Disturbed flow in the juxta-anastomotic area of an arteriovenous fistula correlates with endothelial loss, acute thrombus formation and neointimal hyperplasia.

BACKGROUND: Clinical failure of arteriovenous fistulae (AVF) is frequently due to juxta-anastomotic neointimal hyperplasia (JANIH). Although the mouse AVF model recapitulates human AVF maturation, previous studies focused on the outflow vein distal to the anastomosis. We hypothesized that the juxta-anastomotic area (JAA) has increased NIH compared to the outflow vein. METHOD: AVF were created in C57BL/6 mice without or with chronic kidney disease (CKD). Temporal and spatial changes of the JAA were examined using histology and immunofluorescence. Computational techniques were used to model the AVF. RNA-seq and bioinformatic analyses were performed to compare the JAA with the outflow vein. The jugular vein to carotid artery AVF model was created in Wistar rats. RESULT: The neointima in the JAA shows increased volume compared to the outflow vein. Computational modeling shows increased volume of disturbed flow at the JAA compared to the outflow vein. Endothelial cells are immediately lost from the wall contralateral to the fistula exit, followed by thrombus formation and JANIH. Gene Ontology (GO) enrichment analysis of the 1862 differentially expressed genes (DEG) between the JANIH and the outflow vein identified 525 overexpressed genes. The rat jugular vein to carotid artery AVF showed changes similar to the mouse AVF. CONCLUSION: Disturbed flow through the JAA correlates with rapid endothelial cell loss, thrombus formation, and JANIH; late endothelialization of the JAA channel correlates with late AVF patency. Early thrombus formation in the JAA may influence later development of JANIH.

A central arteriovenous fistula reduces systemic hypertension in a mouse model.

Objective: A central arteriovenous fistula (AVF) has been proposed as a potential novel solution to treat patients with refractory hypertension. We hypothesized that venous remodeling after AVF creation in the hypertensive environment reduces systemic blood pressure but results in increased AVF wall thickness compared with remodeling in the normotensive environment. Methods: A central AVF was performed in C57BL6/J mice previously made hypertensive with angiotensin II (Ang II); mice were sacrificed on postoperative day 7 or 21. Results: In mice treated with Ang II alone, the mean systolic blood pressure increased from 90 ± 5 mmHg to 160 ± 5 mmHg at day 21; however, in mice treated with both Ang II and an AVF, the blood pressure decreased with creation of an AVF. There were significantly more PCNA-positive cells, SM22α/PCNA-positive cells, collagen I deposition, and increased Krüppel-like Factor 2 immunoreactivity in hypertensive mice with an AVF compared with normotensive mice with an AVF. Conclusions: These data show that a central AVF decreases systemic hypertension as well as induces local alterations in venous remodeling.

[Silver Ion Decreases Foreign Body Reaction and Venous Neointimal Hyperplasia through the Inhibition of Interleukin-33 Expression].

INTRODUCTION: Vascular prosthetic grafts are widely used in vascular surgery; however, graft infection remains a major concern. Silver-coated vascular grafts have demonstrated anti-infection properties in clinical settings; however, whether the silver irons influence foreign body reaction or neointimal hyperplasia remains unclear. METHODS: Sodium alginate and hyaluronic acid (SA/HA) hydrogel patches loaded with rhodamine, with or without silver, were fabricated. Patches were implanted in the subcutaneous or abdominal cavity and inferior vena cava of rats. Samples were harvested on day 14 and examined via immunohistochemical and immunofluorescence analyses. RESULTS: Silver hydrogel was found to decrease the foreign body reaction; after subcutaneous and abdominal cavity implantation in rats, the capsule was found to be thinner in the silver hydrogel group than in the control hydrogel group. The silver hydrogel group had fewer CD68-positive cells and proliferating cell nuclear antigen and interleukin-33 (IL-33) dual-positive cells than the control hydrogel group. Additionally, the silver hydrogel patch reduced the neointimal thickness after patch venoplasty in rats, and the number of IL-33- and IL-1ß-positive cells was lower than that in the control patch. CONCLUSION: Silver-loaded SA/HA hydrogel patches decreased the foreign body reaction and venous neointimal hyperplasia in rats by the inhibition of IL-33 expression.

