Project

SFB 1270 ELAINE - ELectrically Active ImplaNts

Goal: European populations are ageing rapidly. By the year 2060, every third person living in Germany will be older than 65. For this reason, the social and socio-economic relevance of regenerative therapies is clearly increasing. This holds particularly true for implants: the older the population grows, the more medical implants for various indication areas are required and the more often they have to be replaced during the course of therapy.

The research vision pursued by the CRC 1270 ELAINE (ELectrically Active ImplaNts) focuses on novel electrically active implants. Specifically, ELAINE addresses implants employed for the regeneration of bone and cartilage, and implants for deep brain stimulation to treat movement disorders.

Three central research objectives are a means to implement the research vision. The first objective is to establish innovative energy autonomous implants that allow a feedback-controlled electrical stimulation. A second objective is efficient systematic multi-scale studies to enable rapid progress in targeted implant improvements and patient-specific therapies. The third long-term objective is to analyse the basic mechanisms of electrical stimulation in bone, cartilage and brain, and to translate this knowledge in clinical practice.

Date: 1 July 2017

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Revathi Appali
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Increasing research has incorporated bioactive glass nanoparticles (BGN) and electric field (EF) stimula- tion for bone tissue engineering and regeneration applications. However, their interplay and the effects of different EF stimulation regimes on osteogenic differentiation of human mesenchymal stem cells (hMSC) are less investigated. In this study, we introduced EF with negligible magnetic field strength through a well-characterized transformer-like coupling (TLC) system, and applied EF disrupted (4/4) or consecutive (12/12) regime on type I collagen (Col) coatings with/without BGN over 28 days. Additionally, dexametha- sone was excluded to enable an accurate interpretation of BGN and EF in supporting osteogenic differ- entiation. Here, we demonstrated the influences of BGN and EF on collagen topography and maintaining coating stability. Coupled with the release profile of Si ions from the BGN, cell proliferation and calcium deposition were enhanced in the Col-BGN samples after 28 days. Further, osteogenic differentiation was initiated as early as d 7, and each EF regime was shown to activate distinct pathways. The disrupted (4/4) regime was associated with the BMP/Smad4 pathways that up-regulate Runx2/OCN gene expression on d 7, with a lesser effect on ALP activity. In contrast, the canonical Wnt/ β-Catenin signaling pathway acti- vated through mechanotransduction cues is associated with the consecutive (12/12) regime, with signifi- cantly elevated ALP activity and Sp7 gene expression reported on d 7. In summary, our results illustrated the synergistic effects of BGN and EF in different stimulation regimes on osteogenic differentiation that can be further exploited to enhance current bone tissue engineering and regeneration approaches.
Max Schröder
added a research item
Psychoacoustic experiments investigate the relation between a sound and its perception by humans. However, the experimental details are often insufficiently documented in scientific publications. Reproducing such investigations thus, often requires much effort due to missing details in the documentation of prerequisites and experimental set-up as well as unpublished research data and statistical analysis. By means of an ABX-listening test detecting the perceptual difference of correlated and uncorrelated measurement noise in binaural room impulse responses, we demonstrate how documentation and reproducibility of such experiments can be improved by technical approaches and methodological aspects. In particular, the documentation of the experiment including the hypothesis, the preparation, and the analysis is realized in an electronic laboratory notebook. Furthermore, the documentation can be used to create a documentation template for similar experiments in order to make them better comparable. Before the experiment, the statistical analysis is implemented and automated processes are set-up in order to evaluate new measurements. Finally, the data and the scripts with their documentation are published following the FAIR principles to ensure their re-usability.
Susanne Staehlke
added 2 research items
For intracellular calcium ions (Ca 2+) mobilization analysis by Calcium Imaging, a human osteoblast-like cell line MG-63 (ATCC ®, CRL1427™) were used [1-3]. The MG-63 cell line has similar characteristics in terms of morphological behavior, adhesion and signaling properties as primary human osteoblasts [3]. Cells were cultured at 37 °C in a humidified atmosphere (5% CO2) in Dulbecco's modified eagle medium (DMEM; Gibco) containing 10% fetal calf serum (FCS; PAA Laboratories) and 1% antibiotic (gentamicin, Ratiopharm GmbH) [1-3]. Cells in the near-confluent state (70-80%) were used for the corresponding in vitro experiments. Therefore, cells were washed with PBS, trypsinized with 0.05% trypsin/0.02% EDTA (PAA) for 5 min and then treated with medium to stop the reaction. After centrifugation, 2x10 6 cells / 2ml were incubated shaking in complete medium at 37°C for a complete independent experiment. For the method, 2.5x10 5 cells were stained per electrical stimulation setup (non-stimulated, 1 V 7.9 Hz, 1 V 20 Hz, 5 V 7.9 Hz or 5 V 20 Hz). First, a wash step was performed with PBS, and after centrifugation, sedimented cells were stained with a membrane-permeable calcium indicator fluo-3/AM (Life Technologies Corporation; 5 μM) in slightly hypotonic 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) buffer [1-3] shaking at 37°C. After incubation for 40 min, cells were centrifuged and then resuspended in 250 µl of isotonic HEPES. In a 12-well plate, 750 µl of isotonic HEPES was placed. Then the stained suspended cells were added, and immediately electrical stimulation by using IonOptix chamber was started under the LSM780 (Carl Zeiss). After 5 min of adhesion phase, the global calcium signal of the attaching cells was visualized using the inverted LSM 780 with a C Apochromat 40× water immersion objective. Fluo-3/AM dye was excited with the argon ion laser at 488 nm (emission at 515 nm). A full frame (512 x 512 pixels) at maximum pinhole aperture was evaluated using Zen2011 (black edition) software (Carl Zeiss) and "time series" mode. The first time series with electrical stimulation included 150 cycles each 2 s. After this time series (total electrical stimulation of 10 min), the electrical stimulation was stopped and a second time series without electrical stimulation was started.
Max Schröder
added a research item
Background Electronic Laboratory Notebooks (ELNs) are used to document experiments and investigations in the wet-lab. Protocols in ELNs contain a detailed description of the conducted steps including the necessary information to understand the procedure and the raised research data as well as to reproduce the research investigation. The purpose of this study is to investigate whether such ELN protocols can be used to create semantic documentation of the provenance of research data by the use of ontologies and linked data methodologies. Methods Based on an ELN protocol of a biomedical wet-lab experiment, a retrospective provenance model of the raised research data describing the details of the experiment in a machine-interpretable way is manually engineered. Furthermore, an automated approach for knowledge acquisition from ELN protocols is derived from these results. This structure-based approach exploits the structure in the experiment’s description such as headings, tables, and links, to translate the ELN protocol into a semantic knowledge representation. To satisfy the Findable, Accessible, Interoperable, and Reuseable (FAIR) guiding principles, a ready-to-publish bundle is created that contains the research data together with their semantic documentation. Results While the manual modelling efforts serve as proof of concept by employing one protocol, the automated structure-based approach demonstrates the potential generalisation with seven ELN protocols. For each of those protocols, a ready-to-publish bundle is created and, by employing the SPARQL query language, it is illustrated that questions about the processes and the obtained research data can be answered. Conclusions The semantic documentation of research data obtained from the ELN protocols allows for the representation of the retrospective provenance of research data in a machine-interpretable way. Research Object Crate (RO-Crate) bundles including these models enable researchers to easily share the research data including the corresponding documentation, but also to search and relate the experiment to each other.
