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Cerebral aneurysm (CA) is a significant health concern that results from pathological dilations of blood vessels in the brain and can lead to severe and potentially life-threatening conditions. While the pathogenesis of CA is complex, emerging studies suggest that endothelial progenitor cells (EPCs) play a crucial role. In this paper, we conducted a comprehensive literature review to investigate the potential role of EPCs in the pathogenesis and treatment of CA. Current research indicates that a decreased count and dysfunction of EPCs disrupt the balance between endothelial dysfunction and repair, thus increasing the risk of CA formation. Reversing these EPCs abnormalities may reduce the progression of vascular degeneration after aneurysm induction, indicating EPCs as a promising target for developing new therapeutic strategies to facilitate CA repair. This has motivated researchers to develop novel treatment options, including drug applications, endovascular-combined and tissue engineering therapies. Although preclinical studies have shown promising results, there is still a considerable way to go before clinical translation and eventual benefits for patients. Nonetheless, these findings offer hope for improving the treatment and management of this condition.
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Arterial stenosis caused by atherosclerosis often requires stent implantation to increase the patency of target artery. However, such external devices often lead to in-stent restenosis due to inadequate re-endothelialization and subsequent inflammatory responses. Therefore, re-endothelialization strategies after stent implantation have been developed to enhance endothelial cell recruitment or to capture circulating endothelial progenitor cells. Notably, recent research indicates that coating stent surfaces with biogenic materials enhances the long-term safety of implantation, markedly diminishing the risk of in-stent restenosis. In this review, we begin by describing the pathophysiology of coronary artery disease and in-stent restenosis. Then, we review the characteristics and materials of existing stents used in clinical practice. Lastly, we explore biogenic materials aimed at accelerating re-endothelialization, including extracellular matrix, cells, and extracellular vesicles. This review helps overcome the limitations of current stents for cardiovascular disease and outlines the next phase of research and development.
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Current gold standard for the replacement of small-diameter blood vessel (ID < 4 mm) is still to utilize the autologous vessels of patients due to the limitations of small-diameter vascular grafts (SDVG) on weak endothelialization, intimal hyperplasia and low patency. Herein, we create the SDVG with the tailored endothelialization by applying the engineered endothelial cell vesicles to camouflaging vascular grafts for the enhancement of vascular remodeling. The engineered endothelial cell vesicles were modified with azide groups (ECVs-N3) through metabolic glycoengineering to precisely link the vascular graft made of PCL-DBCO via click chemistry, and thus fabricating ECVG (ECVs-N3 modified SDVG), which assists inhibition of platelet adhesion and activation, promotion of ECs adhesion and enhancement of anti-inflammation. Furthermore, In vivo single-cell transcriptome analysis revealed that the proportion of ECs in the cell composition of ECVG surpassed that of PCL, and the tailored endothelialization enabled to convert endothelial cells (ECs) into some specific ECs clusters. One of the specific cluster, Endo_C5 cluster, was only detected in ECVG. Consequently, our study integrates the engineered membrane vesicles of ECVs-N3 from native ECs for tailored endothelialization on SDVG by circumventing the limitations of living cells, and paves a new way to construct the alternative endothelialization in vessel remodeling following injury.
