocos.team/).
The colloquium should help us understand how FAIR data and open software code contribute to better reproducibility and more transparency of scientific results, and how working with FAIR communities can make you a happier scientist. I will leave enough time for you to add your own stories and concerns, and to discuss them during the colloquium. Questions are welcome at any time.
Dr. Florian Wieland, Helmholtz-Zentrum Geesthacht
Investigation of bone and cartilage with high resolution synchrotron techniques
- postponed to 24 March 2021
Prof. Dr. Ulrich Hofmann, University of Freiburg
ELECTROCEUTICALS® at the Gates! - Pre-clinical models to feed the next medical revolution
Although it sounds like straight from a science fiction novel, it is the pronounced intention of neuroengineering research to reliably connect living nervous systems to technological devices, comprising brain-machine-interfaces (BMI). The methods developed en route to such noble goal enable a novel class of interventional devices called ELECTROCEUTICALS® or bioelectronic medicine. Electroceuticals achieve their therapeutic effect by stimulating particular positions of the nervous system, in the best of all cases closed-loop controlled by signals from the same tissue (theranostics).
My presentation will briefly review the field of existing electroceuticals and introduce the components needed for complete systems. Among them are implantable micro-electrodes collecting neuronal signals to be processed in situ in embedded systems capable of determining optimal conditions to trigger therapeutic stimulation utilizing same electrodes.
I will present novel multisite micro-electrode arrays -the flexible ones capable of minimizing tissue scaring- as well as wireless, head mounted recording and stimulation hardware for learning experiments with rodents. Exemplary closed-loop stimulation is performed to treat an animal model of Parkinson’s Disease and provides a testbed for a wide range of therapeutic parameters, otherwise not easily accessible in a realistic way.
Prof. Dr. Christine Selhuber-Unkel, University of Kiel
Responsive and Bioinspired Functional Materials for Controlling Living Cells
Cells are dynamic active systems that strongly interact with their environment. They are not only influenced by structural features, but also by the chemical and physical properties of their environment. At the same time, they can actively apply forces and restructure their surroundings. A highly interesting question is therefore how cells sense, transduct and respond to mechanical and electrical stimuli, and which physical principles underlie these processes. For example, we have used photoresponsive push-pull azobenzenes to exert a mechanical oscillatory stimulus to integrin receptors in fibroblast cells. This stimulation causes a significant reinforcement of cell adhesion, both at the molecular and the cellular level, and demonstrates that cells are able to respond to stimuli as tiny as molecular oscillations. Furthermore, 3D microstructured environments provide excellent opportunities for controlling cells at several levels of complexity. It is therefore to be expected that methods providing specifically designed cellular environments, including dynamic environments and microstructures, will provide strategies for physically directing cells to execute autonomous, dynamic, coordinated, and multi-scale behaviors.
Wed, 22.01.2020: Annual IRTG member meeting
Prof. Dr. Dr.h.c. Günther Deuschl, Department of Neurology; UKSH-CK; Christian-Albrechts-University Kiel
Deep Brain Stimulation for Movement Disorders
Deep brain stimulation is an invasive treatment requiring placement of electrodes in the brain combined with a subcutaneously placed pulse generator. This is meanwhile well-established for Parkinson’s disease, dystonia and tremor. The clinical trials and the associated scientific problems will be presented.
As often in clinical neurosciences the huge success of this treatment contrasts with poor knowledge about its mechanism of action. Although we do have an understanding of the function of the basal ganglia and some hypothesis how this treatment may interfere, the exact mechanisms for the two main conditions Parkinson’s and tremor are still a matter of discussion. The available data and current concepts on research strategy will be discussed.
Clinicians are highly interested to improve the therapy. Approaches to achieve this are: to better know the optimal target, to better adapt the stimulation parameters, to develop closed loop stimulation. These are highly active areas of interdisciplinary research.