Julius Zimmermann
added 2 research items
Electrical stimulation for application in tissue engineering and regenerative medicine has received increasing attention in recent years. A variety of stimulation methods, waveforms and amplitudes have been studied. However, a clear choice of optimal stimulation parameters is still not available and is complicated by ambiguous reporting standards. In order to understand underlying cellular mechanisms affected by the electrical stimulation, the knowledge of the actual prevailing field strength or current density is required. Here, we present a comprehensive digital representation, a digital twin, of a basic electrical stimulation device for the electrical stimulation of cells in vitro . The effect of electrochemical processes at the electrode surface was experimentally characterised and integrated into a numerical model of the electrical stimulation. Uncertainty quantification techniques were used to identify the influence of model uncertainties on relevant observables. Different stimulation protocols were compared and it was assessed if the information contained in the monitored stimulation pulses could be related to the stimulation model. We found that our approach permits to model and simulate the recorded rectangular waveforms such that local electric field strengths become accessible. Moreover, we could predict stimulation voltages and currents reliably. This enabled us to define a controlled stimulation setting and to identify significant temperature changes of the cell culture in the monitored voltage data. Eventually, we give an outlook on how the presented methods can be applied in more complex situations such as the stimulation of hydrogels or tissue in vivo .
The frequency-dependent behaviour of the dielectric properties of biological tissues in the frequency range below 1 kHz has been under debate since the past century. Here, we reanalyse the raw data of the main resource of the dielectric properties of biological tissues in impedance representation. Employing a Kramers-Kronig validity test and parameter estimation techniques, we can describe the data by two physical parametric models that correspond to opposing biophysical interpretations: on the one hand the data can be explained only by intrinsic tissue properties, but on the other hand evidence for electrode-specific effects can be found for all tissues under investigation. The first interpretation would justify the continued use of a parametric model comprising four Cole-Cole dispersions, which describe the dielectric properties from extremely low to very high frequencies. As an alternative that is in accordance with the second interpretation, we suggest to omit the slowest of the four dispersions in the model and increase the static conductivity to account for a frequency-independent conductivity below 1 kHz.
Konstantinos Spiliotis
added a research item
A large-scale computational model of the basal ganglia network and thalamus is proposed to describe movement disorders and treatment effects of deep brain stimulation (DBS). The model of this complex network considers three areas of the basal ganglia region: the subthalamic nucleus (STN) as target area of DBS, the globus pallidus, both pars externa and pars interna (GPe-GPi), and the thalamus. Parkinsonian conditions are simulated by assuming reduced dopaminergic input and corresponding pronounced inhibitory or disinhibited projections to GPe and GPi. Macroscopic quantities are derived which correlate closely to thalamic responses and hence motor programme fidelity. It can be demonstrated that depending on different levels of striatal projections to the GPe and GPi, the dynamics of these macroscopic quantities (synchronisation index, mean synaptic activity and response efficacy) switch from normal to Parkinsonian conditions. Simulating DBS of the STN affects the dynamics of the entire network, increasing the thalamic activity to levels close to normal, while differing from both normal and Parkinsonian dynamics. Using the mentioned macroscopic quantities, the model proposes optimal DBS frequency ranges above 130 Hz.
Konstantin Butenko
added a research item
Deep brain stimulation (DBS) is an established therapy for patients with Parkinson’s disease. In silico computer models for DBS allow to pre-select a set of potentially optimal stimulation parameters. If efficacious, they could further carry insight into the mechanism of action of DBS and foster the development of more efficient stimulation approaches. In recent years, the focus has shifted towards DBS-induced firing in myelinated axons, deemed particularly relevant for the external modulation of neural activity. We use the concept of pathway activation modeling, which incorporates advanced volume conductor models and anatomically authentic fiber trajectories to estimate DBS-induced action potential initiation in anatomically plausible pathways that traverse in close proximity to targeted nuclei. We apply the method on a retrospective dataset with the aim of providing a model-based prediction of clinical improvement following DBS (as measured by the motor part of the Unified Parkinson’s Disease Rating Scale). Based on differences in outcome and activation rates for two DBS protocols in a training cohort, we compute a theoretical 100% improvement profile and enhance it by analyzing the importance of profile matching for individual pathways. Finally, we validate the performance of our profile-based predictive model in a test cohort. As a result, we demonstrate the clinical utility of pathway activation modeling in the context of motor symptom alleviation in Parkinson’s patients treated with DBS.
Hans-E. Lange
added a research item
Instrumented implants can improve the clinical outcome of total hip replacements (THRs). To overcome the drawbacks of external energy supply and batteries, energy harvesting is a promising approach to power energy-autonomous implants. Therefore, we recently presented a new piezoelectric-based energy harvesting concept for THRs. In this study, the performance of the proposed energy harvesting system was numerically and experimentally investigated. First, we numerically reproduced our previous results for the physiologically based loading situation in a simplified setup. Thereafter, this configuration was experimentally realised by the implantation of a functional model of the energy harvesting concept into an artificial bone segment. Additionally, the piezoelectric element alone was investigated to analyse the predictive power of the numerical model. We measured the generated voltage for a load profile for walking and calculated the power output. The maximum power for the directly loaded piezoelectric element and the functional model were 28.6 and 10.2 µW, respectively. Numerically, 72.7 µW was calculated. The curve progressions were qualitatively in good accordance with the numerical data. The deviations were explained by sensitivity analysis and model simplifications, e.g., material data or lower acting force levels by malalignment and differences between virtual and experimental implantation. The findings verify the feasibility of the proposed energy harvesting concept and form the basis for design optimisations with increased power output.
Yogesh Deepak Bansod
added a research item
The piezoelectricity of bone is known to play a crucial role in bone adaptation and remodeling. The application of an external stimulus such as mechanical strain or electric field has the potential to enhance bone formation and implant osseointegration. Therefore, in the present study, the objective is to investigate bone remodeling under electromechanical stimulation as a step towards establishing therapeutic strategies. For the first time, piezoelectric bone remodeling in the human proximal tibia under electro-mechanical loads was analyzed using the finite element method in an open-source framework. The predicted bone density distributions were qualitatively and quantitatively assessed by comparing with the computed tomography (CT) scan and the bone mineral density (BMD) calculated from the CT, respectively. The effect of model parameters such as uniform initial bone density and reference stimulus on the final density distribution was investigated. Results of the parametric study showed that for different values of initial bone density the model predicted similar but not identical final density distribution. It was also shown that higher reference stimulus value yielded lower average bone density at the final time. The present study demonstrates an increase in bone density as a result of electrical stimulation. Thus, to minimize bone loss, for example, due to physical impairment or osteoporosis, mechanical loads during daily physical activities could be partially replaced by therapeutic electrical stimulation.
Yogesh Deepak Bansod
added a research item
Presently, total joint replacement (TJR) is a standard procedure in orthopedic surgery. Adequate osseointegration of the implant components still remains a clinical issue. However, active stimulation of bone tissue to enhance bone ongrowth at the implant surfaces has not been widely investigated so far. For the last several years, invasive electromagnetically induced osseotherapy has been employed in clinical practice, e.g., for the treatment of avascular necrosis, femoral neck fractures, and pseudarthrosis. In the present study, the approach of exploiting the electric stimulation effect was transferred to the field of TJR. Therefore, a commercially available total hip stem was instrumented with an electrode on its surface in order to generate an electric field supporting the regeneration of the surrounding bone tissue. The objective was to conduct numerical simulations validated by experimental investigations as a proof of concept for an instrumented electro-stimulative total hip stem. The results revealed that the calculated electric field around a total hip stem fulfills the requirements to stimulate adjacent bone tissue when using clinically applied electric voltages. The derived numerical and experimental data of electric potentials and corresponding electric fields are encouraging for the implementation of active electrical stimulation in uncemented total hip stems to enhance their osseointegration.
Kai Budde
added a research item
Endocytosis plays a pivotal regulatory role in canonical WNT signaling. Internalization of the LRP6 receptor complex can either promote or attenuate canonical WNT signaling, depending on the employed internalization pathway. A detailed analysis of the mechanism of LRP6 internalization and its temporal regulation is crucial to understand the different cellular responses to WNT stimulation under varying conditions and in various cell types. Here, we elucidate the mechanisms involved in the internalization of LRP6 and (re-)evaluate the existing, partly contradicting theories on the regulation of LRP6 receptor internalization. Therefore, we utilize a computational approach that aims at finding a set of mechanisms that accounts for the temporal dynamics of LRP6 receptor internalization upon WNT stimulation. Starting with a simple simulation model, we successively extend and probe the model's behavior based on quantitative measurements. The final model confirms that LRP6 internalization is clathrin-independent in vertebrates and not restricted to microdomains and that the signalosome formation delays the LRP6 internalization within the microdomains. These findings partly revise the current understanding of LRP6 internalization in vertebrates.