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BACKGROUND: The objective of this study is to investigate the incidence, potential risk factors, and clinical outcomes of incomplete device endothelialization (IDE) in atrial fibrillation (AF) patients undergoing Watchman left atrial appendage closure (LAAC). METHODS: In this study, 68 AF patients who underwent successful implantation of the Watchman device without peri-device leak (PDL) during follow-up were included. The endothelialization status was assessed using Transesophageal echocardiography (TEE) and LAA computed tomography angiography (CTA) at 6 weeks and 6 months post-implantation. Adverse cerebro-cardiac events were documented at one-year follow-up. Baseline characteristics, including age, device sizes, and clinical indicators, were analyzed as potential predictors for IDE. RESULTS: IDE was observed in 70.6% and 67.6% of patients at 6 weeks and 6 months after implantation, respectively. Higher levels of high-density lipoprotein cholesterol (HDL-C) [odds ratio (OR): 15.109, 95% confidence interval (CI): 1.637-139.478, p = 0.017 and OR: 11.015, 95% CI: 1.365-88.896, p = 0.024] and lower aspartate aminotransferase (AST) (OR 0.924, 95% CI: 0.865-0.986, p = 0.017 and OR: 0.930, 95% CI: 0.874-0.990, p = 0.023) at baseline were found to be significantly associated with IDE at 6 weeks and 6 months, respectively, although no significant difference in adverse cerebro-cardiac events was noted between incomplete and complete DE groups during 1-year follow-up CONCLUSIONS: IDE is found to be a prevalent occurrence in humans following LAAC. Elevated HDL-C and reduced AST levels are shown to be linked to an increased risk of IDE after LAAC.
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Apéndice Atrial , Fibrilación Atrial , Cateterismo Cardíaco , Ecocardiografía Transesofágica , Humanos , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/epidemiología , Fibrilación Atrial/fisiopatología , Fibrilación Atrial/cirugía , Apéndice Atrial/diagnóstico por imagen , Apéndice Atrial/fisiopatología , Masculino , Femenino , Anciano , Factores de Riesgo , Incidencia , Persona de Mediana Edad , Resultado del Tratamiento , Factores de Tiempo , Cateterismo Cardíaco/efectos adversos , Cateterismo Cardíaco/instrumentación , Angiografía por Tomografía Computarizada , Medición de Riesgo , Anciano de 80 o más Años , Cierre del Apéndice Auricular IzquierdoRESUMEN
Coronary artery bypass grafting (CABG) utilizing saphenous vein grafts (SVGs) stands as a fundamental approach to surgically treating coronary artery disease. However, the long-term success of CABG is often compromised by the development of intimal hyperplasia (IH) and subsequent graft failure. Understanding the mechanisms underlying this pathophysiology is crucial for improving graft patency and patient outcomes. Objectives: This study aims to explore the potential of an ex vivo model utilizing SVG to investigate IH and re-endothelialization. Methods: A thorough histological examination of 15 surplus SVG procured from CABG procedures at Hospital Canselor Tuanku Muhriz, Malaysia, was conducted to establish their baseline characteristics. Results: SVGs exhibited a mean diameter of 2.65 ± 0.93 mm with pre-existing IH averaging 0.42 ± 0.13 mm in thickness, alongside an observable lack of luminal endothelial cell lining. Analysis of extracellular matrix components, including collagen, elastin, and glycosaminoglycans, at baseline and after 7 days of ex vivo culture revealed no significant changes in collagen but demonstrated increased percentages of elastin and glycosaminoglycans. Despite unsuccessful attempts at re-endothelialization with blood outgrowth endothelial cells, the established ex vivo SVG IH model underscores the multifaceted nature of graft functionality and patency, characterized by IH presence, endothelial impairment, and extracellular matrix alterations post-CABG. Conclusions: The optimized ex vivo IH model provides a valuable platform for delving into the underlying mechanisms of IH formation and re-endothelialization of SVG. Further refinements are warranted, yet this model holds promise for future research aimed at enhancing graft durability and outcomes for CAD patients undergoing CABG.
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Although magnesium alloy has received tremendous attention in biodegradable cardiovascular stents, the poor in vivo corrosion resistance and limited endothelialization are still the bottlenecks for its application in cardiovascular stents. Fabrication of the multifunctional bioactive coating with excellent anti-corrosion on the surface is beneficial for rapid re-endothelialization and the normal physiological function recovery of blood vessels. In the present study, a bioactive hydrogel coating was established on the surface of magnesium alloy by copolymerization of sulfobetaine methacrylate (SBMA) and acrylamide (AM) via ultraviolet (UV) polymerization, followed by the immobilization of fucoidan (Fu). The results showed that the as-prepared multifunctional hydrogel coating could enhance the corrosion resistance and the surface wettability of the magnesium alloy surface, endowing it with the ability of selective albumin adsorption; meanwhile, it could augment biocompatibility. The following introduction of fucoidan on the surface could further improve the hemocompatibility characterized by reducing protein adsorption, minimizing hemolysis, and preventing platelet aggregation and activation. Additionally, the immobilized fucoidan promoted endothelial cell (EC) growth, as well as up-regulated the expression of vascular endothelial growth factor (VEGF) and nitric oxide (NO) in endothelial cells (ECs). Consequently, this research paves a novel approach to developing a versatile bioactive coating for magnesium alloy surfaces and lays a foundation in cardiovascular biomaterials.