Prof. Dr. Birgit Liss, University of Ulm
It's complicated: Calcium, dopamine, and Parkinson's disease
Degeneration of dopaminergic neurons in the Substantia nigra (SN DA) causes the motor symptoms of Parkinson’s disease. The mechanisms underlying this age-dependent and region-selective neurodegeneration remain unclear, but activity-related metabolic stress and dysfunctional Ca2+ signaling constitute important factors. SN DA neurons are particularly vulnerable to degenerative stressors due to their demanding Ca2+ entry during action potentials, mediated by Cav channels. Epidemiological evidence correlated use of L-type Cav blockers with a reduced risk for developing Parkinson’s later in life. However, a recent highly anticipated phase-III clinical trial was negative. Our data point to a cell-type specific complex homeostatic interplay of distinct plasma-membrane ion channels with associated neuronal Ca2+ sensors (NCS) - that is important for flexible tuning of SN DA neuron function and viability. We identified Cav2.3, Cav3.1, and NCS-1 as novel potential therapeutic targets for combatting Ca2+ dependent neurodegeneration in Parkinson’s disease.
Dr. Karine Anselme, Institut de Science des Matériaux de Mulhouse (IS2M), CNRS UMR 7361, Mulhouse, France
Materials to control biological cells function: a focus on the role of the nucleus in the cell response
Cells are strongly influenced by their environment which can be described in terms of chemical, topographical and mechanical properties. More specifically, the influence on cell fate of mechanical stimuli applied directly or by changing topography of their microenvironment has been extensively studied over the past two decades [1-3].
The capacity of mechanical forces or of the cell-scale microenvironment to modulate cytoskeletal organization and cell contractility and to induce downstream signaling events is defined as mechanotransduction. The mechanotransduction mechanism justifies the existence of mechanosensors that will translate the mechanical input into a biochemical input inside the cells. While mechanosensing through force sensitive membrane channels, focal adhesions or cell-cell junction proteins at the plasma membrane and within the cytoplasm has been well studied, the role of the cell nucleus as a mechanosensor has been only recently confirmed . In this talk, I will focus on the role of the nucleus in the response of cells to topography at their own scale. Our last experience on living cells behavior on microfabricated surfaces with 2.5D patterns will be detailed as well as our recent discovery of a new cellular ability which we term “curvotaxis” .
 K. Anselme, M. Bigerelle, Role of materials surface topography on mammalian cell response, International Materials Reviews 56(4) (2011) 243-266.
 K. Anselme, A. Ponche, L. Ploux, Materials to control and measure cell function, in: P. Ducheyne, K.E. Healy, D.W. Hutmacher, D.W. Grainger, C.J. Kirkpatrick (Eds.), Comprehensive Biomaterials, Elsevier, Oxford, UK, 2011, pp. 235-255.
 B.J. Nebe, C. Moerke, S. Staehlke, B. Finke, M. Schnabelrauch, K. Anselme, C.A. Helm, M. Frank, H. Rebl, Complex Cell Physiology on Topographically and Chemically Designed Material Surfaces, Materials Science Forum 879 (2017) 78-83.
 K. Anselme, N.T. Wakhloo, P. Rougerie, L. Pieuchot, Role of the Nucleus as a Sensor of Cell Environment Topography, Adv. Healthc. Mater (2018) 1701154.
 L. Pieuchot, J. Marteau, A. Guignandon, T. dos Santos, I. Brigaud, P.F. Chauvy, T. Cloatre, A. Ponche, T. Petithory, P. Rougerie, M. Vassaux, J.L. Milan, N.T. Wakhloo, A. Spangenberg, M. Bigerelle, K. Anselme, Curvotaxis directs cell migration through cell-scale curvature landscapes, Nature Communications 9 (2018) 3995.
Prof. Dr. Julia Glaum, NTNU Norwegian University of Science and Technology, Trondheim
Piezoelectrically active ceramics and their potential for biomedical applications
The ability to convert an electrical field into a mechanical perturbation and vice versa makes piezoelectric materials fundamentally interesting objects of study as well as versatile components for industrial applications. Piezoelectric materials can serve as sensors and actuators in a range of fields covering vibration control in airplanes, ultrasound applications in marine and medical devices or pickups for musical instruments.
In recent years, the value of piezoelectric materials for biomedical applications, as for nerve and bone tissue repair, in vivo sensors or energy harvesting components, has been unfolding.
