Shifting the Balance of Inflammatory and Pro-Resolving Lipid Mediators in Volumetric Muscle Loss Injuries
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Turner, Thomas Colin
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Abstract
Extremity trauma involving large tissue loss (e.g., VML) presents a significant clinical challenge for both general and military populations. The frank loss of musculature characteristic of VML sufficiently disrupts or eliminates the wound’s endogenous repair mechanisms; thus, healing becomes difficult and often results in substantial scar tissue formation, permanent functional impairments, and chronic pain. Skeletal muscle is not well adapted to chronic injury stimulus and host mechanisms of inflammation resolution fail to trigger the shift in local immune cells from a transient pro-inflammatory state to a pro-resolving and pro-regenerative state. To explore the potential molecular facilitators of this persistent inflammation, we examined the biosynthesis of inflammatory lipid mediators and specialized pro-resolving lipid mediators (SPM) after VML injury. Our analysis suggests that critical size VML defects are unable to biosynthesize SPMs after injury and are, thus, burdened by a dysregulated and persistent inflammation. Therefore, we leveraged a modular polyethylene glycol-maleimide biomaterial platform to enable local release of a stable isomer of Resolvin D1 (AT-RvD1) in order to promote endogenous pathways of inflammation resolution. We show that the local delivery of AT-RvD1 is able to promote the molecular and cellular resolution of inflammation, enhance muscle regeneration and significantly improve muscle function after VML. These findings represent an improved understanding of the role of SPMs in the pathogenesis of VML and establish the pro-resolving hydrogel therapeutic as a way to promote functional muscle regeneration after traumatic injury.
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2022-11-07
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Dissertation