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Aleaciones , Materiales Biocompatibles Revestidos , Hidrogeles , Magnesio , Polisacáridos , Stents , Polisacáridos/farmacología , Polisacáridos/química , Magnesio/química , Magnesio/farmacología , Humanos , Hidrogeles/química , Hidrogeles/farmacología , Aleaciones/química , Materiales Biocompatibles Revestidos/química , Materiales Biocompatibles Revestidos/farmacología , Corrosión , Proliferación Celular/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Ensayo de Materiales , Células Endoteliales/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Propiedades de Superficie , Óxido Nítrico/metabolismoRESUMEN
The evolution of endovascular therapies, particularly in the field of intracranial aneurysm treatment, has been truly remarkable and is characterized by the development of various stents. However, ischemic complications related to thrombosis or downstream emboli pose a challenge for the broader clinical application of such stents. Despite advancements in surface modification technologies, an ideal coating that fulfills all the desired requirements, including anti-thrombogenicity and swift endothelialization, has not been available. To address these issues, we investigated a new coating comprising 3-aminopropyltriethoxysilane (APTES) with both anti-thrombogenic and cell-adhesion properties. We assessed the anti-thrombogenic property of the coating using an in vitro blood loop model by evaluating the platelet count and the level of the thrombin-antithrombin (TAT) complex, and investigating thrombus formation on the surface using scanning electron microscopy (SEM). We then assessed endothelial cell adhesion on the metal surfaces. In vitro blood tests revealed that, compared to a bare stent, the coating significantly inhibited platelet reduction and thrombus formation; more human serum albumin spontaneously adhered to the coated surface to block thrombogenic activation in the blood. Cell adhesion tests also indicated a significant increase in the number of cells adhering to the APTES-coated surfaces compared to the numbers adhering to either the bare stent or the stent coated with an anti-fouling phospholipid polymer. Finally, we performed an in vivo safety test by implanting coated stents into the internal thoracic arteries and ascending pharyngeal arteries of minipigs, and subsequently assessing the health status and vessel patency of the arteries by angiography over the course of 1 week. We found that there were no adverse effects on the pigs and the vascular lumens of their vessels were well maintained in the group with APTES-coated stents. Therefore, our new coating exhibited both high anti-thrombogenicity and cell-adhesion properties, which fulfill the requirements of an implantable stent.
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Adhesión Celular , Materiales Biocompatibles Revestidos , Propilaminas , Silanos , Stents , Trombosis , Silanos/química , Silanos/farmacología , Animales , Adhesión Celular/efectos de los fármacos , Humanos , Stents/efectos adversos , Porcinos , Materiales Biocompatibles Revestidos/química , Materiales Biocompatibles Revestidos/farmacología , Propilaminas/farmacología , Propilaminas/química , Adsorción , Trombosis/prevención & control , Fibrinolíticos/farmacología , Fibrinolíticos/química , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismoRESUMEN
Enhancing endothelial cell growth on small-diameter vascular grafts produced from decellularized tissues or synthetic substrates is pivotal for preventing thrombosis. While optimized decellularization protocols can preserve the structure and many components of the extracellular matrix (ECM), the process can still lead to the loss of crucial basement membrane proteins, such as laminin, collagen IV, and perlecan, which are pivotal for endothelial cell adherence and functional growth. This loss can result in poor endothelialization and endothelial cell activation causing thrombosis and intimal hyperplasia. To address this, the basement membrane's ECM is emulated on fiber substrates, providing a more physiological environment for endothelial cells. Thus, fibroblasts are cultured on fiber substrates to produce an ECM membrane substrate (EMMS) with basement membrane proteins. The EMMS then underwent antigen removal (AR) treatment to eliminate antigens from the membrane while preserving essential proteins and producing an AR-treated membrane substrate (AMS). Subsequently, human endothelial cells cultured on the AMS exhibited superior proliferation, nitric oxide production, and increased expression of endothelial markers of quiescence/homeostasis, along with autophagy and antithrombotic factors, compared to those on the decellularized aortic tissue. This strategy showed the potential of pre-endowing fiber substrates with a basement membrane to enable better endothelization.
