3D-Printed Stents Loaded with Panax notoginseng Saponin for Promoting Re-endothelialization and Reducing Local Inflammation in the Carotid Artery of Rabbits.

Endovascular treatment (EVT) using stents has become the primary option for severe cerebrovascular stenosis. However, considerable challenges remain to be addressed, such as in-stent restenosis (ISR) and late thrombosis. Many modified stents have been developed to inhibit the hyperproliferation of vascular smooth muscle cells (SMCs) and protect vascular endothelial cells (VECs), thereby reducing such complications. Some modified stents, such as those infused with rapamycin, have improved in preventing acute thrombosis. However, ISR and late thrombosis, which are long-term complications, remain unavoidable. Panax notoginseng saponin (PNS), a traditional Chinese medicine consisting of various compounds, is beneficial in promoting the proliferation and migration of VECs and inhibiting the proliferation of SMCs. Herein, a 3D-printed polycaprolactone (PCL) stent loaded with PNS (PNS-PCL stent) was developed based on a previous study. In vitro studies confirmed that PNS promotes the migration and proliferation of VECs, which were damaged, by increasing the expression levels of microRNA-126, p-AKT, and endothelial nitric oxide synthase. In vivo, the PNS-PCL stents maintained the patency of the carotid artery in rabbits for up to three months, outperforming the PCL stents. The PNS-PCL stents may present a new solution for the EVT of cerebrovascular atherosclerotic stenosis in the future.

A Hexanuclear Gadolinium(III)-Based Nanoprobe for Magnetic Resonance Imaging of Tumor Apoptosis.

Magnetic resonance imaging (MRI) is instrumental in the noninvasive evaluation of tumor tissues in patients subjected to chemotherapy, thereby yielding essential diagnostic data crucial for the prognosis of tumors and the formulation of therapeutic strategies. Currently, commercially available MRI contrast agents (CAs) predominantly consist of mononuclear gadolinium(III) complexes. Because there is only one Gd(III) atom per molecule, these CAs often require administration in high doses to achieve the desired contrast quality, which inevitably leads to some adverse events. Herein, we develop a six-nuclei, apoptosis-targeting T1 CA, Gd6-ZnDPA nanoprobe, which consists of a hexanuclear gadolinium nanocluster (Gd6) with an apoptosis-targeting group (ZnDPA). The amplification of Gd(III) by the hexanuclear structure generates its high longitudinal relaxivity (44.67 mM-1 s-1, 1T) and low r1/r2 ratio (0.68, 1T). Based on the Solomon-Bloembergen-Morgan (SBM) theory, this notable improvement is primarily ascribed to a long correlation tumbling time (τR). More importantly, the Gd6-ZnDPA nanoprobe shows excellent tumor apoptosis properties with an enhanced MR signal ratio (∼74%) and a long MRI imaging acquisition time window (∼48 h) in 4T1 tumor-bearing mice. This study introduces an experimental gadolinium-based CA for the potential imaging of tumor apoptosis in the context of MRI.

Development of 3D Printed Biodegradable, Entirely X-ray Visible Stents for Rabbit Carotid Artery Implantation.

Biodegradable stents are considered a promising strategy for the endovascular treatment of cerebrovascular diseases. The visualization of biodegradable stents is of significance during the implantation and long-term follow-up. Endowing biodegradable stents with X-ray radiopacity can overcome the weakness of intrinsic radioparency of polymers. Hence, this work focuses on the development of an entirely X-ray visible biodegradable stent (PCL-KIO3) composed of polycaprolactone (PCL) and potassium iodate via physical blending and 3D printing. The in vitro results show that the introduction of potassium iodate makes the 3D-printed PCL stents visualizable under X-ray. So far, there is inadequate study about polymeric stent visualization in vivo. Therefore, PCL-KIO3 stents are implanted into the rabbit carotid artery to evaluate the biosafety and visibility performance. During stent deployment, the visualization of the PCL-KIO3 stent effectively helps to understand the position and dilation status of stents. At 6-month follow-up, the PCL-KIO3 stent could still be observed under X-ray and maintains excellent vessel patency. To sum up, this study demonstrates that PCL-KIO3 stent may provide a robust strategy for biodegradable stent visualization.

The location of metastatic lymph nodes and the evaluation of lymphadenectomy by near-infrared photoacoustic imaging with iridium complex nanoparticles.

