Towards understanding pressure ulcer formation: Coupling an inflammation regulatory network to a tissue scale finite element model

Abstract

Pressure ulcers (PUs) are a major clinical concern affecting more than 2.5 million adults annually in the US. Ischemia is recognized as one of the most important contributors to ulcer formation, triggering a sterile inflammatory cascade that culminates in necrosis of native skin cells and ulceration. While there is a general understanding of the biological elements involved in this process and their interdependence within the biological PU signaling network, this system’s spatio-temporal dynamics have not yet been studied in detail. Here we first present a 0D mathematical description of the PU regulatory network consisting of two cell types – keratinocytes and neutrophils- and six chemical species – TNFα, KC, ROS, DAMPs, O2 and XO. We extend this regulatory network from a set of ordinary differential equations to realistic spatial domains by coupling each species’ dynamic equations to reaction diffusion partial differential equations. Furthermore, we couple this model to mechanical deformation of the spatial domain by including a pressure-sensitive oxygen perfusion term. The total model provides solutions to the regulatory network dynamics at the tissue scale with spatio-temporal detail on the evolution of each species. Among other features, the model correctly predicts patterns of PU formation in response to moderate loads, as seen clinically and experimentally. In conclusion, this work extends our current PU modeling capabilities and improves our understanding of PUs by carefully analyzing the motifs of the regulatory network and by exploring the implications of coupling this system to a tissue scale model of skin mechanics and oxygen perfusion.