Hans-E. Lange
added a research item
Instrumented implants are a promising approach to further improve the clinical outcome of total hip arthroplasties. For the integrated sensors or active functions, an electrical power supply is required. Energy harvesting concepts can provide autonomous power with unlimited lifetime and are independent from external equipment. However, those systems occupy space within the mechanically loaded total hip replacement and can decrease the life span due to fatigue failure in the altered implant. We previously presented a piezoelectric energy harvesting system for an energy-autonomous instrumented total hip stem that notably changes the original implant geometry. The aim of this study was to investigate the remaining structural fatigue failure strength of the metallic femoral implant component in a worst-case scenario. Therefore, the modified hip stem was tested under load conditions based on ISO 7206-4:2010. The required five million cycles were completed twice by all samples (n = 3). Additionally applied cycles with incrementally increased load levels up to 4.7 kN did not induce implant failure. In total, 18 million cycles were endured, outperforming the requirements of the ISO standard. Supplementary finite element analysis was conducted to determine stress distribution within the implant. A high stress concentration was found in the region of modification. The stress level showed an increase compared to the previously evaluated physiological loading situation and was close to the fatigue data from the literature. The stress concentration factor compared to the original geometry amounted to 2.56. The assessed stress level in accordance with the experimental fatigue testing can serve as a maximum reference value for further implant design modifications and optimisations.
Thomas Distler
added a research item
This work explored 3D bioplotting to mimic the intrinsic hierarchical structure of natural articular cartilage. Alginate dialdehyde-gelatine (ADA-GEL) was used as a hydrogel ink to create hierarchically ordered scaffolds. In comparison to previously reported ADA-GEL compositions, we introduce a modified formulation featuring increased amounts of thermally modified gelatine. Gelatine was degraded by hydrolysis which resulted in tailorable printability characteristics further substantiated by rheological analysis. ADA(3.75%w/v)-GEL(7.5%w/v) with gelatine modified at 80 °C for 3 h could be printed in hierarchical complex structures reaching scaffold heights of over 1 cm. The hierarchical structure of the scaffolds was confirmed via µ-CT analysis. To examine mechanical properties as well as the suitability of the hydrogel as a proper matrix for cell seeding and encapsulation, nanoindentation was performed. Elastic moduli in the range of ∼ 5 kPa were measured. Gelatine heat pre-treatment resulted in modifiable mechanical and rheological characteristics of ADA-GEL. In summary, this study demonstrates the possibility to enhance the printability of ADA-GEL hydrogels to fabricate hierarchical scaffold structures with shape stability and fidelity, without the necessity to change the initial hydrogel chemistry by the use of additives or crosslinkers, providing a valuable approach for fabrication of designed scaffolds for cartilage tissue engineering.
Hans-E. Lange
added a research item
Energy harvesting is a promising approach to power novel instrumented implants that have passive sensory functions or actuators for therapeutic measures. We recently proposed a new piezoelectric concept for energy harvesting in total hip replacements. The mechanical implant safety and the feasibility of power generation were numerically demonstrated. However, the power output for the chosen piezoelectric element was low. Therefore, we investigated in the present study different geometry variants for an increased power output for in vivo applications. Using the same finite element model, we focused on new, customised piezoelectric element geometries to optimally exploit the available space for integration of the energy harvesting system, while maintaining the mechanical safety of the implant. The result of our iterative design study was an increased power output from 29.8 to 729.9 µW. This amount is sufficient for low-power electronics.
Simone Krüger
added 2 research items
The three‐dimensional structural investigation of soft tissue samples under near physiological conditions is a challenging task as most established techniques require embedding, staining or cutting the samples, or are limited in penetration depth without further samples processing. These sample manipulations can either induce artefacts or results in a tremendous workload by, e.g. the preparation of multiple two‐dimensional images to retrieve the full volume information. However, a non‐invasive technique allowing to image the soft tissue in three‐dimensional fashion is propagation‐based phase contrast computed tomography. Within this study, we explore the unique properties of this method to assess the three‐dimensional distribution and size of human chondrocytes within collagen scaffolds in a liquid environment without embedding. In order to seek if the identification of differences in cell distribution is possible, we have seeded human cartilage cells on collagen scaffolds that were either unstimulated or stimulated by alternating electric fields for seven days. Analysis of the three‐dimensional cell distributions reveals that the migration depth into the collagen scaffold of the chondrocytes is nearly doubled along with the total number of observable cells due to the presence of an applied electric field. Further analysis shows that no specific size of the chondrogenic cells is observable but rather a general increase of the cell sizes. Our results indicate that propagation‐based phase contrast computed tomography is a suitable tool to determine the three‐dimensional distribution of cells within a soft three‐dimensional biomaterial investigated under aqueous conditions. Moreover, this approach allows to visualize the effects of electric field application on cell migration and orientation in three‐dimensional scaffolds. This article is protected by copyright. All rights reserved.
In cell-based therapies for cartilage lesions, the main problem is still the formation of fibrous cartilage, caused by underlying de-dedifferentiation processes ex vivo. Biophysical stimulation is a promising approach to optimize cell-based procedures and to adapt them more closely to physiological conditions. The occurrence of mechano-electrical transduction phenomena within cartilage tissue is physiological and based on streaming and diffusion potentials. The application of exogenous electric fields can be used to mimic endogenous fields and, thus, support the differentiation of chondrocytes in vitro. For this purpose, we have developed a new device for electrical stimulation of chondrocytes, which operates on the basis of capacitive coupling of alternating electric fields. The reusable and sterilizable stimulation device allows the simultaneous use of 12 cavities with independently applicable fields using only one main supply. The first parameter settings for the stimulation of human non-degenerative chondrocytes, seeded on collagen type I elastin-based scaffolds, were derived from numerical electric field simulations. Our first results suggest that applied alternating electric fields induce chondrogenic re-differentiation at the gene and especially at the protein level of human de-differentiated chondrocytes in a frequency-dependent manner. In future studies, further parameter optimizations will be performed to improve the differentiation capacity of human cartilage cells.
Yogesh Deepak Bansod
added a research item
Bone tissue exhibits piezoelectric properties and thus is capable of transforming mechanical stress into electrical potential. Piezoelectricity has been shown to play a vital role in bone adaptation and remodelling processes. Therefore, to better understand the interplay between mechanical and electrical stimulation during these processes, strain-adaptive bone remodelling models without and with considering the piezoelectric effect were simulated using the Python-based open-source software framework. To discretise numerical attributes, the finite element method (FEM) was used for the spatial variables and an explicit Euler scheme for the temporal derivatives. The predicted bone apparent density distributions were qualitatively and quantitatively evaluated against the radiographic scan of a human proximal femur and the bone apparent density calculated using a bone mineral density (BMD) calibration phantom, respectively. Additionally, the effect of the initial bone density on the resulting predicted density distribution was investigated globally and locally. The simulation results showed that the electrically stimulated bone surface enhanced bone deposition and these are in good agreement with previous findings from the literature. Moreover, mechanical stimuli due to daily physical activities could be supported by therapeutic electrical stimulation to reduce bone loss in case of physical impairment or osteoporosis. The bone remodelling algorithm implemented using an open-source software framework facilitates easy accessibility and reproducibility of finite element analysis made.