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Tissue-engineered heart valve (TEHV) has emerged as a prospective alternative to conventional valve prostheses. The decellularized heart valve (DHV) represents a promising TEHV scaffold that preserves the natural three-dimensional structure and retains essential biological activity. However, the limited mechanical strength, fast degradation, poor hemocompatibility, and lack of endothelialization of DHV restrict its clinical use, which is necessary for ensuring its long-term durability. Herein, we used oxidized chondroitin sulfate (ChS), one of the main components of the extracellular matrix with various biological activities, to cross-link DHV to overcome the above problems. In addition, the ChS-adipic dihydrazide was used to react with residual aldehyde groups, thus preventing potential calcification. The results indicated notable enhancements in mechanical properties and resilience against elastase and collagenase degradation in vitro as well as the ability to withstand extended periods of storage without compromising the structural integrity of valve scaffolds. Additionally, the newly cross-linked valves exhibited favorable hemocompatibility in vitro and in vivo, thereby demonstrating exceptional biocompatibility. Furthermore, the scaffolds exhibited traits of gradual degradation and resistance to calcification through a rat subcutaneous implantation model. In the rat abdominal aorta implantation model, the scaffolds demonstrated favorable endothelialization, commendable patency, and a diminished pro-inflammatory response. As a result, the newly constructed DHV scaffold offers a compelling alternative to traditional valve prostheses, which potentially advances the field of TEHV.
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Sulfatos de Condroitina , Animales , Sulfatos de Condroitina/química , Sulfatos de Condroitina/farmacología , Ratas , Prótesis Valvulares Cardíacas , Ingeniería de Tejidos , Válvulas Cardíacas/efectos de los fármacos , Válvulas Cardíacas/química , Ratas Sprague-Dawley , Andamios del Tejido/química , Ensayo de Materiales , Humanos , Reactivos de Enlaces Cruzados/química , Masculino , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , PorcinosRESUMEN
Vascular injury is central to the pathogenesis and progression of cardiovascular diseases, however, fostering alternative strategies to alleviate vascular injury remains a persisting challenge. Given the central role of cell-derived nitric oxide (NO) in modulating the endogenous repair of vascular injury, NO-generating proteolipid nanovesicles (PLV-NO) are designed that recapitulate the cell-mimicking functions for vascular repair and replacement. Specifically, the proteolipid nanovesicles (PLV) are versatilely fabricated using membrane proteins derived from different types of cells, followed by the incorporation of NO-generating nanozymes capable of catalyzing endogenous donors to produce NO. Taking two vascular injury models, two types of PLV-NO are tailored to meet the individual requirements of targeted diseases using platelet membrane proteins and endothelial membrane proteins, respectively. The platelet-based PLV-NO (pPLV-NO) demonstrates its efficacy in targeted repair of a vascular endothelium injury model through systemic delivery. On the other hand, the endothelial cell (EC)-based PLV-NO (ePLV-NO) exhibits suppression of thrombosis when modified onto a locally transplanted small-diameter vascular graft (SDVG). The versatile design of PLV-NO may enable a promising therapeutic option for various vascular injury-evoked cardiovascular diseases.