However, the boundary conditions that have to be met to make these materials work in an in vivo environment are quite different to the ones in their established industial applications. Material and implant design have to be re-thought to match the requirements e.g. in terms of cytotoxicity, chemical stability and stable performance in the presence of body fluids.
In this presentation, I will given an overview of our latest research on piezoelectric BaTiO3 and (K,Na)NbO3 ceramics for bone implant applications. We’ve been studying these perovskite systems from the viewpoint of Material Science, adapting their microstructure to develop porous scaffolds and tailoring their chemical composition to improve their stability in liquid environments. Furthermore, we have taken the “hospital” view and looked at the impact of pre-implantation proceedures, such as contact-less poling and sterilization, on the performance of our ceramics. The two systems show quite different characteristics and dependencies, which highlights the need for composition-specific research approaches, but as well the flexibility of the group of perovskites to cover different areas of biomedical applications.
Prof. Dr. Kevin Burrage, University of Oxford and Queensland University of Technology
Image based modelling and simulation: Perlin Noise generation of physiologically realistic patterns of fibrosis
Fibrosis, the pathological excess of fibroblast activity, is a significant health issue that hinders the function of many organs in the body, in some cases fatally. However, the severity of fibrosis-derived conditions depends on both the positioning of fibrotic affliction, and the microscopic patterning of fibroblast-deposited matrix proteins within affected regions. Variability in an individual's manifestation of a type of fibrosis is an important factor in explaining differences in symptoms, optimum treatment and prognosis, but a need for ex vivo procedures and a lack of experimental control over conflating factors has meant this variability remains poorly understood.
In this work, we present a computational methodology, based on Perlin noise fields, Fast Fourier Transforms and SMC ABC parameter estimation, for the generation of patterns of fibrosis microstructure. We demonstrate the technique using histological images of four types of cardiac fibrosis. Our generator and automated tuning method prove flexible enough to capture each of these very distinct patterns, allowing for rapid generation of new realisations for high-throughput computational studies. We also demonstrate via simulation, using the generated fibrotic patterns, the importance of micro-scale variability by showing significant differences in electrophysiological impact even within a single class of fibrosis, hence quantifying arrhythmic risk.
The key novel impact of our methodology is, through data enhancement and image based simulation, to remove limitations posed by the availability of ex-vivo data whilst being sophisticated enough to produce physiologically realistic patterns that match the data available and then to use image-based simulation to quantify arrhythmic risk.
IEEE Distinguished Lecturer Prof. Dr. Maurits Ortmanns, University of Ulm
Implantable electronics with Data and Power Telemetry
This talk is given as part of the IEEE Distinguished Lecturer Series and supported by IEEE Solid State Circuits Society
This talk will highlight some of the recent worldwide advances towards the realization of high channel count implantable neural interfaces, covering applications and system examples such as the retinal implant and neural modulators with high efficiency frontends, as well as give an overview of the supporting circuitry, such as transcutaneous data telemetry including safety and security aspects, power telemetry, and adaptive power management. It first reviews the common RF based approaches, and secondly highlights new approaches such as energy harvesting and non-RF communication.
Prof. Dr. Peter Wriggers, University of Hannover
Computational modelling of soft tissue mechanics: multiscale and coupled phenomena
This seminar addresses novel computational methods for the modelling of the mechanics of soft biological tissues, with particular reference to arterial segments. Advancements are presented from three different perspectives: a multiscale hyperelastic constitutive description explicitly accounting for histological and molecular properties is proposed; an elasto-damage constitutive model able to upscale molecular-level damage mechanisms at the macroscale is presented and validated by means of collagen-hybridizing techniques; a computational framework for the coupling of damage with growth-and-remodeling is developed.
The multiscale hyperelastic formulation explicitly describes the nonlinear mechanics of crimped collagen fibers within tissues [1,2]. A multiscale scheme is proposed, coupling the advantages of purely-analytical and computational approaches: low-computational costs despite an explicit dependency of the macroscale response on microstructural properties, such as fiber geometry and histological properties. Mixed variational formulations are also presented to increase the accuracy in the presence of strong anisotropic properties.