Thomas Distler
added a research item
Electroactive hydrogels can be used to influence cell response and maturation by electrical stimulation. However, hydrogel formulations which are 3D printable, electroactive, cytocompatible, and allow cell adhesion, remain a challenge in the design of such stimuli-responsive biomaterials for tissue engineering. Here, a combination of pyrrole with a high gelatin-content oxidized alginate-gelatin (ADA-GEL) hydrogel is reported, offering 3D-printability of hydrogel precursors to prepare cytocompatible and electrically conductive hydrogel scaffolds. By oxidation of pyrrole, electroactive polypyrrole:polystyrenesulfonate (PPy:PSS) is synthesized inside the ADA-GEL matrix. The hydrogels are assessed regarding their electrical/mechanical properties, 3D-printability, and cytocompatibility. It is possible to prepare open-porous scaffolds via bioplotting which are electrically conductive and have a higher cell seeding efficiency in scaffold depth in comparison to flat 2D hydrogels, which is confirmed via multiphoton fluorescence microscopy. The formation of an interpenetrating polypyrrole matrix in the hydrogel matrix increases the conductivity and stiffness of the hydrogels, maintaining the capacity of the gels to promote cell adhesion and proliferation. The results demonstrate that a 3D-printable ADA-GEL can be rendered conductive (ADA-GEL-PPy:PSS), and that such hydrogel formulations have promise for cell therapies, in vitro cell culture, and electrical-stimulation assisted tissue engineering.
Thomas Distler
added a research item
3D-printing technologies, such as biofabrication, capitalize on the homogeneous distribution and growth of cells inside biomaterial hydrogels, ultimately aiming to allow for cell differentiation, matrix remodeling, and functional tissue analogues. However, commonly, only the mechanical properties of the bioinks or matrix materials are assessed, while the detailed influence of cells on the resulting mechanical properties of hydrogels remains insufficiently understood. Here, we investigate the properties of hydrogels containing cells and spherical PAAm microgel beads through multi-modal complex mechanical analyses in the small- and large-strain regimes. We evaluate the individual contributions of different filler concentrations and a non-fibrous oxidized alginate-gelatin hydrogel matrix on the overall mechanical behavior in compression, tension, and shear. Through material modeling, we quantify parameters that describe the highly nonlinear mechanical response of soft composite materials. Our results show that the stiffness significantly drops for cell- and bead concentrations exceeding four million per milliliter hydrogel. In addition, hydrogels with high cell concentrations (≥6 mio ml-1) show more pronounced material nonlinearity for larger strains and faster stress relaxation. Our findings highlight cell concentration as a crucial parameter influencing the final hydrogel mechanics, with implications for microgel bead drug carrier-laden hydrogels, biofabrication, and tissue engineering.
Wiebke Radlof
added 2 research items
Investigating the mechanical behavior is an important point for evaluating the mechanical reliability of additively manufactured (AM) lattice structures. First, the lattice structures were experimentally tested under compression loading. In order to identify the local damage behavior and visualize local strains, digital image correlation (DIC) was used in situ. Additionally, compression tests were numerically simulated with Abaqus, applying the Johnson‐Cook failure model. The numerical results were compared and validated with the experimental data. Moreover, manufacturing‐related imperfections and their influence on the structural behavior were analyzed and taken into account in the numerical simulations.
The present study aims to carry out an experimental, analytical and numerical investigation of the monotonic and fatigue performance of electron beam melted Ti-6Al-4V structures. Therefore, tensile tests, multiple step tests and strain-life tests were performed on machined EBM Ti-6Al-4V solid samples. An elastic-plastic material model in combination with a numerical damage model was examined according to the experimental tensile tests. Analytical models proposed by Ramberg and Osgood as well as Coffin and Manson were obtained to describe the cyclic stress-strain curves and strain-life curves, respectively. The fracture surfaces of the tested samples and the influence of different build directions were analyzed. A prediction of the static and fatigue material properties is of particular importance e.g. for the safe application of additively manufactured load-bearing implant structures. Based on the determined analytical and numerical models, the material and product behavior of complex electron beam melted structures under cyclic loading and fatigue life determination can be investiagted in the early stages of the product development process.
Max Schröder
added a research item
The documentation of wet-lab experiments is essential for the reproducibility of experimental investigations and their results. The semantic representation of such documentation in a machine understandable format allows the implementation of automated understanding and comparison. Objective of this study is to investigate whether a semantic model can be created from the information available in the protocols from the wet-lab. By analysing a protocol from a biomedical wet-lab experiment, we demonstrate that Electronic Laboratory Notebooks could serve as a mechanism for the in-situ knowledge acquisition about experimental investigations. The protocol and the model is available at: https://github.com/m6121/Semantic-Modelling-CA-Imaging
Revathi Appali
added 2 research items
Sensorineural deafness is caused by the loss of peripheral neural input to the auditory nerve, which may result from peripheral neural degeneration and/or a loss of inner hair cells. Provided spiral ganglion cells and their central processes are patent, cochlear implants can be used to electrically stimulate the auditory nerve to facilitate hearing in the deaf or severely hard-of-hearing. Neural degeneration is a crucial impediment to the functional success of a cochlear implant. The present, first-of-its-kind two-dimensional finite-element model investigates how the depletion of neural tissues might alter the electrically induced transmembrane potential of spiral ganglion neurons. The study suggests that even as little as 10% of neural tissue degeneration could lead to a disproportionate change in the stimulation profile of the auditory nerve. This result implies that apart from encapsulation layer formation around the cochlear implant electrode, tissue degeneration could also be an essential reason for the apparent inconsistencies in the functionality of cochlear implants.
Thomas Distler
added a research item
The mechanical behavior of cartilage tissue plays a crucial role in physiological mechanotransduction processes of chondrocytes and pathological changes like osteoarthritis. Therefore, intensive research activities focus on the identification of implant substitute materials that mechanically mimic the cartilage extracellular matrix. This, however, requires a thorough understanding of the complex mechanical behavior of both native cartilage and potential substitute materials to treat cartilage lesions. Here, we perform complex multi-modal mechanical analyses of human articular cartilage and two surrogate materials, commercially available ChondroFillerliquid, and oxidized alginate-gelatin (ADA-GEL) hydrogels. We show that all materials exhibit nonlinearity and compression-tension asymmetry. However, while hyaline cartilage yields higher stresses in tension than in compression, ChondroFillerliquid and ADA-GEL exhibit the opposite trend. These characteristics can be attributed to the materials’ underlying microstructure: Both cartilage and ChondroFillerliquid contain fibrillar components, but the latter constitutes a bi-phasic structure, where the 60% nonfibrillar hydrogel proportion dominates the mechanical response. Of all materials, ChondroFillerliquid shows the most pronounced viscous effects. The present study provides important insights into the microstructure-property relationship of cartilage substitute materials, with vital implications for mechanically-driven material design in cartilage engineering. In addition, we provide a data set to create mechanical simulation models in the future. This article is available under the Creative Commons CC-BY-NC-ND 4.0 license and permits non-commercial use of the work as published, without adaptation or alteration provided the work is fully attributed.