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Óxido Nítrico , Proteolípidos , Lesiones del Sistema Vascular , Óxido Nítrico/metabolismo , Animales , Lesiones del Sistema Vascular/metabolismo , Proteolípidos/metabolismo , Modelos Animales de Enfermedad , Ratones , Humanos , Nanopartículas/química , MasculinoRESUMEN
Macrophages are the primary cell type orchestrating bioresorbable vascular graft (BVG) remodeling and infiltrate from three sources: the adjacent native vessel, circulating blood, and transmural migration from outer surface of the graft. To elucidate the kinetics of macrophage infiltration into the BVG, we fabricated two different bilayer arterial BVGs consisting of a macroporous sponge layer and a microporous electrospun (ES) layer. The Outer ES graft was designed to reduce transmural cell infiltration from the outer surface and the Inner ES graft was designed to reduce cell infiltration from the circulation. These BVGs were implanted in mice as infrarenal abdominal aorta grafts and extracted at 1, 4, and 8 weeks (n = 5, 10, and 10 per group, respectively) for evaluation. Cell migration into BVGs was higher in the Inner ES graft than in the Outer ES graft. For Inner ES grafts, the majority of macrophage largely expressed a pro-inflammatory M1 phenotype but gradually changed to tissue-remodeling M2 macrophages. In contrast, in Outer ES grafts macrophages primarily maintained an M1 phenotype. The luminal surface endothelialized faster in the Inner ES graft; however, the smooth muscle cell layer was thicker in the Outer ES graft. Collagen fibers were more abundant and matured faster in the Inner ES graft than that in the Outer ES graft. In conclusion, compared to macrophages infiltrating from the circulating blood, transmural macrophages from outside promote the acute inflammatory-mediated response for vascular remodeling and subsequent collagen deposition within BVGs. STATEMENT OF SIGNIFICANCE: To elucidate the kinetics of macrophage infiltration into the bioresorbable vascular graft (BVG), two different bilayer arterial BVGs were implanted in mice as infrarenal abdominal aorta grafts. Cell migration into BVGs was higher in the inner electrospun graft which cells mainly infiltrate from outer surface than in the outer electrospun graft which cells mainly infiltrate from the circulating blood. In the inner electrospun grafts, the majority of macrophages changed from the M1 phenotype to the M2 phenotype, however, outer electrospun grafts maintained the M1 phenotype. Collagen fibers matured faster in the Inner electrospun graft. Compared to macrophages infiltrating from the circulating blood, transmural macrophages from outside promote the acute inflammatory-mediated response for vascular remodeling and subsequent collagen deposition within BVGs.
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Implantes Absorbibles , Prótesis Vascular , Movimiento Celular , Colágeno , Inflamación , Macrófagos , Remodelación Vascular , Animales , Macrófagos/metabolismo , Macrófagos/patología , Ratones , Inflamación/patología , Ratones Endogámicos C57BL , Masculino , Aorta Abdominal/patologíaRESUMEN
Tissue-engineered vascular grafts (TEVGs) poised for regenerative applications are central to effective vascular repair, with their efficacy being significantly influenced by scaffold architecture and the strategic distribution of bioactive molecules either embedded within the scaffold or elicited from responsive tissues. Despite substantial advancements over recent decades, a thorough understanding of the critical cellular dynamics for clinical success remains to be fully elucidated. Graft failure, often ascribed to thrombogenesis, intimal hyperplasia, or calcification, is predominantly linked to improperly modulated inflammatory reactions. The orchestrated behavior of repopulating cells is crucial for both initial endothelialization and the subsequent differentiation of vascular wall stem cells into functional phenotypes. This necessitates the TEVG to provide an optimal milieu wherein immune cells can promote early angiogenesis and cell recruitment, all while averting persistent inflammation. In this study, we present an innovative TEVG designed to enhance cellular responses by integrating a physicochemical gradient through a multilayered structure utilizing synthetic (poly (ester urethane urea), PEUU) and natural polymers (Gelatin B), thereby modulating inflammatory reactions. The luminal surface is functionalized with a four-arm polyethylene glycol (P4A) to mitigate thrombogenesis, while the incorporation of adhesive peptides (RGD/SV) fosters the adhesion and maturation of functional endothelial cells. The resultant multilayered TEVG, with a diameter of 3.0 cm and a length of 11 cm, exhibits differential porosity along its layers and mechanical properties commensurate with those of native porcine carotid arteries. Analyses indicate high biocompatibility and low thrombogenicity while enabling luminal endothelialization and functional phenotypic behavior, thus limiting inflammation in in-vitro models. The vascular wall demonstrated low immunogenicity with an initial acute inflammatory phase, transitioning towards a pro-regenerative M2 macrophage-predominant phase. These findings underscore the potential of the designed TEVG in inducing favorable immunomodulatory and pro-regenerative environments, thus holding promise for future clinical applications in vascular tissue engineering.