Sex hormones impact early maturation and immune response in the arteriovenous fistula mouse model.

Arteriovenous fistulae (AVF) fail to mature more frequently in female patients compared with male patients, leading to inferior outcomes and decreased utilization. Since our mouse AVF model recapitulates sex differences in human AVF maturation, we hypothesized that sex hormones mediate these differences during AVF maturation. C57BL/6 mice (9-11 wk) were treated with aortocaval AVF surgery and/or gonadectomy. AVF hemodynamics were measured via ultrasound (days 0-21). Blood was collected for FACS and tissue for immunofluorescence and ELISA (days 3 and 7); wall thickness was assessed by histology (day 21). Inferior vena cava shear stress was higher in male mice (P = 0.0028) after gonadectomy, and they had increased wall thickness (22.0 ± 1.8 vs. 12.7 ± 1.2 µm; P < 0.0001). Conversely, female mice had decreased wall thickness (6.8 ± 0.6 vs. 15.3 ± 0.9 µm; P = 0.0002). Intact female mice had higher proportions of circulating CD3+ T cells on day 3 (P = 0.0043), CD4+ (P = 0.0003) and CD8+ T cells (P = 0.005) on day 7, and CD11b+ monocytes on day 3 (P = 0.0046). After gonadectomy, these differences disappeared. In intact female mice, CD3+ T cells (P = 0.025), CD4+ T cells (P = 0.0178), CD8+ T cells (P = 0.0571), and CD68+ macrophages (P = 0.0078) increased in the fistula wall on days 3 and 7. This disappeared after gonadectomy. Furthermore, female mice had higher IL-10 (P = 0.0217) and TNF-α (P = 0.0417) levels in their AVF walls than male mice. Sex hormones mediate AVF maturation, suggesting that hormone receptor signaling may be a target to improve AVF maturation.NEW & NOTEWORTHY After arteriovenous fistula creation, females have lower rates of maturation and higher rates of failure than males. In a mouse model of venous adaptation that recapitulates human fistula maturation, sex hormones may be mechanisms of the sexual dimorphism: testosterone is associated with reduced shear stress, whereas estrogen is associated with increased immune cell recruitment. Modulating sex hormones or downstream effectors suggests sex-specific therapies and could address disparities in sex differences in clinical outcomes.

Decellularized fish swim bladder patch loaded with mesenchymal stem cells inhibits neointimal hyperplasia.

We previously showed decellularized fish swim bladder can be used as vascular patch and tube graft in rats, mesenchymal stem cells (MSCs) have showed the capability to inhibit neointimal hyperplasia in different animal models. We hypothesized that decellularized fish swim bladder patch loaded with MSCs (bioinspired patch) can inhibit neointimal hyperplasia in a rat aortic patch angioplasty model. Rat MSCs were grown in vitro and flow cytometry was used to confirm their quality. 3.6 × 105 MSCs were mixed into 100 µl of sodium alginate (SA)/hyaluronic acid (HA) hydrogel, two layers of fish swim bladders (5 mm × 5 mm) were sutured together, bioinspired patch was created by injection of hydrogel with MSCs into the space between two layers of fish swim bladder patches. Decellularized rat thoracic aorta patch was used as control. Patches were harvested at days 1 and 14 after implantation. Samples were examined by histology, immunohistochemistry, and immunofluorescence. The decellularized rat thoracic aorta patch and the fish swim bladder patch had a similar healing process after implantation. The bioinspired patch had a similar structure like native aorta. Bioinspired patch showed a decreased neointimal thickness (p = .0053), fewer macrophages infiltration (p = .0090), and lower proliferation rate (p = .0291) compared to the double layers fish swim bladder patch group. Decellularized fish swim bladder patch loaded with MSCs can inhibit neointimal hyperplasia effectively. Although this is a preliminary animal study, it may have a potential application in large animals or clinical research.

Fibronectin 1 derived from tumor-associated macrophages and fibroblasts promotes metastasis through the JUN pathway in hepatocellular carcinoma.

