Acute hemorrhage commonly leads to coagulopathy and organ dysfunction or failure. Recent evidence suggests that damage to the endothelial glycocalyx contributes to these adverse outcomes. The physiological events mediating acute glycocalyx shedding are undefined, however. Here, we show that succinate accumulation within endothelial cells drives glycocalyx degradation through a membrane reorganization-mediated mechanism. We investigated this mechanism in a cultured endothelial cell hypoxia-reoxygenation model, in a rat model of hemorrhage, and in trauma patient plasma samples. We found that succinate metabolism by succinate dehydrogenase mediates glycocalyx damage through lipid oxidation and phospholipase A2-mediated membrane reorganization, promoting the interaction of matrix metalloproteinase 24 (MMP24) and MMP25 with glycocalyx constituents. In a rat hemorrhage model, inhibiting succinate metabolism or membrane reorganization prevented glycocalyx damage and coagulopathy. In patients with trauma, succinate levels were associated with glycocalyx damage and the development of coagulopathy, and the interaction of MMP24 and syndecan-1 was elevated compared to healthy controls.

Severe deep dermal burns present a significant challenge for the clinician, often resulting in complications including infection, scarring, and potentially multisystem organ failure. The current standard of care, which involves debridement and skin coverage, has improved survival rates but remains insufficient for optimal tissue regeneration and functional recovery. Additionally, there can be limited donor skin availability with severe burns, leading to the use of skin substitutes to be applied with varying degrees of success reported. Biomaterial scaffolds, designed to reduce the reliance on skin grafting, could promote improved healing and patient outcomes. Recent research has focused on promoting the proliferative phase of wound healing through the use of extracellular matrix (ECM) mimetic scaffolds; however, these constructs continue to exhibit critical limitations, including mechanical fragility, heightened infection susceptibility, limited morphological conformity to host tissue architecture, and the necessity for secondary surgical intervention for scaffold retrieval. This study presents a bioactive supramolecular polymer capable of rapid self-assembly into nanofibers, which act as a scaffold to promote tissue regeneration following burn injury. The scaffold is biocompatible, biodegradable, and capable of presenting a bioactive peptide designed to reduce acute inflammation and promote keratinocyte migration in the scaffold. The supramolecular polymers significantly accelerated early wound healing in a clinically relevant deep dermal murine burn injury model. This work provides a promising approach to the development of biomaterials that combine both therapeutic strategies, with scaffolding to promote skin regeneration following severe burn injury.