[Organoids for the advancement of intraoperative diagnostic procedures]. / Organoide zur Weiterentwicklung der intraoperativen Diagnostik.

In the context of cancer surgery, there is always a trade-off between oncological safety and preservation of function. This is especially true in pelvic surgery due to the close relationship to the pelvic floor muscles, blood supply and nerves. Currently, risk models, preoperative imaging, the surgeon's assessment, and the intraoperative frozen section serve as the basis for decision-making. New imaging techniques and standardization in frozen section have significantly improved this in recent years. However, limitations remain due to time delays as well as more difficult correct anatomical assignment in the follow-up. Alternative intraoperative techniques may overcome this limitation in the future. Patient-derived organoids have emerged as an important new research vehicle in recent years. They are based on tumor stem cells that, under special culture conditions, form three-dimensional replicas of the original tissue. This makes them ideally suited for testing individual system therapies but also as a validation technique for new intraoperative diagnostic procedures. The Research Training Group 2543/I, which is funded by the German Research Foundation, is researching the potential of new diagnostic methods in an interdisciplinary team regarding validation in addition to intraoperative frozen sections.

Modeling the LPS-induced effects on transcription factor activation and gene expression in murine macrophages.

Macrophages within the liver are of particular importance for a functional defense against bacterial infection. They exhibit a complex response to lipopolysaccharide and secrete a variety of pro-inflammatory cytokines and chemokines that both coordinate the immune response and regulate activity of the macrophages, themselves. In this context, the dynamic of pathway activation and gene expression is important for a better understanding of the role of activated macrophages in healthy and diseased states. Therefore, we present a representative model of LPS-induced macrophage activation that covers the principle regulatory motifs. Based on that, we propose a simplified model with a reduced number of states and parameters that allows estimation of transcription factor activity from gene expression data and can be easily extended to describe the full spectrum of gene regulation in LPS-activated macrophages.

Finite-element-modeling of egg white as a substitute for tissue coagulation during bipolar radiofrequency-induced thermofusion.

Radiofrequency-induced thermofusion is a frequently used electrosurgical procedure for the sealing of blood vessels. A disadvantage of vessel sealing instruments is that the generated thermal energy spreads to the surrounding tissue and may irreversibly damage it. This is particularly problematic when operating close to sensitive structures such as nerves. Given their advantages, there is nonetheless a lot of interest in using bipolar vessel sealing for surgical procedures. To select instruments that may be safely used in such cases, it is important to reliably quantify the thermal spread to the surrounding tissue. Mathematical models can help to evaluate the transient behavior, that is the evolution of the thermal spread over time, more precisely. A finite element model allows for a detailed analysis of inhomogeneities in the spatial temperature distribution. As a first step towards a finite model of the bipolar vessel sealing process, a model of the coagulation of chicken egg white is presented here. Egg white has thermal and electrical properties that are very similar to tissue, making it suitable as a substitute for the analysis of the coagulation process. It has the additional advantage, that the spatial and temporal evolution of the thermal spread can be visually gauged. The presented model describes the experimentally observed spatial temperature distribution, the shape of the coagulated egg white, and the formation of hotspots. Furthermore, it is shown that the model can correctly predict the shape of the coagulated egg white in further experiments.

A mathematical model of bipolar radiofrequency-induced thermofusion.

Bipolar radiofrequency-induced thermofusion has become a widely accepted method successfully used in open and particularly in minimally-invasive surgery for the sealing of blood vessels and tissue of up to several millimeters diameter. Despite its wide-spread application, the thermofusion process itself is not well understood on a quantitative and dynamic level, and manufacturers largely rely on trial-and-error methods to improve existing instruments. To predict the effect of alternative generator control strategies and to allow for a more systematic approach to improve thermofusion instruments, a mathematical model of the thermofusion process is developed. The system equations describe the spatial and temporal evolution of the tissue temperature due to Joule heating and heat transfer, and the loss of tissue water due to vaporization. The resulting effects on the tissue properties, most importantly the electrical resistivity, heat capacity and thermal conductivity, are considered as well. Experimental results indicate that the extent of the lateral thermal damage is directly affected by Joule heating of the lateral tissue. The experimental findings are supported by simulation results using the proposed mathematical model of thermofusion.

Analysis of an apoptotic core model focused on experimental design using artificial data.

The activation of caspases is a central mechanism in apoptosis. To gain further insights into complex processes like this, mathematical modelling using ordinary differential equations (ODEs) can be a very powerful research tool. Unfortunately, the lack of measurement data is a common problem in building such kinetic models, because it practically constrains the identifiability of the model parameters. An existing mathematical model of caspase activation during apoptosis was used in order to design future experimental setups that will help to maximise the obtained information. For this purpose, artificial measurement data are generated in silico to simulate potential experiments, and the model is fitted to this data. The model is also analysed using observability gramian and sensitivity analyses. The used analysis methods are compared. The artificial data approach allows one to make conclusions about system properties, identifiability of parameters and the potential information content of additional measurements for the used caspase activation model. The latter facilitates to improve the experimental design of further measurements significantly. The performed analyses reveal that several kinetic parameters are not at all, or only scarcely, identifiable, and that measurements of activated caspase 8 will maximally improve the parameter estimates. Furthermore, we can show that many assays with inhibitor of apoptosis protein (IAP) knockout cells only provide redundant information for our needs and as such do not have to be carried out.