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In order to treat most vascular diseases, arterial grafts are commonly employed for replacing small-diameter vessels, yet they often cause thrombosis. The growth of endothelial cells along the interior surfaces of these grafts (substrates) is critical to mitigate thrombosis. Typically, endothelial cells are cultured inside these grafts under laminar flow conditions to emulate the native environment of blood vessels and produce an endothelium. Alternatively, the substrate structure could have a similar influence on endothelial cell behavior as laminar flow conditions. In this study, we investigated whether substrates with aligned fiber structures could induce responses in human umbilical vein endothelial cells (HUVECs) akin to those elicited by laminar flow. Our observations revealed that HUVECs on aligned substrates displayed significant morphological changes, aligning parallel to the fibers, similar to effects reported under laminar flow conditions. Conversely, HUVECs on random substrates maintained their characteristic cobblestone appearance. Notably, cell migration was more significant on aligned substrates. Also, we observed that while vWF expression was similar between both substrates, the HUVECs on aligned substrates showed more expression of platelet/endothelial cell adhesion molecule-1 (PECAM-1/CD31), laminin, and collagen IV. Additionally, these cells exhibited increased gene expression related to critical functions such as proliferation, extracellular matrix production, cytoskeletal reorganization, autophagy, and antithrombotic activity. These findings indicated that aligned substrates enhanced endothelial growth and behavior compared to random substrates. These improvements are similar to the beneficial effects of laminar flow on endothelial cells, which are well-documented compared to static or turbulent flow conditions.
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Materiales Biocompatibles , Movimiento Celular , Células Endoteliales de la Vena Umbilical Humana , Ensayo de Materiales , Humanos , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Proliferación Celular/efectos de los fármacos , Tamaño de la Partícula , Propiedades de Superficie , Células Cultivadas , Adhesión CelularRESUMEN
Cell-free tissue-engineered vascular grafts provide a promising alternative to treat cardiovascular disease, but timely endothelialization is essential for ensuring patency and proper functioning post-implantation. Recent studies from our lab showed that blood cells like monocytes (MCs) and macrophages (MÏ) may contribute directly to cellularization and regeneration of bioengineered arteries in small and large animal models. While MCs and MÏ are leucocytes that are part of the innate immune response, they share common developmental origins with endothelial cells (ECs) and are known to play crucial roles during vessel formation (angiogenesis) and vessel repair after inflammation/injury. They are highly plastic cells that polarize into pro-inflammatory and anti-inflammatory phenotypes upon exposure to cytokines and differentiate into other cell types, including EC-like cells, in the presence of appropriate chemical and mechanical stimuli. This review focuses on the developmental origins of MCs and ECs; the role of MCs and MÏ in vessel repair/regeneration during inflammation/injury; and the role of chemical signalling and mechanical forces in MÏ inflammation that mediates vascular graft regeneration. We postulate that comprehensive understanding of these mechanisms will better inform the development of strategies to coax MCs/MÏ into endothelializing the lumen and regenerate the smooth muscle layers of cell-free bioengineered arteries and veins that are designed to treat cardiovascular diseases and perhaps the native vasculature as well.
