An infusible extracellular matrix biomaterial improves survival in a model of severe systemic inflammation.
Publication Year:
2025
PubMed ID:
41173831
Public Summary:
Excessive inflammation across the body can often be lethal in septic and trauma patients when multiple organs begin to have dysfunction. There are currently no effective therapeutics that modulate the inflammation response to promote survival within this patient population. Pro-regenerative extracellular matrix (ECM) biomaterials have shown success for the treatment of local inflammation but have not been fully explored for treating inflammation across the body. Here, we demonstrate the efficacy of an intravenously delivered infusible ECM (iECM) material, which promotes increased survival in a mouse model with severe inflammation by decreasing mediators of inflammation. Lung and kidney failure are associated with higher mortality in this condition in patients compared to other organ failures, and we demonstrate that iECM localizes primarily to kidney and lung tissues in the mouse model. iECM successfully decreased blood vessel leakiness within lung tissue and lowered levels of inflammatory proteins. We also demonstrated that inflammatory cell infiltration into lung tissue was modulated with iECM treatment. In summation, iECM improves survival from severe inflammation by decreasing the local and overall inflammatory signaling pathways that contribute to multiple organ dysfunction. These results provide a strong rationale for translational studies of iECM treatment in inflammatory syndromes, including sepsis and trauma.
Scientific Abstract:
Excess systemic inflammation can often be lethal in septic and trauma patients due to the onset of multiple organ dysfunction syndrome (MODS). As of right now, there are no effective immunomodulatory therapeutics that can promote survival within this patient population. Pro-regenerative extracellular matrix (ECM) biomaterials have shown success for the treatment of local inflammation but have not been fully explored for treating systemic inflammation. Here, we demonstrate the efficacy of an intravenously delivered infusible ECM (iECM) material, which promotes increased survival in a murine model of MODS by decreasing systemic mediators of inflammation. Lung and kidney failure are associated with higher mortality in MODS compared to other organ failures, and we demonstrate that iECM localizes primarily to kidney and lung tissues during systemic inflammation induced by endotoxin. iECM successfully lowered vascular permeability within lung tissue and lowered levels of inflammatory cytokine signaling, such as IL-6, verified via ELISA and gene expression analyses. We also demonstrated that immune cell infiltration into lung tissue was modulated with iECM treatment, with an increase in neutrophil retention in the lung and decreases in pro-inflammatory macrophage presence. In summation, iECM improves survival from severe systemic inflammation by decreasing the local and systemic inflammatory signaling pathways that contribute to MODS. These results provide a strong rationale for translational studies of iECM treatment in systemic inflammatory syndromes, including sepsis and trauma.