In order to describe damage evolution in tissues, a structurally-motivated constitutive model is developed in the framework of continuum damage mechanics . The model includes two internal variables for describing the effects of collagen triple-helical unfolding via interstrand delamination: one governs plastic mechanisms in collagen fibers, leading to a stress softening response of the tissue at the macroscale; the other one describes the loss of fiber structural integrity, leading to tissue final failure. The proposed model is calibrated using experimental data obtained from mechanical tests, showing excellent fitting capabilities. The predicted evolution of internal variables agrees well with independent measurements of molecular-level damage data obtained with collagen hybridizing peptide (CHP) techniques. This allows to obtain an independent a posteriori validation of damage predictions.
The effect of damage on tissue healing response is modelled by introducing a further multiplicatively split of the inelastic deformation gradient which accounts for tissue growth and remodeling (G&R) via a homogenized constrained mixture theory. The gross (time-averaged) effects related to stress-free changes induced by mass variations of each constituent are captured. Numerical examples showing the significance of accounting for the coupling of damage with G&R conclude the presentation. An outlook on the coupling with chemo-biological models is also provided .
 M. Marino, P. Wriggers (2019) Micro-macro constitutive modeling and finite element analytical-based formulations for fibrous materials: A multiscale structural approach for crimped fibers. Computer Methods in Applied Mechanics and Engineering 344:938-969.
 M. Marino, P. Wriggers (2017) Finite strain response of crimped fibers under uniaxial traction: an analytical approach applied to collagen. Journal of the Mechanics and Physics of Solids, 98:429-453.
 M. Marino, M.I. Converse, K.L. Monson, P. Wriggers (2019) Molecular-level collagen damage explains softening and failure of arterial tissues: a quantitative interpretation of CHP data with a novel elasto-damage model. Journal of the Mechanical Behavior of Biomedical Materials, accepted for publication.
 M. Marino, G. Pontrelli, G. Vairo, P. Wriggers (2017) A chemo-mechano-biological formulation for the effects of biochemical alterations on arterial mechanics: the role of molecular transport and multiscale tissue remodeling. Journal of the Royal Society Interface 14:20170615.
Prof. Dr. Bernard Zeigler, University of Arizona
Why should we develop simulation models in pairs?
The conventional approach to model construction for simulation is to focus on a single model and follow a more or less structured development cycle. Why should we put in twice the time and effort to develop two models rather than one? The answer lies in the fact that like most greedy heuristics, short-sightedness at the beginning may be much more costly in the end. This talk champions the cause of the pairs-of-models approach. We show how this approach eventually leads to better results than initially attempting to construct a complex model, followed later by having to revert to a simpler model when increasing complexity makes progress hard to achieve. We show how pairs-of-models development can be supported by computational tools for relating structure and behavior between models. Benefits of pairs of models, and eventually families of models, include the ability to perform mutual cross-calibration, avoid the usual difficulties in harmonizing the underlying ontologies, and narrow the search for plausible parameter assignments.
Lecture as part of workshop "One simulation model is not enough!" - Link
Dr. Harald Kusch, University of Göttingen, Dr. Alexander Minges, University of Düsseldorf and Dr. Caterina Barillari, ETH Zürich
„Thementag Elektronische Laborbücher“, organized by SFB 1270 ELAINE, the IUK Wissenschaftsverbund and the Rostock University Library
Please klick here for details.
Prof. Dr. Michael Gelinsky, TU Dresden
Strontium-modified calcium phosphate cements for the therapy of osteoporosis-related bone fractures and defects
Strontium as divalent ion is used successfully as therapeutic in the systemic therapy of osteoporosis since many years. Therefore it is obvious that many researchers have tried to include strontium(II) in materials, developed for the healing of bone defects, especially those in osteoporotic patients. We have established a new and very easy method to modify a hydroxyapatite (HA)-forming, self-setting calcium phosphate bone cement (CPC) with Sr2+ ions and evaluated the physico-chemical and mechanical properties, ion release and the response of human mesenchymal stem cells (hMSC) as well as osteoclast-like cells in vitro. We could demonstrate both a stimulative effect on hMSC proliferation and osteogenic differentiation as well as a reduction of osteoclastic material degradation.
