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Covalent modification of pericardial patches for sustained rapamycin delivery inhibits venous neointimal hyperplasia.

ABSTRACT: Prosthetic grafts and patches are commonly used in cardiovascular surgery, however neointimal hyperplasia remains a significant concern, especially under low flow conditions. We hypothesized that delivery of rapamycin from nanoparticles (NP) covalently attached to patches allows sustained site-specific delivery of therapeutic agents targeted to inhibit localized neointimal hyperplasia. NP were covalently linked to pericardial patches using EDC/NHS chemistry and could deliver at least 360?ng rapamycin per patch without detectable rapamycin in serum; nanoparticles were detectable in the liver, kidney and spleen but no other sites within 24?hours. In a rat venous patch angioplasty model, control patches developed robust neointimal hyperplasia on the patch luminal surface characterized by Eph-B4-positive endothelium and underlying SMC and infiltrating cells such as macrophages and leukocytes. Patches delivering rapamycin developed less neointimal hyperplasia, less smooth muscle cell proliferation, and had fewer infiltrating cells but retained endothelialization. NP covalently linked to pericardial patches are a novel composite delivery system that allows sustained site-specific delivery of therapeutics; NP delivering rapamycin inhibit patch neointimal hyperplasia. NP linked to patches may represent a next generation of tissue engineered cardiovascular implants.

SUBMITTER: Bai H

PROVIDER: S-EPMC5223139 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Covalent modification of pericardial patches for sustained rapamycin delivery inhibits venous neointimal hyperplasia.

Bai Hualong H Lee Jung Seok JS Chen Elizabeth E Wang Mo M Xing Ying Y Fahmy Tarek M TM Dardik Alan A

Scientific reports 20170110

Prosthetic grafts and patches are commonly used in cardiovascular surgery, however neointimal hyperplasia remains a significant concern, especially under low flow conditions. We hypothesized that delivery of rapamycin from nanoparticles (NP) covalently attached to patches allows sustained site-specific delivery of therapeutic agents targeted to inhibit localized neointimal hyperplasia. NP were covalently linked to pericardial patches using EDC/NHS chemistry and could deliver at least 360 ng rapa ...[more]

PMID: 28071663

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Project description:Background and objectivesThere is increasing evidence that microRNAs (miRNAs) play crucial roles in the regulation of neointima formation. However, the translational evidence of the role of miRNAs in dialysis vascular access is limited.Design, setting, participants, & measurementsmiRNA expression in tissues was assessed by using venous tissues harvested from ten patients on dialysis who received revision or removal surgery, and ten patients who were predialysis and received creation surgery of arteriovenous fistulas served as controls. To extend these findings, 60 patients who received angioplasty of dialysis access were enrolled and the levels of circulating miRNAs were determined before and 2 days after angioplasty. Clinical follow-up was continued monthly for 6 months. The primary outcome of angioplasty cohort was target lesion restenosis within 6 months after angioplasty.ResultsIn the surgery cohort, the expressions of miR-21, miR-130a, and miR-221 were upregulated in stenotic tissues, whereas those of miR-133 and miR-145 were downregulated. In situ hybridization revealed similar expression patterns of these miRNAs, localized predominantly in the neointima region. Twenty eight patients in the angioplasty cohort developed restenosis within 6 months. The levels of circulating miR-21, miR-130a, miR-221, miR-133, and miR-145 significantly increased 2 days after angioplasty. Kaplan-Meier plots showed that patients with an increase of miR-21 expression level >0.35 have a higher risk of patency loss (hazard ratio, 4.45; 95% confidence interval, 1.68 to 11.7). In a multivariable analysis, postangioplasty increase of miR-21 expression was independently associated with restenosis (hazard ratio, 1.20; 95% confidence interval, 1.07 to 1.35 per one unit increase of miR-21 expression level; P=0.001).ConclusionsCertain miRNAs are differentially expressed in the stenotic venous segments of dialysis accesses. An increase in blood miR-21 level with angioplasty is associated with a higher risk of restenosis.