OBJECTIVE: Intercellular communication in the tumor microenvironment is a potential regulator of metastasis. To explore the specific mechanism, we performed a multi-omics analysis of hepatocellular carcinoma. MATERIALS AND METHODS: Multiple omics data including scRNA-seq, ATAC-seq, RNA-seq, and methylation data were obtained from GEO and TCGA databases. SCENIC was used to identify key transcription factors and their Regulatory networks. ScMLnet was used to explore the mechanism of intercellular communication in the microenvironment. Multiple omics studies based on RNA-seq, ATAC-seq, and methylation data were used to explore downstream mechanisms of key transcription factors. Based on the analysis of cell differentiation trajectory and transcription subtypes, the regulation of cell communication on tumor subtypes was studied, and possible therapeutic compounds were explored. The universality of this mechanism was investigated by post-Pan-cancer analysis. RESULTS: JUN and its regulatory network play a key role in HCC, which was mainly positively correlated with tumor-associated macrophages and fibroblasts. Intercellular communication analysis showed that macrophage and fibroblast-derived FN1 could increase JUN by TNFRSF11B/SMAD3. Multiomics analysis showed that KIF13A was a key downstream gene of JUN, which was involved in the activation of the hippo pathway. Analysis of cell differentiation trajectory, transcriptome subtypes, and neural network modeling showed that intercellular communication in the microenvironment can regulate the transcriptome characterization of HCC. Pan-cancer analysis indicates that this mechanism may be universal. CONCLUSION: FN1 derived from tumor-associated macrophages and fibroblasts promotes metastasis and alters transcriptome subtypes through the JUN-Hippo signaling pathway in HCC, which may be universal in cancers.

Non-Surgical treatment Versus Surgery for Iatrogenic Femoral Artery Pseudoaneurysms: Systematic Review and Meta-Analysis.

Objectives: This study compared results of non-surgical treatment (compression and ultrasound guided thrombin injection (UGTI)) and surgery to treat iatrogenic femoral artery pseudoaneurysms. Methods: PubMed and Embase databases were searched up to October 2021. Primary outcome measure was success rate, and other outcomes examined were complication rate, reintervention rate. Two authors independently reviewed and extracted data. Data were presented as the odds ratios (ORs) with 95% confidence intervals (CIs). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to appraise the quality of the body of evidence. Results: Eight studies were included. A total of 623 patients with pseudoaneurysm undergoing treatment were included, of which 163 subjects underwent surgery, 397 subjects underwent compression, and 63 subjects underwent UGTI. The success rate was significantly lower in the non-surgery group (OR 0.24, 95% CI, 0.08-0.69, I 2 = 0%). The complication rate was significantly lower in the non-surgery group (OR 0.10, 95% CI, 0.03 -0.29, I 2 = 0%). Patients in the non-surgery group tended to have a lower, but statistically insignificant, reintervention rate (OR 0.11, 95% CI, 0.01-1.06, I 2 = 35%). Further, the GRADE assessment showed that these results (success rate, complication rate, and reintervention rate) were of very low quality. Conclusions: Available evidence shows that it is reasonable to regard non-surgical treatment as the primary treatment for iatrogenic femoral artery pseudoaneurysms, and surgery as a remedy after failure of non-surgical treatment in some cases.

Wood-Derived Vascular Patches Loaded With Rapamycin Inhibit Neointimal Hyperplasia.