Histopathology evaluation and lymphadenectomy of node-positive patients is the usual procedure in clinical therapy. However, it requires days for the histopathology result analysis, which impedes intraoperative decision-making and immediate treatment. Noninvasive real-time imaging of metastatic lymph nodes can overcome these defects and help medical workers evaluate lymph nodes and make the operation decision more efficiently. Herein we developed iridium(III)-cyanine complex/bovine serum albumin (BSA)-based nanoparticles which are conjugated with folic acid (FA) (IrCy-FA NPs). The synthesized IrCy-FA NPs exhibit good biocompatibility, strong near-infrared absorption, and impressive lymph node accumulation and can serve as a photoacoustic (PA) imaging probe for lymph node imaging. Besides, the lymph nodes enriched with IrCy-FA NPs showing green color are easily visible to the naked eye, suggesting their potential as an intraoperative indicator. The real-time PA imaging with excellent contrast and high spatial resolution can promote efficient and reliable quantitative analysis of lymph nodes in vivo. By employing IrCy-FA NPs as the PA agent for lymph node imaging, we achieve effective pre-operative and post-operative evaluations of metastatic lymph nodes in lymphadenectomy. This study may provide helpful information for PA imaging guided colocalization and evaluation of lymph nodes and facilitate this method towards clinical trials.

An integrative analysis of single-cell and bulk transcriptome and bidirectional mendelian randomization analysis identified C1Q as a novel stimulated risk gene for Atherosclerosis.

Background: The role of complement component 1q (C1Q) related genes on human atherosclerotic plaques (HAP) is less known. Our aim is to establish C1Q associated hub genes using single-cell RNA sequencing (scRNA-seq) and bulk RNA analysis to diagnose and predict HAP patients more effectively and investigate the association between C1Q and HAP (ischemic stroke) using bidirectional Mendelian randomization (MR) analysis. Methods: HAP scRNA-seq and bulk-RNA data were download from the Gene Expression Omnibus (GEO) database. The C1Q-related hub genes was screened using the GBM, LASSO and XGBoost algorithms. We built machine learning models to diagnose and distinguish between types of atherosclerosis using generalized linear models and receiver operating characteristics (ROC) analyses. Further, we scored the HALLMARK_COMPLEMENT signaling pathway using ssGSEA and confirmed hub gene expression through qRT-PCR in RAW264.7 macrophages and apoE-/- mice. Furthermore, the risk association between C1Q and HAP was assessed through bidirectional MR analysis, with C1Q as exposure and ischemic stroke (IS, large artery atherosclerosis) as outcomes. Inverse variance weighting (IVW) was used as the main method. Results: We utilized scRNA-seq dataset (GSE159677) to identify 24 cell clusters and 12 cell types, and revealed seven C1Q associated DEGs in both the scRNA-seq and GEO datasets. We then used GBM, LASSO and XGBoost to select C1QA and C1QC from the seven DEGs. Our findings indicated that both training and validation cohorts had satisfactory diagnostic accuracy for identifying patients with HPAs. Additionally, we confirmed SPI1 as a potential TF responsible for regulating the two hub genes in HAP. Our analysis further revealed that the HALLMARK_COMPLEMENT signaling pathway was correlated and activated with C1QA and C1QC. We confirmed high expression levels of C1QA, C1QC and SPI1 in ox-LDL-treated RAW264.7 macrophages and apoE-/- mice using qPCR. The results of MR indicated that there was a positive association between the genetic risk of C1Q and IS, as evidenced by an odds ratio (OR) of 1.118 (95%CI: 1.013-1.234, P = 0.027). Conclusion: The authors have effectively developed and validated a novel diagnostic signature comprising two genes for HAP, while MR analysis has provided evidence supporting a favorable association of C1Q on IS.

An Improved Surgical Technique to Increase Neck Width of Elastase-Induced Aneurysm Model in Rabbits: A Prospective Study.

