Monday, August 20, 2018

PLGA from PolySciTech used in development of localized anti-restenosis treatment for use in cardiovascular surgery


One of the complications which commonly results from mechanical-type heart-therapy, such as balloon angioplasty, stenosis, or other surgical techniques, is the occurrence of restenosis due to rapid regrowth of the tissue of the arterial walls in response to mechanical stress/damage. This natural tissue reaction to damage hinders the usefulness of these therapeutic techniques by reclosing the vessel. Recently, researchers at University of California and Harvard Medical School used multiple types of PLGA (Polyvivo AP021 and others) from PolySciTech (www.polyscitech.com) to design a system to release resolving D1 into the arterial walls, which prevents excessive inflammation and restenosis. This research holds promise to reduce the incidence of this potentially life-threatening complication. Read more: Wu, Bian, Evan C. Werlin, Mian Chen, Giorgio Mottola, Anuran Chatterjee, Kevin D. Lance, Daniel A. Bernards et al. "Perivascular delivery of resolvin D1 inhibits neointimal hyperplasia in a rabbit vein graft model." Journal of vascular surgery (2018). https://www.sciencedirect.com/science/article/pii/S0741521418313491

“Abstract: Objective: Inflammation is a key driver of excessive neointimal hyperplasia within vein grafts. Recent work demonstrates that specialized proresolving lipid mediators biosynthesized from omega-3 polyunsaturated fatty acids, such as resolvin D1 (RvD1), actively orchestrate the process of inflammation resolution. We investigated the effects of local perivascular delivery of RvD1 in a rabbit vein graft model. Methods: Ipsilateral jugular veins were implanted as carotid interposition grafts through an anastomotic cuff technique in New Zealand white rabbits (3-4 kg; N = 80). RvD1 (1 μg) was delivered to the vein bypass grafts in a perivascular fashion, using either 25% Pluronic F127 gel (Sigma-Aldrich, St. Louis, Mo) or a thin bilayered poly(lactic-co-glycolic acid) (PLGA) film. No treatment (bypass only) and vehicle-loaded Pluronic gels or PLGA films served as controls. Delivery of RvD1 to venous tissue was evaluated 3 days later by liquid chromatography-tandem mass spectrometry. Total leukocyte infiltration, macrophage infiltration, and cell proliferation were evaluated by immunohistochemistry. Elastin and trichrome staining was performed on grafts harvested at 28 days after bypass to evaluate neointimal hyperplasia and vein graft remodeling. Results: Perivascular treatments did not influence rates of graft thrombosis (23%), major wound complications (4%), or death (3%). Leukocyte (CD45) and macrophage (RAM11) infiltration was significantly reduced in the RvD1 treatment groups vs controls at 3 days (60%-72% reduction; P < .01). Cellular proliferation (Ki67 index) was also significantly lower in RvD1-treated vs control grafts at 3 days (40%-50% reduction; P < .01). Treatment of vein grafts with RvD1-loaded gels reduced neointimal thickness at 28 days by 61% vs bypass only (P < .001) and by 63% vs vehicle gel (P < .001). RvD1-loaded PLGA films reduced neointimal formation at 28 days by 50% vs bypass only (P < .001). RvD1 treatment was also associated with reduced collagen deposition in vein grafts at 28 days. Conclusions: Local perivascular delivery of RvD1 attenuates vein graft hyperplasia without associated toxicity in a rabbit carotid bypass model. This effect appears to be mediated by both reduced leukocyte recruitment and decreased cell proliferation within the graft. Perivascular PLGA films may also impart protection through biomechanical scaffolding in this venous arterialization model. Our studies provide further support for the potential therapeutic role of specialized proresolving lipid mediators such as D-series resolvins in modulating vascular injury and repair. Clinical Relevance: Autologous vein bypass grafts are the most durable means for revascularization in peripheral vascular disease; however, midterm and long-term outcomes are limited by vein graft hyperplasia with associated vein graft failure. Endogenous proresolving lipid mediators such as resolvin D1 have the potential to attenuate vein graft hyperplasia by accelerating repair. This study provides proof of concept for local delivery of resolvin D1 to reduce inflammation and to improve the healing response after vein bypass grafting. Keywords: Inflammation Resolution Resolvins Lipid mediator Neointimal hyperplasia Vein graft”

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