Thomas Distler
added a research item
Cartilage regeneration is a clinical challenge. In recent years, hydrogels have emerged as implantable scaffolds in cartilage tissue engineering. Similarly, electrical stimulation has been employed to improve matrix synthesis of cartilage cells, and thus to foster engineering and regeneration of cartilage tissue. The combination of hydrogels and electrical stimulation may pave the way for new clinical treatment of cartilage lesions. To find the optimal electric properties of hydrogels, theoretical considerations and corresponding numerical simulations are needed to identify well-suited initial parameters for experimental studies. We present the theoretical analysis of a hydrogel in a frequently used electrical stimulation device for cartilage regeneration and tissue engineering. By means of equivalent circuits, finite element analysis, and uncertainty quantification, we elucidate the influence of the geometric and dielectric properties of cell-seeded hydrogels on the capacitive-coupling electrical field stimulation. Moreover, we discuss the possibility of cellular organisation inside the hydrogel due to forces generated by the external electric field. The introduced methodology is easily reusable by other researchers and allows to directly develop novel electrical stimulation study designs. Thus, this study paves the way for the design of future experimental studies using electrically conductive hydrogels and electrical stimulation for tissue engineering. Julius Zimmermann et al 2020 molecules 25(20) 4759 | https://doi.org/10.3390/molecules25204750 | This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
Hans-E. Lange
added a research item
To improve the clinical outcome of total hip replacements (THRs), instrumented implants with sensory functions for implant monitoring and diagnostics or actuators for therapeutic measures are a promising approach. Therefore, an adequate energy source is needed. Batteries and external power supplies bring shortcomings e.g. limited lifetime or dependency on external equipment. Energy harvesting has the clear benefit of providing continuous and independent power for fully autonomous implants. Our present study evaluates by means of finite element analysis (FEA) the capabilities of a concept of a piezoelectric energy harvesting system (ring shaped multilayer piezoelectric element of 5 mm diameter and 2.5 mm height) integrated in a femoral hip stem. The deformations from a modified load-bearing implant are used to generate electric power for various instrumentation purposes. Besides the expected amount of converted energy, the influence on the stress distribution of the instrumented implant is analysed. The results show that the local stress increase for the modified implant geometry does not exceed the stress of the original reference model. The maximum generated open circuit voltage of 11.9 V can be processed in standard energy harvesting circuitry whereas an average power output amounts up to 8.1 µW. In order to increase the electric power in an upcoming design optimization, a sensitivity analysis is performed to identify the most important influencing parameters with regard to power output and implant safety.
Revathi Appali
added 2 research items
Mesenchymal stem cell dynamics involves cell proliferation and cell differentiation into cells of distinct functional type, such as osteoblasts, adipocytes, or chondrocytes. Electrically active implants influence these dynamics for the regeneration of the cells in damaged tissues. How applied electric field influences processes of individual stem cells is a problem mostly unaddressed. The mathematical approaches to study stem cell dynamics have focused on the stem cell population as a whole, without resolving individual cells and intracellular processes. In this paper, we present a theoretical framework to describe the dynamics of a population of stem cells, taking into account the processes of the individual cells. We study the influence of the applied electric field on the cellular processes. We test our mean-field theory with the experiments from the literature, involving \emph{in vitro} electrical stimulation of stem cells. We show that a simple model can quantitatively describe the experimentally observed time-course behavior of the total number of cells and the total alkaline phosphate activity in a population of mesenchymal stem cells. Our results show that the stem cell differentiation rate is dependent on the applied electrical field, confirming published experimental findings. Moreover, our analysis supports the cell density-dependent proliferation rate. Since the experimental results are averaged over many cells, our theoretical framework presents a robust and sensitive method for determining the effect of applied electric fields at the scale of an individual cell. These results indicate that the electric field stimulation may be effective in promoting bone regeneration by accelerating osteogenic differentiation.
Objective: Measuring neuronal cell activity using microelectrode arrays reveals a great variety of derived signal shapes within extracellular recordings. However, possible mechanisms responsible for this variety have not yet been entirely determined, which might hamper any subsequent analysis of the recorded neuronal data. Methods: To investigate this issue, we propose a computational model based on the finite element method describing the electrical coupling between an electrically active neuron and an extracellular recording electrode in detail. This allows for a systematic study of possible parameters that may play an essential role in defining or altering the shape of the measured electrode potential. Results: Our results indicate that neuronal geometry, neurite structure, as well as the actual pathways of input potentials that evoke action potential generation, have a significant impact on the shape of the resulting extracellular electrode recording and explain most of the known variations of signal shapes. Conclusion: The presented models offer a comprehensive insight into the effect of geometrical and morphological factors on the resulting electrode signal. Significance: Computational modeling complemented with experimental measurements shows much promise to yield meaningful insights into the electrical activity of a neuronal network.
Abdul Razzaq Farooqi
added a research item
Background and objective: The self-repair capability of articular cartilage is limited because of non-vascularization and low turnover of its extracellular matrix. Regenerating hyaline cartilage remains a significant clinical challenge as most non-surgical and surgical treatments provide only mid-term relief. Eventually, further pain and mobility loss occur for many patients in the long run due to further joint deterioration. Repair of articular cartilage tissue using electroactive scaffolds and biophysical stimuli like electrical and osmotic stimulation may have the potential to heal cartilage defects occurring due to trauma, osteoarthritis, or sport-related injuries. Therefore, the focus of the current study is to present a computational model of electroactive hydrogels for the cartilage-tissue repair as a first step towards an optimized experimental design. Methods: The multiphysics transport model that mainly includes the Poisson-Nernst-Planck equations and the mechanical equation is used to find the electrical stimulation response of the polyelectrolyte hydrogels. Based upon this, a numerical model on electromechanics of electroactive hydrogels seeded with chondrocytes is presented employing the open-source software FEniCS, which is a Python library for finite-element analysis. Results: We analyzed the ionic concentrations and electric potential in a hydrogel sample and the cell culture medium, the osmotic pressure created due to ionic concentration variations and the resulting hydrogel displacement. The proposed mathematical model was validated with examples from literature. Conclusions: The presented model for the electrical and osmotic stimulation of a hydrogel sample can serve as a useful tool for the development and analysis of a cartilaginous scaffold employing electrical stimulation. By analyzing various parameters, we pave the way for future research on a finer scale using open-source software.
Thomas Distler
added a research item
Mimicking the mechanical properties of native human tissues is one key route in tissue engineering. However, the successful creation of functional tissue equivalents requires the comprehensive understanding of the complex and nonlinear mechanical properties of both native tissues and biomaterials. Here, we demonstrate that it is possible to replicate the complex mechanical behavior of soft tissues, exemplary shown for porcine brain tissue, under multiple loading conditions, compression, tension, and torsional shear, through simple blends of alginate and gelatin hydrogels. Alginate exhibits a pronounced compression-tension asymmetry and a nonlinear behavior, while gelatin shows an almost linear response. Blended together, alginate-gelatin (ALG-GEL) hydrogels can resemble the characteristic nonlinear, conditioning, and compression-tension-asymmetric behavior of brain tissue. We demonstrate that hydrogel concentration and incubation effectively tune the stiffness and loading-mode-specific stress relaxation behavior. The stiffness increases with increasing hydrogel concentration and decreases with increasing incubation time. In addition, we observe slower stress relaxation after long incubation times. Our systematic approach highlights the importance of single component, multi-modal mechanical analysis of hydrogels to understand the distinct structure-mechanics relation of each hydrogel component to eventually mimic the response of native tissues. The presented dataset will allow for the structurally derived compositional design of hydrogels for a broad variety of tissue engineering applications.
Max Schröder
added a research item
In this study, we propose a new open-source simulation platform that comprises computer-aided design and computer-aided engineering tools for highly automated evaluation of electric field distribution and neural activation during Deep Brain Stimulation (DBS). It will be shown how a Volume Conductor Model (VCM) is constructed and examined using Python-controlled algorithms for generation, discretization and adaptive mesh refinement of the computational domain, as well as for incorporation of heterogeneous and anisotropic properties of the tissue and allocation of neuron models. The utilization of the platform is facilitated by a collection of predefined input setups and quick visualization routines. The accuracy of a VCM, created and optimized by the platform, was estimated by comparison with a commercial software. The results demonstrate no significant deviation between the models in the electric potential distribution. A qualitative estimation of different physics for the VCM shows an agreement with previous computational studies. The proposed computational platform is suitable for an accurate estimation of electric fields during DBS in scientific modeling studies. In future, we intend to acquire SDA and EMA approval. Successful incorporation of open-source software, controlled by in-house developed algorithms, provides a highly automated solution. The platform allows for optimization and uncertainty quantification (UQ) studies, while employment of the open-source software facilitates accessibility and reproducibility of simulations.