Background: Patches are commonly used to close blood vessels after vascular surgery. Most currently used materials are either prosthetics or animal-derived; although natural materials, such as a leaf, can be used as a patch, healing of these natural materials is not optimal; rhodamine and rapamycin have been used to show that coating patches with drugs allow drug delivery to inhibit neointimal hyperplasia that may improve patch healing. Wood is abundant, and its stiffness can be reduced with processing; however, whether wood can be used as a vascular patch is not established. We hypothesized that wood can be used as a vascular patch and thus may serve as a novel plant-based biocompatible material. Method: Male Sprague-Dawley rats (aged 6-8 weeks) were used as an inferior vena cava (IVC) patch venoplasty model. After softening, wood patches coated with rhodamine and rapamycin were implanted into the rat subcutaneous tissue, the abdominal cavity, or the IVC. Samples were explanted on day 14 for analysis. Result: Wood patches became soft after processing. Patches showed biocompatibility after implantation into the subcutaneous tissue or the abdominal cavity. After implantation into the IVC, the patches retained mechanical strength. There was a significantly thinner neointima in wood patches coated with rapamycin than control patches (146.7 ± 15.32 µm vs. 524.7 ± 26.81 µm; p = 0.0001). There were CD34 and nestin-positive cells throughout the patch, and neointimal endothelial cells were Eph-B4 and COUP-TFII-positive. There was a significantly smaller number of PCNA and α-actin dual-positive cells in the neointima (p = 0.0003), peri-patch area (p = 0.0198), and adventitia (p = 0.0004) in wood patches coated with rapamycin than control patches. Piezo1 was expressed in the neointima and peri-patch area, and there were decreased CD68 and piezo1 dual-positive cells in wood patches coated with rapamycin compared to control patches. Conclusion: Wood can be used as a novel biomaterial that can be implanted as a vascular patch and also serve as a scaffold for drug delivery. Plant-derived materials may be an alternative to prosthetics or animal-based materials in vascular applications.

Outcomes of transcarotid artery revascularization: A systematic review.

BACKGROUND: Ischemic stroke and disability caused by carotid artery stenosis have always been worldwide problems. At present, carotid endarterectomy (CEA) and transfemoral carotid artery stenting (TFCAS) have been commonly used to treat carotid artery stenosis. Recently, transcarotid artery revascularization (TCAR) seems to be another option. METHODS: We searched PubMed and Embase to find literatures comparing TCAR with TFCAS and CEA. The primary outcomes were stroke, myocardial infarction (MI), transient ischemic attack (TIA), death, cranial nerve injure (CNI), and operative time. Secondary outcomes were stroke, death, MI in the elderly; cost; radiation; and entry site complication. RESULTS: Initial search of the literature included 165 articles, of which 12 studies were chosen in the end. These studies demonstrated high technical success rate of TCAR. Patients who received TCAR had lower risks of death, stroke/death and less radiation exposure compared to TFCAS. In meta analysis, the risk of stroke was significantly lower in TCAR group than TFCAS (OR 0.63; 95%CI 0.47-0.85). And there was no significant difference in TIA and MI. TCAR was associated with shorter operative time, lower risk of CNI and less blood loss compared to CEA. In older patients, the effect of TCAR was significantly better than that of TFCAS. CONCLUSION: TCAR is associated with a lower risk of perioperative stroke compared to TFCAS. TCAR is also associated with shorter operative time, lower risk of CNI and less blood loss compared to CEA. TCAR may be a promising treatment option besides TFCAS and CEA.

Delivery of rivaroxaban and chitosan rapamycin microparticle with dual antithrombosis and antiproliferation functions inhibits venous neointimal hyperplasia.

Neointimal hyperplasia is a complex process after vascular interventions, acute platelet deposition and smooth muscle cell proliferation both contributed to this process. There are still no perfect solutions to solve this problem. Rivaroxaban is a novel anticoagulant that has been widely used in clinic, it has a good pharmacological effects both in vivo and in vitro. Chitosan microparticle rapamycin (MP-rapa) was fabricated, interspaces of polyglycolic acid (PGA) scaffold were used as a reservoir of MP-rapa, and the scaffold was coated with hyaluronic acid rivaroxaban (MP-rapa-riva). Scanning electronic microscopy (SEM) photographs were taken and water contact angles were measured, rat inferior vena cava (IVC) patch venoplasty model was used; patches were harvested at day 14 and examined by immunohistochemistry and immunofluorescence. SEM photographs showed the microparticles rapamycin were inside the interspace of the scaffold, hyaluronic acid rivaroxaban was also successfully coated onto the surface of the scaffold. There was a thinner neointima, fewer proliferating cell nuclear antigen (PCNA) positive cells, fewer macrophages in the MP-rapa and MP-rapa-riva grafts compared to the control PGA graft. The result showed that this scaffold with dual anticoagulation and antiproliferation functions can effectively inhibit venous neointimal hyperplasia, although this is an animal experiment, it showed promising potential clinical application in the future.