These advantageous properties were also confirmed in an animal study in which the strontium-modified CPC was implanted in a critical size femoral bone defect in osteoporotic rats.
Finally, this CPC in a pasty, ready-to-use formulation is also suitable for fabrication of macroporous scaffolds by means of extrusion 3D printing and we demonstrated the versatility of this approach for manufacturing of patient-specific bone scaffolds, biphasic constructs for defects at tissue interfaces and even for bioprinting applications.
Prof. Dr. Madeleine Lowery, University College Dublin
Multiscale Modelling of the Neuromuscular System for Closed Loop Deep Brain Stimulation
Deep brain stimulation (DBS) is an effective therapy for treating the symptoms of Parkinson’s disease. Despite its success, the mechanisms of DBS are not yet fully understood and there is a need to improve DBS to improve long-term stimulation across a wider patient population, limit side-effects, and extend stimulator battery life. Currently DBS operates in an ‘open-loop’ manner, with stimulus parameters empirically set and remaining fixed over time. The development of ‘closed-loop’ DBS systems, offer the possibility to continuously adjust stimulation parameters based on patient symptoms and side-effects. This offers to the potential to increase therapeutic efficacy while reducing side-effects, costs and energy. This talk will explore how computational modelling can be used to provide insight into the changes that occur within the human nervous system in Parkinson’s disease and how deep brain stimulation alters this behavior at the level of the individual cell and at the system level. Using the computational model, the ability of different closed-loop control systems to control biomarkers based on the local field potential recorded from the subthalamic nucleus are examined. Finally, preliminary results examining the response of the electrode tissue interface to in vivo chronic stimulation will be discussed.
Prof. Dr. Rüdiger Köhling, University of Rostock
EEG and rhythm generation, plus some remarks on the physical propagation of signals
The talk will address mechanisms of field potential generation in excitable tissues, as well as more specifically, current hypotheses on the physiological bases of EEG bands (a, b, q and d) and fast oscillations. In this context, the role of cortico-thalamic interactions vs. intracortical rhythm generation will be discussed. In addition, the talk will take the opportunity for a critical re-appraisal of mechanical wave propagation in neurons.
Prof. Dr. Thomas Heimburg, Niels Bohr Institute University of Copenhagen
The excitability of nerves and the role of anesthetics
It is a central paradigm in biology that excitatory events in cells are of purely electrical nature. The nervous impulse is attributed to the electrical activity of a class of proteins called voltage-gated ion channels. However, it is widely unknown that during the nerve pulse also the temperature, the thickness and the length of nerves change, i.e., properties that do not manifest themselves on the molecular scale. Furthermore, in contrast to expectations one finds no dissipation of energy in experiments on nerves. Many properties of nerve pulses rather resemble those of sound or solitons, respectively. Solitons are sound-pulses that travel without changes in shape and without dissipation of energy. The electrical pulses in classical electrophysiology and electromechanical solitons differ largely in their physical implications.
In this presentation we show that in the electromechanical approach, the excitability of the nerve membrane can be compared to the free energy difference between the liquid and the solid phase of the biomembrane. Anesthetics change this free energy difference due to melting point depression. This reduces the excitability of the nerve membrane and leads to an increase in stimulation threshold. We compare the theoretical experiment with the outcome of clinical experiments on the human median nerve and other nerve systems. We demonstrate that the electromechanical theory is able to provide a good understanding for anesthesia and its effect on nerve excitability.
Dr. Ilja Klebanov, Zuse Institute Berlin
Simultaneous parameter estimation for many patients
In systems medicine, we are often faced with parametrized models, where the patient-specific parameters have to be inferred from large data sets involving many patients. The natural approach would be to consider each patient separately, however, a lot of information can be gained by analyzing the data set as a whole. This concept of 'borrowing information' is the essence of so-called empirical Bayes methods, which build up an informative prior from the data before performing individual Bayesian inference for each patient. Guided by a simple example, we will discuss how this can be accomplished in a consistent way.