Thomas Distler
added a research item
Critical size bone defects are regularly treated by auto- and allograft transplantation. However, such treatments require to harvest bone from patient donor sites, with often limited tissue availability or risk of donor site morbidity. Not requiring bone donation, three-dimensionally (3D) printed implants and biomaterial-based tissue engineering (TE) strategies promise to be the next generation therapies for bone regeneration. We present here polylactic acid (PLA)-bioactive glass (BG) composite scaffolds manufactured by fused deposition modeling (FDM), involving the fabrication of PLA-BG composite filaments which are used to 3D print controlled open-porous and osteoinductive scaffolds. We demonstrated the printability of PLA-BG filaments as well as the bioactivity and cytocompatibility of PLA-BG scaffolds using pre-osteoblast MC3T3E1 cells. Gene expression analyses indicated the beneficial impact of BG inclusions in FDM scaffolds regarding osteoinduction, as BG inclusions lead to increased osteogenic differentiation of human adipose-derived stem cells in comparison to pristine PLA. Our findings confirm that FDM is a convenient additive manufacturing technology to develop PLA-BG composite scaffolds suitable for bone tissue engineering. Front. Bioeng. Biotechnol., 24 June 2020 | https://doi.org/10.3389/fbioe.2020.00552 The article has been published open-access under the CC BY 4.0 creative commons license | https://creativecommons.org/licenses/by/4.0/
Max Schröder
added 2 research items
Thorough documentation of biological experiments is necessary for their replicability. This becomes even more evident when individual steps of in vitro wet-lab experiments are to be incorporated into computer simulation models. In the highly interdisciplinary field of electrical stimulation of biological cells, not only biological but also physical aspects play a crucial role. Simulations may help to identify parameters that influence cells and thereby reveal new insights into mechanisms of the cell biological system. However, missing or misleading documentation of the electrical stimulation step within wet-lab experiments may lead to discrepancies between reported and simulated electrical quantities. In addition, this threatens the replicability of electrical stimulation experiments. Thus, we argue that a minimal set of information is needed to enable a translation of electrical stimulation experiments of biological cells into computer simulation experiments and to support replicability. This set includes detailed information about the electronic devices and components, their set-up as well as the applied stimulus and shall be integrated into an existing guideline for cell biological experiments. Ideally, the documentation should also contain measured properties of the cellular and experimental environment. Furthermore, a realization of our proposed documentation requirements within electronic lab notebooks may provide a crucial step toward a more seamless integration of wet-lab data into simulations. Based on two exemplary studies, we demonstrate the relevance of our claim.
The analysis of digital data plays an essential role in today's research investigations. Literate programming techniques interweave documentation and source code in order to provide a comprehensive view on the research process. Jupyter Notebooks are a recent mechanism of literate programming that furthermore enables the execution of the source code in order to integrate also the results. Thus, they provide a promising method of encoding reproducible research investigations. This chapter introduces the basic concepts of Jupyter Notebooks by employing a biomedical running example. Furthermore, aspects of preservation, readability, and executability as well as sharing of the experiments are discussed by proposing example workflows.
Thomas Distler
added a research item
Hydrogels that allow the successful long-term in vitro culture of cell-biomaterial systems to enable the maturation of tissue engineering constructs are highly relevant in regenerative medicine. Naturally derived polysaccharide-based hydrogels promise to be one material group with enough versatility and chemical functionalization capability to tackle the challenges associated with long-term cell culture. We report a marine derived oxidized alginate, alginate di-aldehyde (ADA), and gelatine (GEL) system (ADA-GEL), which is crosslinked via ionic (Ca2+) and enzymatic (microbial transglutaminase, mTG) interaction to form dually crosslinked hydrogels. The crosslinking approach allowed to tailor the stiffness of the hydrogels in a wide range (from < 5 kPa to 120 kPa), without altering the initial hydrogel chemistry. It was possible to control the degradation behaviour of the hydrogels to be stable for up to 30 days of incubation. Increasing concentrations of mTG crosslinker solutions allowed to tune the degradation behaviour of the ADA-GEL hydrogels from fast (< 7 days) to moderate (14 days) and slow (> 30 days) degradation kinetics. The cytocompatibility of mTG crosslinked ADA-GEL was assessed via NIH-3T3 fibroblasts and ATDC-5 mouse teratocarcinoma cells. Both cell types showed highly increased cellular attachment on mTG crosslinked ADA-GEL in comparison to Ca2+ crosslinked hydrogels. In addition, ATDC-5 cells showed a higher proliferation on mTG crosslinked ADA-GEL hydrogels in comparison to tissue culture polystyrene control substrates. Further, the attachment of human umbilical vein endothelial cells (HUVEC) on ADA-GEL (+) mTG was confirmed, proving the suitability of mTG+Ca2+ crosslinked ADA-GEL for several cell types. Summarizing, a promising platform to control the properties of ADA-GEL hydrogels is presented, with potential to be applied in long-term cell culture investigations such as cartilage, bone, and blood vessel-engineering, as well as for biofabrication approaches.
Revathi Appali
added a research item
Mesenchymal stem cell dynamics involves cell proliferation and cell differentiation into cells of distinct functional type, such as osteoblasts, adipocytes, or chondrocytes. Electrically active implants influence these dynamics for the regeneration of the cells in damaged tissues. How applied electric field influences processes of individual stem cells is a problem mostly unaddressed. The mathematical approaches to study stem cell dynamics have focused on the stem cell population as a whole, without resolving individual cells and intracellular processes. In this paper, we present a theoretical framework to describe the dynamics of a population of stem cells, taking into account the processes of the individual cells. We study the influence of the applied electric field on the cellular processes. We test our mean-field theory with the experiments from the literature, involving in vitro electrical stimulation of stem cells. We show that a simple model can quantitatively describe the experimentally observed time-course behavior of the total number of cells and the total alkaline phosphate activity in a population of mesenchymal stem cells. Our results show that the stem cell differentiation rate is dependent on the applied electrical field, confirming published experimental findings. Moreover, our analysis supports the cell density-dependent proliferation rate. Since the experimental results are averaged over many cells, our theoretical framework presents a robust and sensitive method for determining the effect of applied electric fields at the scale of the individual cell. These results indicate that the electric field stimulation may be effective in promoting bone regeneration by accelerating osteogenic differentiation.
Simone Krüger
added 3 research items
Electrical stimulation is a promising approach to enhance cell viability and differentiation. We aim to develop a stimulation device for the investigation and realization of cartilaginous cell engineering. The stimulation setup is capable of applying well-defined electric fields to several scaffolds at the same time. The setup consists of a flat plate with multiple test tubes for the scaffolds. A flexible printed circuit board containing a separate pair of electrodes for each tube is fixed at the bottom of the plate. In this context, numerical simulation using Finite Element Method (FEM) is a valuable tool to gain a better understanding of the electric field distribution in such devices. The thin insulating layer of the flexible printed circuit board allows sufficient field strength to be achieved at moderate input voltages but presents challenges for modelling. In simulations, thin layers would usually require a fine discretization with many degrees of freedom (DOF). This leads to large models, which are expensive regarding memory and computation time. Based on the 'contact impedance' boundary condition available in COMSOL Multiphysics® 5.4, an alternative approach is proposed that can model thin layers in capacitively coupled setups. The resulting electric field distribution in the new stimulation setup is presented and discussed.
Treatment of cartilage lesions remains a clinical challenge. Therefore, biophysical stimuli like electric fields seem to be a promising tool for chondrocytic differentiation and treatment of cartilage lesions. In this in vitro study, we evaluated the effects of low intensity capacitively coupled electric fields with an alternating voltage of 100 mVRMS (corresponds to 5.2 × 10−5 mV/cm) or 1 VRMS (corresponds to 5.2 × 10−4 mV/cm) with 1 kHz, on human chondrocytes derived from osteoarthritic (OA) and non-degenerative hyaline cartilage. A reduction of metabolic activity after electrical stimulation was more pronounced in non-degenerative cells. In contrast, DNA contents in OA cells were significantly decreased after electrical stimulation. A difference between 100 mVRMS and 1 VRMS was not detected. However, a voltage-dependent influence on gene and protein expression was observed. Both cell types showed increased synthesis rates of collagen (Col) II, glycosaminoglycans (GAG), and Col I protein following stimulation with 100 mVRMS, whereas this increase was clearly higher in OA cells. Our results demonstrated the sensitization of chondrocytes by alternating electric fields, especially at 100 mVRMS, which has an impact on chondrocytic differentiation capacity. However, analysis of further electrical stimulation parameters should be done to induce optimal hyaline characteristics of ex vivo expanded human chondrocytes.
