ECM-Mimetic Hydrogel-Based Delivery of Small Molecule Drug and Biomimetic Polymer Fabrication to Enhance Regeneration After Volumetric Muscle Loss Injury
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Van Slyke, Natalie Margarette
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Abstract
Traumatic or surgical loss of appendage skeletal muscle, otherwise known as volumetric muscle loss (VML), is responsible for over half of combat-related disabilities within the U.S. service member population. Current treatments often fail to restore full limb functionality, as the VML-induced chronic dyregulated immune response often results in the formation of disabling scar tissue. To counteract the pro-inflammatory wound microenvironment caused by VML, this study explored how nanofiber scaffolds and unstructured biomaterials combined with sphingosine-1-phosphate (S1P) receptor interaction impacted VML healing. S1P receptor 3 (S1PR3) was antagonistically targeted by VPC01091 because of its contribution towards pro-inflammatory conditions and tendency to prevent macrophage migration out of the wound site. Systemic and local delivery of VPC01091 was assessed in vivo to determine if S1PR3 antagonism generally improved VML healing and if localized release through biomaterials had any worthwhile impact. This impact was assessed through quantification of percent fibrosis and centrally located nuclei identified by Gomori’s Trichrome staining and DAPI immunostaining respectively. PEG-based biomaterials either utilized electrospinning to obtain a nanofiber scaffold structure or were crosslinked to form bulk hydrogels. Additionally, fatty acid-derived polyester development was explored as a possible component alternative through a degradation study and drug loading/release study. The study’s findings demonstrated more regenerative metrics with the addition of VPC01091 to the VML wound site, with VPC01091 released via nanofiber scaffold having significantly more centrally located nuclei compared to unloaded and VPC01091-loaded bulk hydrogels. Considering the fatty acid-derived polymers, the C6-based polymer demonstrated a lower degradation rate and more drug release. These findings indicate that biomaterials given a nanofiber scaffold structure paired with VPC01091 has potential to improve VML healing, which could be further enhanced by changing the biomaterial’s components. Regarding this, longer chain fatty acid-derived polyesters were proven to be a possible pathway for future studies to explore. Overall, these findings indicate that biomaterial implantation paired with S1PR3 antagonistic small molecule drug release has potential to serve as an immunotherapeutic treatment for VML.
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Undergraduate Research Option Thesis