Prof. Dr. Volker Mehrmann, TU Berlin, Modelling, Simulation and Control of Constrained Multi-Physics Systems
Modelling, Simulation and Control of Constrained Multi-Physics Systems
Motivated from modeling modern energy transport networks, in particular those arising in coupling different physical domains, the energy based modeling framework of port-Hamiltonian systems is discussed. The classical port-Hamiltonian approach is systematically extended to constrained dynamical systems (partial-differential-algebraic equations). A new algebraically and geometrically defined system structure is derived, which has many nice mathematical properties. It is shown that this structure is invariant under Galerkin projections, changes of basis, and that a dissipation inequality holds. If such a system is controllable and observable then it is automatically stable and passive. Furthermore, the new representation is very robust to perturbations in the system structure. The advantages and the success of the new framework is illustrated by examples from gas transport, synchronization of power systems and the development of a new turbine.
We also discuss open problems associated with the new model approach. These include the adequate choice of time-integration methods that guarantee the dissipation inequality, the generation of such systems from pure input-output data, as well as good model reduction and optimal control techniques that make optimal use of the structure.
Dieter Scharnweber, TU Dresden, Institute of Materials Science, Max Bergmann Center of Biomaterials
Some like it sweet – from protein/glycosaminoglycan interactions to functional biomaterials
Numerous biological processes such as tissue formation, remodeling and healing are strongly influenced by the composition and the biochemical properties of the cellular microenvironment. Glycosaminoglycans (GAGs), as major component of the native extracellular matrix (ECM) can be chemically functionalized and thereby modified in their binding profiles, both for direct cell inter-action and for interaction with mediator proteins (e.g. growth factors). Thus GAGs and their derivatives are promising candidates for the design of functional biomaterials to control healing processes in healthy and health-compromised patients.
The lecture will present multidisciplinary studies aiming to improve our understanding on structure property relationships of GAG derivatives in their interaction with biological mediator proteins as well as on the biological effects of these interactions. This will be discussed exemplarily for key signaling molecules of healing processes in bone and skin.
Prominent effects are (i) anti-inflammatory, immunomodulatory properties towards macro¬pha¬ges/ dendritic cells, (ii) enhanced osteogenic differentiation of human mesenchymal stromal cells, (iii) al-tered differentiation of fibroblasts to myofibroblasts, (iv) reduced osteoclast activity and (v) im¬pro-ved osseointegration of dental implants in minipigs.
The resulting knowledge enables the consortium of our Transregio 67 for an advanced design of functional biomaterials to selectively control and promote healing processes as will be shown for bone and skin regeneration.
Prof. Dr. Lars Timmermann, Marburg and Prof. Dr. Gerd Kempermann, Dresden – DBS and adult neurogenesis - CRC 1270 ELAINE supported session as part of the 2018 Scientific meeting of the MDS Non-Motor PD Study Group; Universitätsplatz 1, free meeting registration for CRC members through the IRTG office, see https://ctnr.med.uni-rostock.de/parkinson2018-rostock/
María Angeles Péres, M2BE-Multiscale in Mechanical and Biological Engineering, Aragon Institute for Engineering Research – I3A, Aragón Institute of Health Sciences –IACS, University of Zaragoza, Zaragoza, Spain (firstname.lastname@example.org)
Multiscale modeling of bone mechanobiology: from cell proliferation and migration to bone remodeling simulations
Skeletal mechanobiology aims to discover how mechanical forces modulate morphological and structural fitness of the skeletal tissues – bone, cartilage, ligament and tendon . Mechanobiological models have been used to explain mechanoregulation in fracture healing, callus growth, distraction osteogeneis, bone ingrowth into porous implants and tissue engineering. The proliferation/migration of cells has been modelled by considering it to be analogous to diffusion. However, using a diffusion model to simulate cell dispersal means that proliferation and migration tend to create a smooth variation in cell density, but such a constraint is not physiological nor is it necessary if a more general random-walk model is used. Furthermore, random-walk models can simulate not only a preferred direction to migration but proliferation can also be explicitly modelled by multiplying cell numbers during dispersal, or several cell populations could be included simultaneously . A random-walk model was also used to simulate proliferation, migration and differentiation of adult muscle satellite cells . The model was validated with an invitro cell culture. Additionally, several examples where the random-walk model were used (mechanobiological simulations of tissue differentiation and cement infiltration within open-cell structures resembling osteoporotic bone) will be presented in this lecture.