Systematic Review and Meta-Analysis of Published Studies on Endovascular Repair of Abdominal Aortic Aneurysm With the p-Branch.

Background: Endovascular treatment of juxtarenal or pararenal abdominal aortic aneurysms is more popular than open surgery, mainly because it reduces perioperative mortality and morbidity. The custom-made fenestrated devices need to be tailored to each patient, so these devices require extra manufacturing and shipping time. The increased wait time may increase the risk of aneurysm rupture in some patients. In some situations, "Off-the-shelf" (OTS) fenestrated grafts can be used. The Cook Zenith p-Branch device (William Cook Australia, Brisbane, Australia) is a relatively common OTS. This study aimed to systematically evaluate all published experiences with p-Branch. Methods: We searched PubMed, Embase, and Cochrane to find works of literature that reported on the outcomes of patients treated with the p-Branch stent-grafts. Then we conducted an assessment of quality and meta-analysis of the results. The primary endpoints were the application rate of p-Branch stent-graft (type A, B), technical success rate, and early re-intervention rate. We estimated pooled proportions and 95% CIs. Results: Initial search of the literature included 111 articles, of which 7 studies were included in the end. A total of 260 patients were enrolled in these studies, and 218 patients were eventually treated with p-Branch. The pooled application rate of type A devices was 48% (95% CI, 29-67%), and pooled application rate of type B devices was 30% (95% CI, 16-44%). The pooled technical success rate was 87% (95% CI, 75-98%). The early re-intervention rate was 10% (95% CI, 3-17%). Midterm renal infarct rate (after 30 days) was 3% (95% CI, 0-6%). Midterm re-intervention rate (after 30 days) was 30% (95% CI, 3-57%). Midterm renal failure rate (after 30 days) was 6% (95% CI, 2-10%). Conclusions: This pooled analysis indicated an acceptable technical success rate after p-Branch stent-graft implantation, with early and midterm re-intervention rate and renal failure rate that cannot be ignored. The p-Branch repair of juxtarenal abdominal aortic aneurysms may be an appropriate and safe option, especially in emergency situations.

The Current State of Vascular Surgery Presence in Bilibili Video Platform of China.

Background: With the development of the Internet, more and more patients search for disease-related information on video platforms during the treatment process, and physicians also look for learning materials through these video platforms. Bilibili is one of the most popular video platforms in China. This study evaluated information on various interesting topics, and related surgical procedures searched through Bilibili. Method: The Bilibili platform was independently queried for 12 common vascular diseases or related surgical procedures between October and November 2021 by two independent authors using the Baidu search engine. Information about the video and uploader was collected, and descriptive analyses of the overall and first-page results were performed. Results: A total of 3,998 search results were retrieved by searching 12 vascular-related topics, of which 2,225 actual videos (55.7%) were finally confirmed to be related to medicine. Videos for the public accounted for 84.8% of these 2,225 videos. In addition, 50.5% of the video results were uploaded by vascular surgeons, 12.4% by other specialties, 17.7% by organizations, and 19.4% by other individuals. The total number of videos searched for varicose vein and peripheral vascular diseases was the largest, and the total number of leg amputation videos was the smallest. The largest number of videos for medical professionals was about pulmonary embolism, and the smallest was about leg amputation. On the first pages, 168 results (70.0%) were actually medically relevant, and only 7.7% of the videos were uploaded by vascular surgeons. Conclusion: On the Bilibili platform, videos about vascular diseases are extensive but not comprehensive. The videos uploaded by vascular surgeons are rare, and the results searched are not precise. The online presence of vascular surgeons needs to be improved, which may partially solve the problem of low-quality videos due to the lack of strict management and censorship.

Intramural injection of pluronic gel loaded with drugs to alleviate arterial injury.

