Aspirin-Triggered Resolvin D1-modified materials promote the accumulation of pro-regenerative immune cell subsets and enhance vascular remodeling

Abstract

Many goals in tissue engineering rely on modulating cellular localization and polarization of cell signaling, including the inhibition of inflammatory infiltrate, facilitation of inflammatory cell egress, and clearance of apoptotic cells. Omega-3 polyunsaturated fatty acid-derived resolvins are gaining increasing recognition for their essential roles in inhibition of neutrophil invasion into inflamed tissue and promotion of macrophage phagocytosis of cellular debris as well as their egress to the lymphatics. Biomaterial-based release of lipid mediators is a largely under-explored approach that provides a method to manipulate local lipid signaling gradients in vivo and direct the recruitment and/or polarization of anti-inflammatory cell subsets to suppress inflammatory signaling and enhance angiogenesis and tissue regeneration. The goal of this study was to encapsulate Aspirin-Triggered Resolvin D1 (AT-RvD1) into a degradable biomaterial in order to elucidate the effects of sustained, localized delivery in a model of sterile inflammation. Flow cytometric and imaging analysis at both 1 and 3 days after injury showed that localized AT-RvD1 delivery was able significantly increase the accumulation of anti-inflammatory monocytes and M2 macrophages while limiting the infiltration of neutrophils. Additionally, cytokine profiling and longitudinal vascular analysis revealed a shift towards a pro-angiogenic profile with increased concentrations of VEGF and SDF-1α, and increased arteriolar diameter and tortuosity. These results demonstrate the ability of locally-delivered AT-RvD1 to increase pro-regenerative immune subpopulations and promote vascular remodeling.

Aspirin-triggered resolvin D1 attenuates PDGF-induced vascular smooth muscle cell migration via the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway

“…In a recent report, AT-RvD1 was detected by liquid chromatography–tandem mass spectrometry (LC-MS/MS)-based metabololipidomics in human plasma from patients affected by coronary heart disease treated with aspirin with and without an EPA and DHA supplement [26]. AT-RvD1 released from a bio-degradable material has been recently shown to decrease neutrophil infiltration and to increase the anti-inflammatory monocyte/macrophage population in a murine model [38]. In another recent study, AT-RvD1 has been shown to suppress TGF-β-induced migration and invasion of A549 lung cancer cells [39].…”

Quantitative Analysis of Immune Cell Subset Infiltration of Supraspinatus Muscle After Severe Rotator Cuff Injury

“…Because these typically “pro-regenerative” MP subpopulations predominate the SS as early as day 7, increasing their recruitment may offer only modest therapeutic efficacy for muscle degeneration, which occurs over weeks. A more promising strategy may be to bias recruited cells toward pro-regenerative cytokine secretion using appropriately engineered delivery of immune modulatory molecules[44], [49], [50]. …”

Resolution of vascular injury: Specialized lipid mediators and their evolving therapeutic implications

“…The device eluted biologically active RvD1 for more than 3 weeks in vitro. A similar approach was taken by Sok et al in loading AT-RvD1 into PLGA scaffolds implanted under mouse skin (Sok, Tria et al 2017). Sustained release of SPM (e.g.…”