Synchronization and critical behavior in beta-cell networks: Towards the engineering of the islets of Langerhans

The pancreatic islets of Langerhans' are multicellular micro-organs which are integral to maintaining glucose homeostasis through secretion of insulin. Beta cells within islets synchronize their insulin release through cell-cell communication to create large bursts to meet physiological needs. However, in patients with diabetes there is a reduction in this cell-cell coupling which leads to a hindered insulin response.;To better characterize the effect of cell-cell coupling in β-cell synchronization, we studied the differences in real-time coupling dynamics between 2D and 3D cell structures. Using a novel system for aggregating β-cells back into 3D structures of defined size, we were able to show that the uncoordinated behavior seen in 2D cell networks is ameliorated by the 3D cell structure. Using this system to aggregate primary islet cells, we found that the resulting `pseudo-islets' had higher viability and functionality compared to normal islets at two week, indicating they may yield higher post-transplant viability and increase transplant effectiveness.;Applying these findings to a network model of cell synchronization, we were then able to theoretically show how reductions in the fractal dimension of cell coupling (number of nearest neighbors a cell can coupling with) can lead to a diabetic phenotype. Furthermore, we were able to apply this model in a predictive manner to forecast the existence of a critical point of cell coupling, below which a diabetic phenotype is established. This was then verified through islet with genetic mutations.