BACKGROUND: Balloon angioplasty, stent implantation, and application of an arterial clamp during surgery can induce artery injury such as elastin breaks and endothelium injury, but there is little research focused on the injury induced by these therapeutic manipulations. We established a simple and reproducible small animal aortic injury model and examined intramural injection as a potential therapeutic method to alleviate injury. MATERIALS AND METHODS: The abdominal aorta of male Sprague Dawley (SD) rats or C57BL/6 J mice was clamped sequentially throughout its length. Transforming growth factor ß1 (TGFß1), SB431542, lipopolysaccharide (LPS), Necrostatin-1 (Nec-1), rapamycin, or MHY1485 contained in Pluronic gel was injected intramurally at day 0 or day 7. Animals were fed with chow containing 0.25% beta-aminopropionitrile (BAPN) to evaluate the influence of BAPN. All samples were harvested and examined by immunohistochemistry and immunofluorescence. RESULTS: The clamped rat aorta showed luminal dilation, elastin fiber breaks, neointimal hyperplasia, and dissection (days 0-90). Intramural injection of TGFß1, rapamycin and Nec-1 showed a protective effect on the injured aorta, whereas SB431542, MHY1485 and LPS showed more severe wall damage. The aortic lumen in rats fed with BAPN was significantly larger than in control rats (day 7). Mouse aorta showed similar injury with neointimal hyperplasia and elastin fiber breaks. CONCLUSIONS: The rodent arterial injury model is reproducible and may mimic early changes of arterial injury. The model accommodates intramural injection of different drugs that may show mechanisms of arterial injury. Although this is a preliminary animal model, the intramural injection method may have potential clinical application in the future.

A Systematic Review and Meta-Analysis of Seasonal and Monthly Variability in the Incidence of Acute Aortic Dissection.

BACKGROUND: This study explored seasonal and monthly variations of the incidence of acute aortic dissection (AAD). METHODS: MEDLINE, EMBASE, and the Cochrane Library databases were searched up to July 2021. Temporal variation in the incidence of AAD was analyzed including all studies analyzing seasonal and monthly aggregations. Then, we performed subgroup analyses according to the type of AAD. Two authors independently reviewed and extracted data. RESULTS: Twenty-seven studies for a total of 128,101 patients were included. Our results showed that the incidence of AAD was highest in winter and lowest in summer. Regardless of type A or type B, the incidence of AAD was significantly higher in winter than in summer and autumn. Nonetheless, there was no significant difference between spring and winter, and between summer and autumn. Results may be limited by the quality of the included articles. However, in the sensitivity analysis that excluded low-quality studies, results did not change significantly. In addition, the pooled incidence was highest in January and lowest in August. CONCLUSIONS: Our data strongly support the presence of distribution patterns in the incidence of AAD, characterized by significantly higher risk in winter and in January. These distribution patterns of AAD incidence may help to develop better prevention strategies.

Egg Shell Membrane as an Alternative Vascular Patch for Arterial Angioplasty.

Introduction: The egg shell membrane (ESM) is always considered as waste, but recent studies have shown that it has the potential to yield rapid re-endothelialization in vitro. We hypothesized that ESM and heparin-conjugated ESM (HESM) can be used as arterial patch in a rat aortic angioplasty model. Method: Sprague-Dawley rat (200 g) abdominal aortic patch angioplasty model was used. Decellularized rat thoracic aorta (TA) patch was used as the control; ESM patch was made of raw chicken egg; heparin-coated ESM (HESM) patch was made by using dopamine; anticoagulation properties were verified using platelet adhesion tests; the TA, ESM, and HESM patches were implanted to the rat aorta and harvested at day 14; and the samples were examined by immunohistochemistry and immunofluorescence. Result: The ESM patch showed a similar healing process to the TA patch; the cells could migrate and infiltrate into both patches; there was a neointima with von Willebrand factor-positive endothelial cells; the endothelial cells acquired arterial identity with Ephrin-B2- and dll-4-positive cells; there were proliferating cell nuclear antigen (PCNA)-positive cells, and PCNA and alpha smooth muscle actin dual-positive cells in the neointima in both groups. Heparin was conjugated to the patch successfully and showed a strong anticoagulation property in vitro. HESM could decrease mural thrombus formation after rat aortic patch angioplasty. Conclusion: The ESM is a natural scaffold that can be used as a vascular patch; it showed a similar healing process to decellularized TA patch; HESM showed anticoagulation property both in vitro and in vivo; and the ESM may be a promising vascular graft in the clinic.

