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

Ziraldo C, Solovyev A, Allegretti A, Krishnan S, Henzel MK, Sowa GA, Brienza D, An G, Mi Q, Vodovotz Y - PLoS Comput. Biol. (2015)

Bottom Line: PU remain a significant burden in cost of care and quality of life despite improved mechanistic understanding and advanced interventions.Tissue-level features of the PUABM recapitulated visual patterns of ulcer formation in individuals with SCI.Sensitivity analysis of model parameters suggested that increasing oxygen availability would reduce PU incidence.

View Article: PubMed Central - PubMed

Affiliation: Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America; Joint PhD Program in Computational Biology, University of Pittsburgh and Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America; Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus

In silico clinical trials suggest little efficacy for corticosteroids or DAMP inhibitors.Simulations are shown at t = 700 h. We varied both the dose and timing of corticosteroid administration, simulated as an injection into the bloodstream, under (A) alternating pressure and (B) 40% initial injury conditions. When inflammatory cells were neutralized early enough but pressure continued, overall damage decreased, but ulceration was not prevented. Without continuous pressure cycles, the earliest dose of steroids was successful in stemming ulcer formation, but later applications did not. We then varied both the dose and timing of administration of a neutralizing antibody to HMGB1, simulated as a topical cream applied to the entire field. This targeted approach had (C) no apparent effect during simulations with alternating pressure, but (D) was able to slow ulcer formation after a 40% initial injury without pressure.
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pcbi.1004309.g006: In silico clinical trials suggest little efficacy for corticosteroids or DAMP inhibitors.Simulations are shown at t = 700 h. We varied both the dose and timing of corticosteroid administration, simulated as an injection into the bloodstream, under (A) alternating pressure and (B) 40% initial injury conditions. When inflammatory cells were neutralized early enough but pressure continued, overall damage decreased, but ulceration was not prevented. Without continuous pressure cycles, the earliest dose of steroids was successful in stemming ulcer formation, but later applications did not. We then varied both the dose and timing of administration of a neutralizing antibody to HMGB1, simulated as a topical cream applied to the entire field. This targeted approach had (C) no apparent effect during simulations with alternating pressure, but (D) was able to slow ulcer formation after a 40% initial injury without pressure.

Mentions: In silico (simulated) clinical trials are an inexpensive and increasingly popular means of gleaning translational knowledge from computational models [55–59]. Accordingly, these methods were utilized to test both current and hypothetical or cutting-edge therapies for inflammation in the setting of post-SCI PU. The feasibility of corticosteroids as a treatment was examined for this indication using the PUABM, varying dose and timing of corticosteroids to investigate whether reducing inflammation could delay time of ulceration and/or lead to less tissue damage (Fig 6). Corticosteroid administration was simulated as suppressing all inflammatory mechanisms. This effect was implemented by the following rule: any activated macrophages or neutrophils die upon encountering at least a threshold amount of steroid in their local vicinity of steroid (S6 Fig). We note that doses do not correlate directly to clinical doses, but instead to degree of functionality. For example, a simulated high dose (5) of corticosteroids shuts down macrophage and neutrophil activity completely, whereas lower doses all some cells to live and takes longer to see an effect. In simulations where corticosteroids were administered at the highest dose and before 250 hours, total damage was reduced. However, with simulated pressure cycling, PU still formed, suggesting that the lack of inflammation driven by macrophages and neutrophils was insufficient to ameliorate the damaging effects of ischemia and reperfusion (Fig 6A). By comparison, simulations with an initial acute injury but without pressure responded more favorably to steroid intervention (Fig 6B). These simulation results agree with the global sensitivity analysis of Fig 5B. It appeared that all doses of corticosteroids greater than zero were sufficient to achieve the full effect in both cases in the PUABM. There was, however, more damage incurred when corticosteroids were introduced at later times. While overall damage in simulations in which corticosteroids were introduced late was still less than simulations without corticosteroids, timeliness of corticosteroid application was anti-correlated with tissue damage incurred. This is likely related to the self-perpetuating nature of the pro-inflammatory mediators in this model. We hypothesize that early interruption of the positive feedback cycle was more effective in reducing inflammatory activity than the same amount of treatment later.


