ELAINE Lecture Series
Next Talk: Wed, 16.10.19: Prof. Dr. Birgit Liss
Location: LL&M Building, 18051 Rostock, Albert Einstein Str. 25, Room 110
Starting time: 14:00
Schedule of ELAINE Colloquia
Prof. Dr. Petra Schwille, MPI for Biochemistry, Martinsried
Prof. Dr. Ulrich Hofmann, University of Freiburg
Electroceuticals at the Gates! - Pre-clinical models to feed the next medical revolution
Prof. Dr. Christine Selhuber-Unkel, University of Kiel
Wed, 22.01.20: no public lecture due to Annual IRTG Member Meeting
Prof. Dr. Dr.h.c. Günther Deuschl, University of Kiel
Deep Brain Stimulation for Parkinson's Disease
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 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.
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 (email@example.com)
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.
 Van der Meulen and Huiskes (2002). J Biomech, 35: 401-414
 Pérez and Prendergast (2007). J Biomech, 40: 2244-2253
 Garijo et al. (2012). J Theor Biol, 314: 1-9
 Mellon and Tanner (2012). Int Mater Rev 57: 235-255
 Garijo et al. (2014). Comput Methods Appl Mech Engrg, 271: 253-268
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.