Background: Rabbit elastase-induced aneurysms have widely been used to test various endovascular materials over the past two decades. However, wide-necked aneurysms cannot be stably constructed. Objective: The purpose of the study was to increase the neck width of the elastase-induced aneurysm model in rabbits via an improved surgical technique with two temporary clips. Materials and Methods: Fifty-four elastase-induced aneurysms in rabbits were successfully created. Group 1 was (n = 34) composed of cases in which two temporary aneurysm clips were placed closely medially and laterally to the origin of the right common carotid artery (RCCA), respectively. Group 2 (n = 20) included cases in which a single temporary aneurysm clip was placed crossed the origin of RCCA. Digital subtraction angiography (DSA) was performed before and immediately after elastase incubation and 3 weeks later. The diameter of the origin of RCCA before and immediately after elastase incubation and aneurysm sizes of the two groups were measured and compared. Moreover, the correlation analysis was performed between the diameter of the origin of RCCA immediately after elastase incubation and aneurysm neck width. Results: The mean aneurysm neck and dome width of group 1 were both significantly larger than that of group 2 (p-value < 0.001 and p-value = 0.005, respectively). Moreover, the proportion of wide-necked aneurysms (neck width ≥4 mm) in group 1 was significantly larger than that in group 2 (p-value = 0.004) and the mean dome to neck ratio (D/N) of group 1 was smaller than that of group 2 (p-value = 0.008). Furthermore, there was a positive correlation between the diameter of the origin of RCCA immediately after elastase incubation and aneurysm neck width. Conclusion: The improved surgical technique with two temporary clips, focusing on the direct contact of elastase with the origin of RCCA, could increase the neck width of elastase-induced aneurysm models in rabbits.

The different recanalization rates of posterior communicating artery aneurysms with a fetal posterior communicating artery and anterior communicating artery aneurysms with a variation of the unilateral A1 segment.

BACKGROUND: Posterior communicating artery (PcomA) aneurysms are more likely to recanalize than anterior communicating artery (AcomA) aneurysms. However, it is still unclear whether the recanalization rate of these aneurysms is a result of involvement from the fetal posterior cerebral artery (fPCA) in PcomA aneurysms and variation of the unilateral A1 segment in AcomA aneurysms. The purpose of this study is to retrospectively evaluate the different recanalization rates between PcomA aneurysms with fPCA and AcomA aneurysms with a variation of the unilateral A1 segment. METHODS: We retrospectively collected information regarding 214 patients, each with communicating segment aneurysms between January 2013 and January 2020. Follow-up documentation on clinical and imaging data was comparatively analyzed between variant types, and recanalization rates of the variant and normal types were analyzed by stratification. RESULTS: Of the 84 variant-type aneurysms (PcomA with fPCA and AcomA with a variation of the unilateral A1 segment, 41/43), complete recanalization occurred in 23 patients (27.4%), and it was significantly more likely to occur in PcomA aneurysms with fPCA (39.1%) than in AcomA aneurysms with a variation of the unilateral A1 segment (16.3%). Stent-assisted coil embolization (SACE) has been shown to reduce recanalization (OR =0.092, 95% CI: 0.011 to 0.790, P=0.03). Additionally, variant types and the normal type (non-fetal, 106, and bilateral A1 symmetry, 24) have different odds ratios (OR) of recanalization (P=0.04), and the OR of the variant subtypes was significant, unlike the normal type (P=0.49). CONCLUSIONS: This study suggests that PcomA aneurysms with fPCA are more likely to recanalize than AcomA aneurysms with a variation of the unilateral A1 segment.

Activated Platelet-Homing Nanoplatform for Targeting Magnetic Resonance Imaging of Aneurysm-Related Thrombus in Rabbits.

Thrombosis is closely related to the instability of intracranial aneurysm (IA), whose rupture is associated with high morbidity and mortality. It is difficult to detect an IA-related thrombus because traditional magnetic resonance imaging (MRI) and even contrast-enhanced MRI cannot clearly distinguish a thrombus from the surrounding tissues. Herein, a nanoplatform [(MFe2O4-ZnDPA nanoparticles (NPs)], consisting of Zn0.4Co0.6Fe2O4@Zn0.4Mn0.6Fe2O4 NPs for imaging and Zn(II)-bis(dipicolylamine) (ZnDPA) for thrombus targeting, is constructed to target an experimental aneurysm-related thrombus in rabbits via MRI. In vitro experiments including platelet safety evaluation primarily prove that MFe2O4-ZnDPA NPs with a high MRI transverse relaxation time (T2) have good biocompatibility. MFe2O4-ZnDPA NPs could target a thrombus via the special interaction between ZnDPA and phosphatidylserine of activated platelets in the thrombus through MRI and Fe quantification assays. Moreover, after MFe2O4-ZnDPA NPs are injected into the ear vein of common carotid artery aneurysm model rabbits, MRI shows that MFe2O4-ZnDPA NPs could accumulate in the aneurysm-related thrombus from 0 to 15 min after injection and decrease in the next 45 min. Meanwhile, MFe2O4-ZnDPA NPs could decrease the MRI T2 signal of the aneurysm-related thrombus to enhance the outline of the aneurysm. This study demonstrates that a nanoplatform can enhance the detection of an aneurysm-related thrombus as well as aneurysm itself to assist further treatment of IA.