A Computational, Tissue-Realistic Model of Pressure Ulcer Formation in Individuals with Spinal Cord Injury

People with spinal cord injury (SCI) are predisposed to pressure ulcers (PU). PU remain a significant burden in cost of care and quality of life despite improved mechanistic understanding and advanced interventions. An agent-based model (ABM) of ischemia/reperfusion-induced inflammation and PU (the PUABM) was created, calibrated to serial images of post-SCI PU, and used to investigate potential treatments in silico. Tissue-level features of the PUABM recapitulated visual patterns of ulcer formation in individuals with SCI. These morphological features, along with simulated cell counts and mediator concentrations, suggested that the influence of inflammatory dynamics caused simulations to be committed to “better” vs. “worse” outcomes by 4 days of simulated time and prior to ulcer formation. Sensitivity analysis of model parameters suggested that increasing oxygen availability would reduce PU incidence. Using the PUABM, in silico trials of anti-inflammatory treatments such as corticosteroids and a neutralizing antibody targeted at Damage-Associated Molecular Pattern molecules (DAMPs) suggested that, at best, early application at a sufficiently high dose could attenuate local inflammation and reduce pressure-associated tissue damage, but could not reduce PU incidence. The PUABM thus shows promise as an adjunct for mechanistic understanding, diagnosis, and design of therapies in the setting of PU.Author Summary: A virtual pressure ulcer was created as a platform to test therapies and determine the mechanisms most correlated with unfavorable outcomes. A layer of tissue fed with oxygen and diffusible molecules via blood vessels could develop an ulcer if pressure was applied, by simulating constriction of blood vessels in a circular region. Simulated ulcers were visually similar to digital photographs of ulcers in individuals with spinal cord injury in their irregular shapes, jagged edges, and overall progression in time. Statistical analyses of simulation outputs revealed that inflammation was an important determinant of ulcer severity and overall tissue damage. However, simulated clinical trials revealed that blocking the negative effects of inflammation could not prevent ulceration, and in order to be beneficial at all for this specific type of ulcer, anti-inflammatory treatments must be applied during the earliest stages of ulcer formation—before many clinical signs of ulceration appear.