Kanebratt, K. P. | bioRxiv Science

bioRxiv2023

Diseased human pancreas and liver microphysiological system for preclinical diabetes research

Current research on metabolic disorders such as type 2 diabetes relies on animal models because multi-organ diseases cannot be well studied with the standard in vitro assays. Here, we connect models of key metabolism organs, pancreas and liver, on a microfluidic chip to enable diabetes research in a human-based preclinical system. Aided by mechanistic mathematical modelling, we developed a two-organ microphysiological system (MPS) that replicates clinically-relevant phenotypes of diabetic dysregulation both in the liver and pancreas compartments. Exposure to hyperglycemia and high cortisone created a diseased pancreas-liver MPS which displayed beta-cell dysfunction, steatosis, elevated ketone-body secretion, increased glycogen storage, and upregulated gluconeogenic machinery. In turn, normoglycemia and physiological cortisone concentration maintained glucose tolerance and stable liver and beta-cell functions. This method was evaluated for repeatability in two laboratories and was effective in multiple pancreatic islet donors. The model also provides a platform to identify new therapeutic targets as demonstrated with a liver-secreted IL-1R2 protein that induced islet proliferation.

cell biology↗

bioRxiv2023

3D Cell Cultures Amplify Diffusion Signals

Biophysical models can predict the behavior of cell cultures including 3D cell aggregates (3DCAs), thereby reducing the need for costly and time-consuming experiments. Specifically, mass transfer models enable studying the transport of nutrients, oxygen, signaling molecules, and drugs in 3DCA. These models require the defining of boundary conditions (BC) between the 3DCA and surrounding medium. However, accurately modeling the BC that relates the inner and outer boundary concentrations at the border between the 3DCA and the medium remains a challenge that this paper addresses using both theoretical and experimental methods. The provided biophysical analysis indicates that the concentration of molecules inside boundary is higher than that at the outer boundary, revealing an amplification factor that is confirmed by a particle-based simulator (PBS). Due to the amplification factor, the PBS confirms that when a 3DCA with a low concentration of target molecules is introduced to a culture medium with a higher concentration, the molecule concentration in the medium rapidly decreases. The theoretical model and PBS simulations were used to design a pilot experiment with liver spheroids as the 3DCA and glucose as the target molecule. Experimental results agree with the proposed theory and derived properties. Author summaryThe primary objective of our research was to enable the development of reliable biophysical models for three-dimensional cell aggregates (3DCAs). To achieve this goal, we employed a combination of theoretical and experimental methods to derive and characterize the amplification boundary condition (BC), which represents the relation of inner and outer boundary concentrations at the border between a 3DCA and its surrounding medium. By understanding the amplificaiton BC, we can better comprehend the transport and diffusion processes that occur within 3DCAs. The significance of our research lies in its potential to advance the understanding of 3DCAs and their underlying biophysical processes. This knowledge is crucial for a wide range of applications, including drug design and analysis of drug dosages within tissues. This factor may provide insight into the mechanisms behind tumor development and morphogenesis. In particular, the packed structure of cancer tumors enables them to receive and trap a higher concentration of nutrients and oxygen molecules based on the amplification factor. Thus, this study could contribute to the development of novel approaches to manage and treat cancerous tissues.

biophysics↗