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

Ziraldo C, Solovyev A, Allegretti A, Krishnan S, Henzel MK, Sowa GA, Brienza D, An G, Mi Q, Vodovotz Y - PLoS Comput. Biol. (2015)

In silico clinical trials suggest little efficacy for corticosteroids or DAMP inhibitors.Simulations are shown at t = 700 h. We varied both the dose and timing of corticosteroid administration, simulated as an injection into the bloodstream, under (A) alternating pressure and (B) 40% initial injury conditions. When inflammatory cells were neutralized early enough but pressure continued, overall damage decreased, but ulceration was not prevented. Without continuous pressure cycles, the earliest dose of steroids was successful in stemming ulcer formation, but later applications did not. We then varied both the dose and timing of administration of a neutralizing antibody to HMGB1, simulated as a topical cream applied to the entire field. This targeted approach had (C) no apparent effect during simulations with alternating pressure, but (D) was able to slow ulcer formation after a 40% initial injury without pressure.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4482429&req=5

pcbi.1004309.g006: In silico clinical trials suggest little efficacy for corticosteroids or DAMP inhibitors.Simulations are shown at t = 700 h. We varied both the dose and timing of corticosteroid administration, simulated as an injection into the bloodstream, under (A) alternating pressure and (B) 40% initial injury conditions. When inflammatory cells were neutralized early enough but pressure continued, overall damage decreased, but ulceration was not prevented. Without continuous pressure cycles, the earliest dose of steroids was successful in stemming ulcer formation, but later applications did not. We then varied both the dose and timing of administration of a neutralizing antibody to HMGB1, simulated as a topical cream applied to the entire field. This targeted approach had (C) no apparent effect during simulations with alternating pressure, but (D) was able to slow ulcer formation after a 40% initial injury without pressure.
Mentions: In silico (simulated) clinical trials are an inexpensive and increasingly popular means of gleaning translational knowledge from computational models [55–59]. Accordingly, these methods were utilized to test both current and hypothetical or cutting-edge therapies for inflammation in the setting of post-SCI PU. The feasibility of corticosteroids as a treatment was examined for this indication using the PUABM, varying dose and timing of corticosteroids to investigate whether reducing inflammation could delay time of ulceration and/or lead to less tissue damage (Fig 6). Corticosteroid administration was simulated as suppressing all inflammatory mechanisms. This effect was implemented by the following rule: any activated macrophages or neutrophils die upon encountering at least a threshold amount of steroid in their local vicinity of steroid (S6 Fig). We note that doses do not correlate directly to clinical doses, but instead to degree of functionality. For example, a simulated high dose (5) of corticosteroids shuts down macrophage and neutrophil activity completely, whereas lower doses all some cells to live and takes longer to see an effect. In simulations where corticosteroids were administered at the highest dose and before 250 hours, total damage was reduced. However, with simulated pressure cycling, PU still formed, suggesting that the lack of inflammation driven by macrophages and neutrophils was insufficient to ameliorate the damaging effects of ischemia and reperfusion (Fig 6A). By comparison, simulations with an initial acute injury but without pressure responded more favorably to steroid intervention (Fig 6B). These simulation results agree with the global sensitivity analysis of Fig 5B. It appeared that all doses of corticosteroids greater than zero were sufficient to achieve the full effect in both cases in the PUABM. There was, however, more damage incurred when corticosteroids were introduced at later times. While overall damage in simulations in which corticosteroids were introduced late was still less than simulations without corticosteroids, timeliness of corticosteroid application was anti-correlated with tissue damage incurred. This is likely related to the self-perpetuating nature of the pro-inflammatory mediators in this model. We hypothesize that early interruption of the positive feedback cycle was more effective in reducing inflammatory activity than the same amount of treatment later.

Bottom Line: PU remain a significant burden in cost of care and quality of life despite improved mechanistic understanding and advanced interventions.Tissue-level features of the PUABM recapitulated visual patterns of ulcer formation in individuals with SCI.Sensitivity analysis of model parameters suggested that increasing oxygen availability would reduce PU incidence.

View Article: PubMed Central - PubMed

Affiliation: Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America; Joint PhD Program in Computational Biology, University of Pittsburgh and Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America; Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus