A computational, tissue-realistic model of pressure ulcer formation in individuals with spinal cord injury

Abstract

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 SummaryA 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.

Predictors of pressure ulcer incidence following traumatic spinal cord injury: a secondary analysis of a prospective longitudinal study

“…The primary aim was to obtain information related to the incidence of pressure ulcers, the occurrence of urinary tract infections, data associated with depression and pain status, with the goal to develop a model of inflammation and healing in pressure ulcer development following SCI. 28 The RERC protocol received approval from the University of Pittsburgh Institutional Review Board. After obtaining informed consent, clinical data, plasma and urine samples were collected three times per week when the subject was in acute care, weekly in inpatient rehabilitation and annually after discharge to outpatient care for the duration of the study, up to 5 years (2008-2012).…”

Systems biology: transforming our understanding of disease

“…Understanding the pathways and the mediators could lead to new management approaches for this notoriously difficult-to-treat condition. However, the underlying complexity and the fact that the biological effects produced by a particular pathway or mediator depend on timing and context makes identifying targets problematic using conventional approaches 4 -and that's where systems biology and an in silico model come in.…”

“…But these anti-inflammatory approaches did not reduce the incidence of pressure ulcers and to have any chance of working must be applied early, even before many signs of clinical ulceration emerge. 4 Recently, researchers developed a computer model of the lifecycle of the bacterium Mycoplasma genitalium (see Figure 1), a common cause of sexuallytransmitted disease (STD). The model reproduced the whole bacterial cell, including all 525 genes, the other molecular components and their interactions.…”

Simulation enabled search for explanatory mechanisms of the fracture healing process

“…Simulations using selected parameterizations bore a close resemblance to histological observations of an epithelial layer, cell clusters, and single cells. Ziraldo et al described an agent-based model of ischemia/reperfusion-induced inflammation coupled with pressure ulcer formation and progression in humans with a spinal cord injuries [ 17 ]. Serial photographic images spanning several clinical stages were used to calibrate progression and healing of virtual pressure ulcers.…”