Adventitial injection of HA/SA hydrogel loaded with PLGA rapamycin nanoparticle inhibits neointimal hyperplasia in a rat aortic wire injury model.

Neointimal hyperplasia is a persistent complication after vascular interventions, and it is also the leading cause of vascular graft restenosis and failure after arterial interventions, so novel treatment methods are needed to treat this complication. We hypothesized that adventitial injection of HA/SA hydrogel loaded with PLGA rapamycin nanoparticle (hydrogel-PLGA-rapamycin) could inhibit neointimal hyperplasia in a rat aortic wire injury model. The HA/SA hydrogel was fabricated by the interaction of hyaluronic acid (HA), sodium alginate (SA), and CaCO3; and loaded with PLGA rapamycin nanoparticle or rhodamine uniformly. A SD rat aortic wire injury induced neointimal hyperplasia model was developed, the control group only received wire injury, the adventitial application group received 10 µL hydrogel-PLGA-rapamycin after wire injury, and the adventitial injection group received 10 µL hydrogel-PLGA-rapamycin injected into the aortic adventitia after wire injury. Tissues were harvested at day 21 and analyzed by histology and immunohistochemical staining. Hydrogel loaded with rhodamine can be successfully injected into the aortic adventitia and was encapsuled by the adventitia. The hydrogel could be seen beneath the adventitia after adventitial injection but was almost degraded at day 21. There was a significantly thinner neointima in the adventitial application group and adventitial injection group compared to the control group (p = 0.0009). There were also significantly fewer CD68+ (macrophages) cells (p = 0.0012), CD3+ (lymphocytes) cells (p = 0.0011), p-mTOR+ cells (p = 0.0019), PCNA+ cells (p = 0.0028) in the adventitial application and adventitial injection groups compared to the control group. The endothelial cells expressed arterial identity markers (Ephrin-B2 and dll-4) in all these three groups. Adventitial injection of hydrogel-PLGA-rapamycin can effectively inhibit neointimal hyperplasia after rat aortic wire injury. This may be a promising drug delivery method and therapeutic choice to inhibit neointimal hyperplasia after vascular interventions.

PLGA Nanoparticle Rapamycin- or Necrostatin-1-Coated Sutures Inhibit Inflammatory Reactions after Arterial Closure in Rats.

Background: The inflammatory reaction of sutures and oozing after arterial closure depends on the suture material and the amount of oozing surrounding the sutures. Anti-inflammation coatings have been proven to be an effective strategy to decrease this reaction. The aim of this study was to establish an arterial closure oozing model in rats and to test the effect of poly (lactic-co-glycolic acid) (PLGA) nanoparticle (NP) rapamycin- or necrostatin-1(NEC-1)-coated sutures on the inflammatory reaction after arterial closure. Methods and Materials: A 10 mm arteriotomy was carried out on the carotid artery of Sprague-Dawley rats and closed using 11-0 sutures. PLGA NP-rapamycin and NEC-1 were made. The 11/0 nylon sutures were coated with PLGA NP-rapamycin and NEC-1. Sutures were examined by scanning electron microscopy, hemolysis test, and cumulative release. The carotid arteriotomy was closed using uncoated PLGA NP-rapamycin- and NP-NEC-1-coated sutures. The carotid artery was harvested on day 7. Tissues were examined by histology and immunohistochemistry. Results: There were severe inflammatory reactions in the oozing arteries compared to the normal healing arteries (P = 0.0192). PLGA NP-rapamycin- and NEC -1-coated sutures reduced foreign body reaction compared to the uncoated sutures. There were significantly smaller number of CD3 (P = 0.0068), CD45 (P = 0.0300), and CD68 (P = 0.0011) cells in the PLGA NP-rapamycin- and NP-NEC-1-coated groups compared to the uncoated group. There was a smaller number of p-mTOR (P = 0.0198)-positive cells in the PLGA NP-rapamycin-coated group compared to the uncoated group. There was a smaller number of TNFα (P = 0.0198)-positive cells in the PLGA NP-NEC-1-coated group compared to the uncoated group. Conclusions: In this rat carotid artery oozing model, PLGA NP-rapamycin- or NP-NEC-1-coated sutures can inhibit inflammatory reaction and foreign body reaction. Although this was a small rodent animal experiment, this coated suture may have a potential clinical application in the future.