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Prótesis Vascular , Macrófagos , Monocitos , Regeneración , Ingeniería de Tejidos , Humanos , Monocitos/metabolismo , Monocitos/trasplante , Ingeniería de Tejidos/métodos , Animales , Macrófagos/metabolismo , Neovascularización Fisiológica , Fenotipo , Implantación de Prótesis Vascular/instrumentación , Implantación de Prótesis Vascular/efectos adversos , Células Endoteliales/metabolismo , Células Endoteliales/trasplante , Diseño de Prótesis , Mecanotransducción CelularRESUMEN
Stent migration is a rare but serious complication of venous stenting, often presenting with chest pain, shortness of breath, and signs of heart failure. Potential complications include arrhythmia, perforation, and valve destruction. Here we present an asymptomatic patient with a late presentation of right common iliac vein stent migration to the right atrium.
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BACKGROUND: The prognostic impact of left atrial appendage (LAA) patency, including those with and without visible peri-device leak (PDL), post-LAA closure in patients with atrial fibrillation, remains elusive. METHODS: Patients with atrial fibrillation implanted with the WATCHMAN 2.5 device were prospectively enrolled. The device surveillance by cardiac computed tomography angiography was performed at 3 months post-procedure. Adverse events, including stroke/transient ischemic attack (TIA), major bleeding, cardiovascular death, all-cause death, and the combined major adverse events (MAEs), were compared between patients with complete closure and LAA patency. RESULTS: Among 519 patients with cardiac computed tomography angiography surveillance at 3 months post-LAA closure, 271 (52.2%) showed complete closure, and LAA patency was detected in 248 (47.8%) patients, including 196 (37.8%) with visible PDL and 52 (10.0%) without visible PDL. During a median of 1193 (787-1543) days follow-up, the presence of LAA patency was associated with increased risks of stroke/TIA (adjusted hazard ratio for baseline differences, 3.22 [95% CI, 1.17-8.83]; P=0.023) and MAEs (adjusted hazard ratio, 1.12 [95% CI, 1.06-1.17]; P=0.003). Specifically, LAA patency with visible PDL was associated with increased risks of stroke/TIA (hazard ratio, 3.66 [95% CI, 1.29-10.42]; P=0.015) and MAEs (hazard ratio, 3.71 [95% CI, 1.71-8.07]; P=0.001), although LAA patency without visible PDL showed higher risks of MAEs (hazard ratio, 3.59 [95% CI, 1.28-10.09]; P=0.015). Incidences of stroke/TIA (2.8% versus 3.0% versus 6.7% versus 22.2%; P=0.010), cardiovascular death (0.9% versus 0% versus 1.7% versus 11.1%; P=0.005), and MAEs (4.6% versus 9.0% versus 11.7% versus 22.2%; P=0.017) increased with larger PDL (0, >0 to ≤3, >3 to ≤5, or >5 mm). Older age and discontinuing antiplatelet therapy at 6 months were independent predictors of stroke/TIA and MAEs in patients with LAA patency. CONCLUSIONS: LAA patency detected by cardiac computed tomography angiography at 3 months post-LAA closure is associated with unfavorable prognosis in patients with atrial fibrillation implanted with WATCHMAN 2.5 device. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03788941.