During joint movement and mechanical loading, electric potentials occur within cartilage tissue guiding cell development and regeneration. Exposure of cartilage exogenous electric stimulation (ES) may imitate these endogenous electric fields and promote healing processes. Therefore, the present study investigated the influence of electric fields on human chondrocytes, mesenchymal stem cells and the co‑culture of the two. Human chondrocytes isolated from articular cartilage obtained post‑mortally and human mesenchymal stem cells derived from bone marrow (BM‑MSCs) were seeded onto a collagen‑based scaffold separately or as co‑culture. Following incubation with the growth factors over 3 days, ES was performed using titanium electrodes applying an alternating electric field (700 mV, 1 kHz). Cells were exposed to an electric field over 7 days under either hypoxic or normoxic culture conditions. Following this, metabolic activity was investigated and synthesis rates of extracellular matrix proteins were analyzed. ES did not influence metabolic activity of chondrocytes or BM‑MSCs. Gene expression analyses demonstrated that ES increased the expression of collagen type II mRNA and aggrecan mRNA in human chondrocytes under hypoxic culture conditions. Likewise, collagen type II synthesis was significantly increased following exposure to electric fields under hypoxia. BM‑MSCs and the co‑culture of chondrocytes and BM‑MSCs revealed a similar though weaker response regarding the expression of cartilage matrix proteins. The electrode setup may be a valuable tool to investigate the influence of ES on human chondrocytes and BM‑MSCs contributing to fundamental knowledge including future applications of ES in cartilage repair.
Ursula van Rienen
added 2 research items
Electrical stimulation of biological samples such as tissues and cell cultures attracts growing attention due to its capability of enhancing cell activity, proliferation and differentiation. Eventually, profound knowledge of the underlying mechanisms paves the way for innovative therapeutic devices. Capacitive coupling is one option of delivering electric fields to biological samples and has advantages with regard to biocompatibility. However, the mechanism of interaction is not well understood. Experimental findings could be related to voltage-gated channels, which are triggered by changes of the transmembrane potential (TMP). Numerical simulations by the Finite Element method (FEM) provide a possibility to estimate the TMP. For realistic simulations of in vitro electric stimulation experiments, a bridge from the mesoscopic level down to the cellular level has to be found. A special challenge poses the ratio between the cell membrane (a few nm ) and the general setup (some cm ). Hence, a full discretization of the cell membrane becomes prohibitively expensive for 3D simulations. We suggest using an approximate FE method that makes 3D multi-scale simulations possible. Starting from an established 2D model, the chosen method is characterized and applied to realistic in vitro situations. A to date not investigated parameter dependency is included and tackled by means of Uncertainty Quantification (UQ) techniques. It reveals a strong, frequency-dependent influence of uncertain parameters on the modeling result. <br
Electrical stimulation of biological samples such as tissues and cell cultures attracts growing attention due to its capability of enhancing cell activity, proliferation and differentiation. Eventually, profound knowledge of the underlying mechanisms paves the way for innovative therapeutic devices. Capacitive coupling is one option of delivering electric fields to biological samples and has advantages with regard to biocompatibility. However, the mechanism of interaction is not well understood. Experimental findings could be related to voltage-gated channels, which are triggered by changes of the transmembrane potential (TMP). Numerical simulations by the Finite Element method (FEM) provide a possibility to estimate the TMP. For realistic simulations of in vitro electric stimulation experiments, a bridge from the mesoscopic level down to the cellular level has to be found. A special challenge poses the ratio between the cell membrane (a few nm ) and the general setup (some cm ). Hence, a full discretization of the cell membrane becomes prohibitively expensive for 3D simulations. We suggest using an approximate FE method that makes 3D multi-scale simulations possible. Starting from an established 2D model, the chosen method is characterized and applied to realistic in vitro situations. A to date not investigated parameter dependency is included and tackled by means of Uncertainty Quantification (UQ) techniques. It reveals a strong, frequency-dependent influence of uncertain parameters on the modeling result. <br
Thomas Distler
added a research item
The prevalence of large bone defects is still a major problem in surgical clinics. It is, thus, not a surprise that bone-related research, especially in the field of bone tissue engineering, is a major issue in medical research. Researchers worldwide are searching for the missing link in engineering bone graft materials that mimic bones, and foster osteogenesis and bone remodeling. One approach is the combination of additive manufacturing technology with smart and additionally electrically active biomaterials. In this study, we performed a three-dimensional (3D) printing process to fabricate piezoelectric, porous barium titanate (BaTiO3) and hydroxyapatite (HA) composite scaffolds. The printed scaffolds indicate good cytocompatibility and cell attachment as well as bone mimicking piezoelectric properties with a piezoelectric constant of 3 pC/N. This work represents a promising first approach to creating an implant material with improved bone regenerating potential, in combination with an interconnected porous network and a microporosity, known to enhance bone growth and vascularization.
Frank Krüger
added a research item
As the importance of data in today’s research increases, the effective management of research data is of central interest for reproducibility. Research is often conducted in large interdisciplinary consortia that collaboratively collect and analyse such data. This raises the need of intra-consortia data sharing. In this article, we propose the use of data management platforms to facilitate this exchange among research partners. Based on the experiences of a large research project, we customized the CKAN software to satisfy these needs for intra-consortia data sharing.
Thomas Distler
added a research item
Electrically conductive biomaterials are gaining increasing interest owing to their potential to be used in smart, biosensoric and functional tissue-engineered scaffolds and implants. In combination with 3D printing technology, this class of materials might be one of the most advanced approaches towards future medical implants regarding potential functionalities and design possibilities. Conductive hydrogels themselves have been researched for potential sensoric and tissue engineering applications for more than a decade, while the 3D printing of such functional materials is still under early exploration. This review aims to provide a short insight into the most recent developments of 3D printable and electrically conductive hydrogels. It also provides a summary of the last few years of research in this field, with key scope on 3D printing for biomedical applications. The final literature search was conducted in May 2019, with the specific keywords ‘3D’, ‘printing’, ‘conductive’, ‘hydrogel’, ‘biocompatible’ and combinations of the latter, using advanced search in the databases Scopus®, Web of Science® (Web of Knowledge®) and Google Scholar®. A total of 491 results were gained, while 19 recent publications were identified with the above-mentioned criteria and keywords, which are the studies finally discussed in the paper. The key results have been summarised, and the remaining challenges in the field and the scope for future research activities have been discussed.
Max Schröder
added a research item
The reproducibility of scientific results gains increasing attention. In the context of biomedical engineering, this applies to experimental studies of three different kinds: in-vivo, in-vitro, and in-silico. Numerical modelling and finite element simulation of bio-electric systems are intricate processes involving manifold steps. A typical example of this process is the electrical stimulation at alloplastic reconstruction plates of the mandible. During the bio-electric modelling and simulation process, diverse methods realised in various software tools are exploited. To comprehensibly render how the final model has been developed requires a thorough documentation. We exploit the W3C provenance model PROV to structure this process and to make it accessible for modellers and for automatic analyses. Different entity types, such as data, model, software, literature, assumptions, and mathematical equations are distinguished; roles of entities within an activity are revealed as well as the involved researchers. In addition, we identify five process patterns: 1) information extraction from the literature; 2) generation of a geometrical model which uses data as input; 3) composition of several geometrical or mathematical models into a combined model; 4) parameterisation, which augments the input model by additional properties; and, finally, 5) refinement, which uses a model in addition to an assumption and generates an enhanced model. By modelling provenance information of a typical bio-electric modelling and simulation process as well as identifying provenance patterns, we provide a first step towards a better documentation of academic investigations in that scientific field.