ADAM17: A novel treatment target for aneurysms.

PURPOSE: The mechanisms underlying abdominal aortic aneurysms (AAAs) are still not fully understood, previous researches showed ADAM17 is increased in aneurysm. We hypothesized that inhibiting ADAM17 can decrease AAA formation and progression. MATERIALS AND METHODS: Aneurysm models were established in mouses and rats by aortic adventitial CaCl2 incubation and aortic pericardial patch angioplasty respectively. In mouse, control (no treatment) or SA/HA hydrogel loaded with TAPI-1 (ADAM17 inhibitor) were adventitial applied; in rat, control and TAPI-1 coated pericardial patch were used in rat aortic pericardial patch angioplasty. Samples were harvested on day 14 or 30 and analyzed by immunofluorescence. Bioinformatics analysis and immunostaining analysis were carried out to confirm the therapeutic potential of ADAM17 in the human AAA. RESULTS: ADAM17 was highly expressed in mouses, rats and human aneurysms. Adventitial application of SA/HA hydrogel loaded TAPI-1 or TAPI-1 conjugated pericardial patch can decrease AAA formation and progression in mouses and rats, respectively. Bioinformatic analysis showed ADAM17 promotes transformation of M1 macrophages and synthetic vascular smooth muscle cells, together with immunostaining analysis and results from animal models, the therapeutic potential of ADAM17 in the human AAA were confirmed. CONCLUSION: We showed that local delivery of ADAM17 inhibitor can inhibit aneurysm formation and progression in mouse and rat, these results showed ADAM17 plays an important role in the aneurysm formation and may be a potential treatment target.

Antegrade in situ laser fenestration of aortic stent graft during endovascular aortic repair: A case report.

BACKGROUND: The endovascular repair of juxtarenal abdominal aortic aneurysms (JAAA) usually requires combination treatment with various stent graft modifications to preserve side branch patency. As a feasible technique, according to the situation, antegrade in situ laser fenestration still needs to be improved. CASE SUMMARY: This report describes a case that was successfully treated with endovascular repair facilitated by antegrade in situ laser fenestration while maintaining renal arterial flow. Laser fenestration was performed using a steerable sheath positioned in the stent graft lumen in front of the renal artery ostium. With the bare stent region unreleased, renal artery perfusion could be maintained and accurate positioning could be achieved by angiography in real time. CONCLUSION: This study suggests the feasibility and short-term safety of this novel antegrade in situ laser fenestration technique for select JAAA patients.

Biodegraded PCl and gelatin fabricated vascular patch in rat aortic and inferior vena cava angioplasty.

Novel synthetic prosthesis materials for patch angioplasty are continuously under development and optimization. When a nonwoven-based gelatin membrane is coupled with an electrospun layer of polycaprolactone (PCL), these biohybrid polymer membranes (BHMs) possess higher mechanical properties in aqueous environments. We hypothesized that BHMs can also be used as vascular patches, and we tested our hypothesis in a rat IVC venoplasty and aortic arterioplasty model. Patch venoplasty and arterioplasty were performed in SD rats (200 g), the patches were harvested at day 14, and samples were analyzed by immunohistochemistry and immunofluorescence. The BHM patches were almost degraded, with few parts remaining after 14 days. There was a line of CD34- and nestin-positive cells on the endothelium, with some cells were CD34 and nestin dual-positive, macrophages and leukocytes also participated in the patch healing process. There were PCNA-positive cells in the neointima and peri-patch area, with some cells were also PCNA and α-actin dual-positive. Arterial neointimal endothelial cells were Ephrin-B2- and dll-4-positive, and venous neointimal endothelial cells were Eph-B4- and COUP-TFII-positive. BHM shares a similar healing process like other patch materials, and BHM may have potential applications in vascular surgery.