Project description:Introduction: We recently showed that a decellularized leaf scaffold can be loaded with polylactic-co-glycolic acid (PLGA)-based rapamycin nanoparticles, this leaf patch can then inhibit venous neointimal hyperplasia in a rat inferior vena cava (IVC) venoplasty model. IL-33 plays a role in the neointimal formation after vascular injury. We hypothesized that plant leaves can absorb therapeutic drug solution and can be used as a patch with drug delivery capability, and plant leaves absorbed with IL-33 antibody can decrease venous neointimal hyperplasia in the rat IVC venoplasty model. Method: A human spiral saphenous vein (SVG) graft implanted in the popliteal vein was harvested from a patient with trauma and analyzed by immunofluorescence. Male Sprague-Dawley rats (aged 6-8 weeks) were used to create the IVC patch venoplasty model. Plant leaves absorbed with rhodamine, distilled water (control), rapamycin, IL-33, and IL-33 antibody were cut into patches (3 × 1.5 mm2) and implanted into the rat IVC. Patches were explanted at day 14 for analysis. Result: At day 14, in the patch absorbed with rhodamine group, immunofluorescence showed rhodamine fluorescence in the neointima, inside the patch, and in the adventitia. There was a significantly thinner neointima in the plant patch absorbed with rapamycin (p = 0.0231) compared to the patch absorbed with distilled water. There was a significantly large number of IL-33 (p = 0.006) and IL-1β (p = 0.012) positive cells in the human SVG neointima compared to the human great saphenous vein. In rats, there was a significantly thinner neointima, a smaller number of IL-33 (p = 0.0006) and IL-1β (p = 0.0008) positive cells in the IL-33 antibody-absorbed patch group compared to the IL-33-absorbed patch group. Conclusion: We found that the natural absorption capability of plant leaves means they can absorb drug solution efficiently and can also be used as a novel drug delivery system and venous patch. IL-33 plays a role in venous neointimal hyperplasia both in humans and rats; neutralization of IL-33 by IL-33 antibody can be a therapeutic method to decrease venous neointimal hyperplasia.

Project description: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 ?g) 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.

Project description:Arteriovenous fistulas (AVFs) used for hemodialysis fail because of venous neointimal hyperplasia (VNH). There are 1,500,000 patients that have end stage renal disease worldwide and the majority requires hemodialysis. In the present study, the role of the intermediate early response gene X-1 (IEX-1), also known as IER-3 in the pathogenesis of VNH was evaluated. In human samples removed from failed AVF, there was a significant increase in IEX-1 expression localized to the adventitia. In Iex-1-/- mice and wild type (WT) controls, chronic kidney disease was induced and an AVF placed 28 days later by connecting the carotid artery to jugular vein. The outflow vein was removed three days following the creation of the AVF and gene expression analysis demonstrated a significant decrease in vascular endothelial growth factor-A (Vegf-A) and monocyte chemoattractant protein-1 (Mcp-1) gene expression in Iex-1-/- mice when compared to WT mice (P<0.05). At 28 days after AVF placement, histomorphometric and immune-histochemical analyses of the outflow vein demonstrated a significant decrease in neointimal hyperplasia with an increase in average lumen vessel area associated with a decrease in fibroblast, myofibroblast, and Ly6C staining. There was a decrease in proliferation (Ki-67) and an increase in the TUNEL staining in Iex-1 KO mice compared to WT. In addition, there was a decrease in Vegf-A, Mcp-1, and matrix metalloproteiniase-9 (Mmp-9) staining. Iex-1 expression was reduced in vivo and in vitro using nanoparticles coated with calcitriol, an inhibitor of Iex-1 that demonstrated that Iex-1 reduction results in decrease in Vegf-A. In aggregate, these results indicate that the absence of IEX-1 gene results in reduced VNH accompanied with a decrease in proliferation, reduced fibroblast, myofibroblast, and Ly6C staining accompanied with increased apoptosis mediated through a reduction in Vegf-A/Mcp-1 axis and Mmp-9. Adventitial delivery of nanoparticles coated with calcitriol reduced Iex-1 and VNH.

Dataset Information

Covalent modification of pericardial patches for sustained rapamycin delivery inhibits venous neointimal hyperplasia.

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Covalent modification of pericardial patches for sustained rapamycin delivery inhibits venous neointimal hyperplasia.

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