Current research projects at the IHCE

The successful implantation of the human embryo and the subsequent uncomplicated course of pregnancy critically depend on the invasion of trophoblasts, invasive cells of the embryo, into the maternal tissue. Failures in this process are often associated with pregnancy pathologies such as preeclampsia and fetal intrauterine growth restriction, which can cause severe complications for both mother and fetus, including preterm births and late miscarriages. In the first trimester of pregnancy, maternal uterine arteries are closed by trophoblasts, while the veins are already open and connected to the placenta. The reasons for these differences in the invasion process have not yet been fully understand. We hypothesize that this difference in trophoblast invasion is related to the influence of factors from primary endothelial cells that line the interior wall of blood vessels. Due to the lack of suitable 3D models and the limitations of animal models, we have developed a novel, matrix-based 3D vessel model system to study the differences in trophoblast invasion between maternal arteries and veins. This model uses a biodegradable PCL/PLA matrix that can be seeded with cells on both sides and incorporated into a metal housing, creating an inner and outer compartment for different cell culture conditions and cell-cell contact. The system is perfusable to expose endothelial cells to in vivo-like shear rates and mimic maternal blood flow. By combining primary human endothelial cells and native first trimester placental villi, our model offers unique opportunities for studying early trophoblast invasion. Our project uses innovative approaches such as the mRNA-based in situ padlock method and computer-assisted quantitative image analysis, along with traditional histological, immunological, and biochemical methods. This integrative approach enables a detailed examination of trophoblast invasion and its interactions with the maternal vascular system at an unprecedented level of accuracy and depth. The aim of this project is to gain fundamental insights into trophoblast invasion and potential mechanisms of pregnancy complications. It aims to contribute to the development of new prognostic, diagnostic, and therapeutic approaches for the early detection and treatment of pregnancy pathologies and to generate new insights for potential follow-up projects.

The current decentralised management of medical devices in healthcare facility databases leads to aconsiderable delay in the ability of the federal and state governments to respond in the event of a necessary redistribution of medical resources in the event of a crisis. Basic medical care in Austria is defined by comprehensive care planning, but crises repeatedly show that planning instruments can only be used well and adapted to a situation if the required data is available and provides the necessary information in a suitable form for users and decision-makers. The present research project "MEDLOK - Medical technology products and their localisation for needs-based use in crisis management" deals with the scientific questions of a possible distribution of medical devices in crisis situations or in the event of the failure of individual supply regions. The methodological approach of centralised management and use of existing equipment data from different hospitals in Austria is intended to show whether and to what extent added value in terms of resilience can be achieved for patient care in times of crisis. The assessment of the location and accessibility of the hospitals, the geographical proximity of the affected regions and the risk profile of the population in the catchment area of the hospitals are essential in order to provide decision-makers with a solide basis for decision-making. For this reason, geographical data should be used to collect and visualise this information. Geographic information technology and geospatial artificial intelligence also make it possible to simulate alternative courses of action and demonstrate their effects. From a scientific and technical point of view, it would be desirable to use these IT technologies in the event of a crisis. This would make it possible for decision-makers to see what quantity of equipment is available in what geographical proximity to a crisis area. It could also show how gaps for a supply area can be avoided if medical equipment is moved from hospitals to facilities in a crisis area. In addition, the creation of a central data repository for the most important medical devices in the event of a crisis also offers the possibility of introducing a standardised nomenclature for medical devices. This could ensure a standardised data structure in the area of medical device management, which does not yet exist and is not yet practised in Europe. Finally, a demonstrator of the MEDLOK system will be validated and tested by the participating project and healthcare partners in a proof-of-concept. In a test environment, previously defined fictitious crisis scenarios will be handled and processed using newly developed user-friendly interfaces. The results will provide important findings for the further development and future implementation of the MEDLOK approach and are an important part of the dissemination of the project results. Overall, the project offers a pioneering approach to improving crisis response in the healthcare sector and ensuring the efficient supply of life-saving medical technology products.

Dissertant will be supported in the selection of lectures, literature research and in the definition of the specification of the corresponding microfluidic system.

The drug induction of cell senescence shows high potential for cancer treatment. The research project focuses on the investigation of bioelectrical parameters and their possible role in the formation of senescence in resistant lung cancer cells treated with appropriate CDK4/6 inhibitors. By looking at biochemical and electrophysiological aspects, the study aims to gain a deeper understanding of senescence mechanisms, which may form the basis for innovative, combined therapeutic approaches for the treatment of lung cancer.

Computational modeling and simulation of cell electrophysiology is an established tool for the analysis of bioelectricity of excitable cells. However, only a few mathematical models have been developed to simulate bioelectric cell functions of nonexcitable cells, e.g., to describe voltage-dependent modulation of cell secretion, calcium dynamics, or activation of T lymphocytes. These first experiments, based on the consideration of the most important ion channel types in a mathematical model, impressively demonstrate the potential of such models for an accurate simulation and reliable prediction of cellular processes and activities even in non-excitable cells. In carcinogenesis, the membrane potential Vm generated by ion channel and pump proteins is important for determining the state of differentiation and proliferation. One possibility for carcinogenesis is the disruption of electrical gradients or mechanisms by which they are sensed by cells. Vm is thus an important non-genetic biophysical biomarker candidate of the cancer microenvironment that regulates growth and carcinogenesis. Cancerous and proliferative tissues are generally more positively charged or depolarized than nonproliferative cells. Pharmacological blockade of ion channels is therefore a popular method to "perturb" the membrane potential Vm. Membrane potential has been studied as an important regulator of proliferation in a number of cell types, suggesting that modulation of Vm is required for both G1/S phase and G2/M phase transitions. The in silico lung cancer cell model project now aims to further develop the world's first digital ion current model of a human A549 lung adenocarcinoma cell, published in 2021, by using a hidden Markov modeling (HMM) approach and data from patch clamp measurements for model parameterization and validation. First, based on our preliminary work, the original cell model will be extended to include additional plasmalemmal ion channels and a description of intracellular calcium dynamics. In the next step, the basic model of cell cycle phase G0 will be adapted and reparameterized with respect to the number of expressed ion channels, function and interaction with other channels during the transition from one cell cycle phase to another phase (G0, G1, S, G2/M). For model validation, selected scenarios of ion channel modulations are performed by comparing model simulations with experimental data. The model is then used to investigate two highly relevant research questions in human lung adenocarcinoma using model simulations and laboratory experiments. We here present for the first time an experimentally validated in silico cell model of a lung cancer cell line that allows a deeper understanding of the potential roles and interactions of ion channels in tumor development and progression through targeted modulation of selected ion channels using in silico simulations and in vitro measurements. Specifically, inhibition of CRAC channels is expected to significantly alter local calcium concentration and impair or disrupt KCa3.1 channel activity, thereby impeding the G1/S transition and arresting the cell by depolarizing the membrane potential.