Abdul Razzaq Farooqi
added a research item
The intrinsic regeneration potential of hyaline cartilage is highly limited due to the absence of blood vessels, lymphatics, and nerves, as well as a low cell turnover within the tissue. Despite various advancements in the field of regenerative medicine, it remains a challenge to remedy articular cartilage defects resulting from trauma, aging, or osteoarthritis. Among various approaches, tissue engineering using tailored electroactive scaffolds has evolved as a promising strategy to repair damaged cartilage tissue. In this approach, hydrogel scaffolds are used as artificial extracellular matrices, and electric stimulation is applied to facilitate proliferation, differentiation, and cell growth at the defect site. In this regard, we present a simulation model of electroactive hydrogels to be used for cartilage–tissue engineering employing open-source finite-element software FEniCS together with a Python interface. The proposed mathematical formulation was first validated with an example from the literature. Then, we computed the effect of electric stimulation on a circular hydrogel sample that served as a model for a cartilage-repair implant.
Revathi Appali
added a research item
Electric stimulation of neural tissues has been an effective clinical intervention to address a variety of pathological issues such as profound deafness, retinal diseases, and Parkinson's disease. However, the knowledge about the exact mechanism of neural excitation, especially activation sites is still ambiguous. Nevertheless, in silico models utilize two approaches namely activating function and sub-threshold potential to predict the activation sites of neural tissues. This paper studies the applicability of these two approaches to model the electric stimulation of pyramidal neuron and spiral ganglion neurons using finite element models. The simulation results suggest that the activating function could be prone to geometrical irregularities of the neural tissues, yet realistically predicts the activation sites on the myelinated neurons. In contrast, the sub-threshold potential predicts the activation of unmyelinated axons by considering the electrophysiological properties of neural tissues. The present study suggests that it is necessary to choose an appropriate method to estimate the neural activation sites while modeling the extracellular stimulation of neural tissues.
Frank Krüger
added a research item
Developing and applying software for simulation-based research in open science must satisfy two opposing requirements. On the one hand, simulation software needs to evolve continuously to adapt to technical advances and changing requirements. On the other hand, fixed versions of specific software artifacts must be made available persistently to make simulation results reproducible. These requirements are especially challenging for complex software with many constraints, such as the build environment or dependencies on other software. In this article we show how existing technologies and concepts can be leveraged to tackle these challenges. In particular, we discuss how open source software, build tools, automatic dependency management, and persistent artifact storage contribute to effective and credible simulation-based research.
Yogesh Deepak Bansod
added 2 research items
Natural bone remodeling is the mechanism that regulates the relationship between bone morphology and external mechanical loads applied to it. This phenomenon has been studied extensively, including multiple numerical models that have been formulated to predict the density distribution and its evolution in several bone types. However, despite these models, bone remodeling mechanism under different stimuli is still not well understood. We implemented a recently proposed electromechanically driven bone remodeling model that encompasses both mechanical and therapeutic electrical stimuli using an open-source software framework, and studied a two-dimensional (2D) plate model and a femur bone model, respectively. For discretization, we employed the finite element method (FEM) for the spatial quantities and Euler scheme for the time derivatives. The simulation results demonstrate that the density distribution is changed under electrical stimulation, generally resulting in a greater mass deposition. This study supports the possibility of enhancing and accelerating the bone remodeling process via simultaneous application of electrical and mechanical stimulus.
Max Schröder
added a research item
Virtual research environments play a central role in today’s interdisciplinary research. They provide a secure and convenient way for collaboration and traceable research. While all-in-one solutions exist that enable researchers to collaborate during the entire research data lifecycle, we argue that a flexible virtual research environment can also be composed of off-the -shelf services. In that vein, we introduce the virtual research environment of the CRC 1270 ELAINE and discuss different implementation aspects.
Frank Krüger
added a research item
Electrical stimulation is a promising therapeutic approach for the regeneration of large bone defects. Innovative electrically stimulating implants for critical size defects in the lower jaw are under development and need to be optimized in silico and tested in vivo prior to application. In this context, numerical modelling and simulation are useful tools in the design process. In this study, a numerical model of an electrically stimulated minipig mandible was established to find optimal stimulation parameters that allow for a maximum area of beneficially stimulated tissue. Finite-element simulations were performed to determine the stimulation impact of the proposed implant design and to optimize the electric field distribution resulting from sinusoidal low-frequency ( f = 20 Hz ) electric stimulation. Optimal stimulation parameters of the electrode length h el = 25 m m and the stimulation potential φ stim = 0.5 V were determined. These parameter sets shall be applied in future in vivo validation studies. Furthermore, our results suggest that changing tissue properties during the course of the healing process might make a feedback-controlled stimulation system necessary.
Max Schröder
added a research item
With the advent of Open Science, researchers have started to publish their research artefacts (i. e., data, software, and other products of the investigations) in order to allow others to reproduce their investigations. While this publication is beneficial for science in general, it often lacks a comprehensive documentation and completeness with respect to the artefacts. This, in turn, prevents the successful reproduction of the analyses. Typical examples are missing scripts, incomplete datasets or specification of used software. Moreover, issues about licences often create legal concerns. This is true for the use of commercial software but also for the publication of research artefacts without proper sharing licence. As a result, the sole publication of research artefacts does not automatically result in reproducible research. To empirically confirm this, we have been systematically analysing research publications that also published their investigations as Jupyter notebooks. In this paper, we present preliminary results of this analysis for five publications. The results show, that the quality of the published research artefacts must be improved in order to assure reproducibility.
Ursula van Rienen
added a research item
Hyaline cartilage undergoes many substantial age-related physiochemical and biomechanical changes that reduce its ability to overcome the effects of mechanical stress and injury. In quest of therapeutic options, magnetic stimulation and electrical stimulation (ES) have been proposed for improving tissue engineering approaches for the repair of articular cartilage. The aim of this study is to summarize in silico investigations involving induced electrical properties of cartilage tissue due to various biophysical stimuli along their respective mathematical descriptions. Based on these, a preliminary numerical study involving electromechanical transduction in bovine cartilage tissue has been carried out using an open source finite element computational software. The simulation results have been compared to experimental results from the literature. This study serves as a basis for further in silico studies to better understand the behavior of hyaline cartilage tissue due to ES and to find an optimal stimulation protocol for the cartilage regeneration. Moreover, it provides an overview of the basic models along with mathematical description and scope for future research regarding electrical behavior of the cartilage tissue using open source software. Impact Statement The presented research summarizes the basic models with mathematical description regarding electrical behavior of the cartilage tissue. A preliminary numerical study involving electromechanical transduction in bovine cartilage tissue sample has been carried out using an open source finite element software. This research will provide scope for future research regarding electrical behavior of the cartilage tissue using open source software.
Ursula van Rienen
added an update
More information can be found here:
 
Frank Krüger
added a project goal
European populations are ageing rapidly. By the year 2060, every third person living in Germany will be older than 65. For this reason, the social and socio-economic relevance of regenerative therapies is clearly increasing. This holds particularly true for implants: the older the population grows, the more medical implants for various indication areas are required and the more often they have to be replaced during the course of therapy.
The research vision pursued by the CRC 1270 ELAINE (ELectrically Active ImplaNts) focuses on novel electrically active implants. Specifically, ELAINE addresses implants employed for the regeneration of bone and cartilage, and implants for deep brain stimulation to treat movement disorders.
Three central research objectives are a means to implement the research vision. The first objective is to establish innovative energy autonomous implants that allow a feedback-controlled electrical stimulation. A second objective is efficient systematic multi-scale studies to enable rapid progress in targeted implant improvements and patient-specific therapies. The third long-term objective is to analyse the basic mechanisms of electrical stimulation in bone, cartilage and brain, and to translate this knowledge in clinical practice.