In bone mechanobiology, bone cells respond directly or indirectly to the local strains engendered in their neighbourhood by external loading activity . This process is named bone remodeling, which is the continuous turnover of bone matrix and mineral by bone resorption and formation in the adult skeleton. The mechanical environment plays an essential role in the regulation of bone remodeling in intact bone and during bone repair. During decades, a great number of numerically implemented mathematical laws have been proposed, but most of them present different problems and stability, convergence or dependence of the initial conditions . Therefore, bone remodelling challenges, problematic and their applicability will be also presented in this lecture from a macroscale point of view.
Summarizing, previous computational models range from microscale to macroscale approaches. The development of a multiscale procedure can be used to deeply understand the mechanisms involved in bone mechanoregulation and/or bone diseases as osteoporosis.
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Dr. Stefan Lehner, TÜV SÜD Product Service
Rahmenbedingungen für die Zulassung von Medizinprodukten im Zuge der neuen Medizinprodukteverordnung (MDR)
Nach der Bekanntmachung der neuen amtlichen Fassung der Europäischen Medizinprodukte-Verordnung (Medical Device Regulation, MDR) am 05. Mai 2017 im EU-Amtsblatt trat diese am 25. Mai 2017 endgültig in Kraft. Die MDR ersetzt die beiden bestehenden Richtlinien MDD 93/42/EWG über Medizinprodukte (Medical Device Directive) sowie AIMD 90/385/EWG über aktive implantierbare Medizinprodukte (Active Implantable Medical Devices) und ist nach einer dreijährigen Übergangszeit ab dem 26. Mai 2020 verpflichtend anzuwenden.
Mit der Einführung der MDR werden die Anforderungen an den Inhalt der Technischen Dokumentation zukünftig deutlich detaillierter geregelt, auch ist der Inhalt von den Herstellern kontinuierlich zu aktualisieren. Beispielweise erhält jedes Medizinprodukt zur vereinfachten Rückverfolgbarkeit in Zukunft eine eindeutige Produktidentifizierungsnummer (UDI). Auch die Klassifizierung einiger Produkte ändert sich. So müssen eine Reihe von Implantaten, die bisher in Klasse IIb eingestuft waren, nun die Anforderungen von Klasse III Produkten erfüllen. Die MDR erfordert zudem eine strengere klinische Überwachung nach dem Inverkehrbringen der Medizinprodukte.
Prof. Dr. Sascha Spors, University of Rostock
The reproducibility of results is one of the main principles of the scientific method. The irreproducibility of a wide range of scientific results has recently drawn significant attention. Besides problems in the research methods themselves, results were often not reproducible since necessary supplementary material as protocols, data and implementations were not available. Another issue is the lacking availability of data for further research by third parties. In many cases only the published results are available to other researchers. Open Science focuses on the ease of access and reproducibility of scientific results. This contribution introduces the concept of reproducibility and addresses common concerns. Best practices for Open Science in acoustics research are discussed and illustrated at examples.
Dr. Tofail Syed, University of Limerick
Piezoelectricity in biological building blocks and potential physiological relevance
Piezoelectric materials produces electricity when deformed and vice versa. Hierarchical biological structures such as bone, tendon, wood and silk have been known to show weak piezoelectricity when compared to technical piezoelectric polymers and ceramics. Their physiological significance is still a matter of speculation. Synthetic polypeptides have recently shown significant piezoelectricity to merit their use in technical applications. Our group has successfully predicted and quantitatively measured piezoelectricity in synthetic bone mineral hydroxyapatite and globular protein lysozyme and amino acids. In this colloquium we will discuss fundamental principles of piezoelectricity and emphasise the need for considering fundamental building blocks to understand physiological significance of piezoelectricity.