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Apéndice Atrial , Fibrilación Atrial , Cateterismo Cardíaco , Angiografía por Tomografía Computarizada , Ataque Isquémico Transitorio , Accidente Cerebrovascular , Humanos , Apéndice Atrial/fisiopatología , Apéndice Atrial/diagnóstico por imagen , Masculino , Femenino , Anciano , Fibrilación Atrial/fisiopatología , Fibrilación Atrial/mortalidad , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/terapia , Fibrilación Atrial/diagnóstico por imagen , Estudios Prospectivos , Factores de Riesgo , Ataque Isquémico Transitorio/etiología , Factores de Tiempo , Resultado del Tratamiento , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/mortalidad , Anciano de 80 o más Años , Persona de Mediana Edad , Cateterismo Cardíaco/efectos adversos , Cateterismo Cardíaco/instrumentación , Medición de Riesgo , Hemorragia , Diseño de PrótesisRESUMEN
To successfully engineer large-sized tissues, establishing vascular structures is essential for providing oxygen, nutrients, growth factors and cells to prevent necrosis at the core of the tissue. The diameter scale of the biofabricated vasculatures should range from 100 to 1,000 µm to support the mm-size tissue while being controllably aligned and spaced within the diffusion limit of oxygen. In this review, insights regarding biofabrication considerations and techniques for engineered blood vessels will be presented. Initially, polymers of natural and synthetic origins can be selected, modified, and combined with each other to support maturation of vascular tissue while also being biocompatible. After they are shaped into scaffold structures by different fabrication techniques, surface properties such as physical topography, stiffness, and surface chemistry play a major role in the endothelialization process after transplantation. Furthermore, biological cues such as growth factors (GFs) and endothelial cells (ECs) can be incorporated into the fabricated structures. As variously reported, fabrication techniques, especially 3D printing by extrusion and 3D printing by photopolymerization, allow the construction of vessels at a high resolution with diameters in the desired range. Strategies to fabricate of stable tubular structures with defined channels will also be discussed. This paper provides an overview of the many advances in blood vessel engineering and combinations of different fabrication techniques up to the present time.
This review covers several aspects and advancements of engineered blood vessel biofabrication, which are essential for establishment of large-sized tissues in different areas of biomedical applications.
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BACKGROUND AND AIMS: Vascular injury-induced endothelium-denudation and profound vascular smooth muscle cells (VSMCs) proliferation and dis-regulated apoptosis lead to post-angioplasty restenosis. Coptisine (CTS), an isoquinoline alkaloid, has multiple beneficial effects on the cardiovascular system. Recent studies identified it selectively inhibits VSMCs proliferation. However, its effects on neointimal hyperplasia, re-endothelialization, and the underlying mechanisms are still unclear. METHODS: Cell viability was assayed by 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and cell counting kit-8 (CCK-8). Cell proliferation and apoptosis were measured by flow cytometry and immunofluorescence of Ki67 and TUNEL. Quantitative phosphoproteomics (QPP) was employed to screen CTS-responsive phosphor-sites in the key regulators of cell proliferation and apoptosis. Neointimal hyperplasia was induced by balloon injury of rat left carotid artery (LCA). Adenoviral gene transfer was conducted in both cultured cells and LCA. Re-endothelialization was evaluated by Evan's blue staining of LCA. RESULTS: 1) CTS had strong anti-proliferative and pro-apoptotic effects in cultured rat VSMCs, with the EC50 4â¼10-folds lower than that in endothelial cells (ECs). 2) Rats administered with CTS, either locally to LCA's periadventitial space or orally, demonstrated a potently inhibited balloon injury-induced neointimal hyperplasia, but had no delaying effect on re-endothelialization. 3) The QPP results revealed that the phosphorylation levels of Pak1S144/S203, Pak2S20/S197, Erk1T202/Y204, Erk2T185/Y187, and BadS136 were significantly decreased in VSMCs by CTS. 4) Adenoviral expression of phosphomimetic mutants Pak1D144/D203/Pak2D20/D197 enhanced Pak1/2 activities, stimulated the downstream pErk1T202/Y204/pErk2T185/Y187/pErk3S189/pBadS136, attenuated CTS-mediated inhibition of VSMCs proliferation and promotion of apoptosis in vitro, and potentiated neointimal hyperplasia in vivo. 5) Adenoviral expression of phosphoresistant mutants Pak1A144/A203/Pak2A20/A197 inactivated Pak1/2 and totally simulated the inhibitory effects of CTS on platelet-derived growth factor (PDGF)-stimulated VSMCs proliferation and PDGF-inhibited apoptosis in vitro and neointimal hyperplasia in vivo. 6) LCA injury significantly enhanced the endogenous phosphorylation levels of all but pBadS136. CTS markedly attenuated all the enhanced levels. CONCLUSIONS: These results indicate that CTS is a promising medicine for prevention of post-angioplasty restenosis without adverse impact on re-endothelialization. CTS-directed suppression of pPak1S144/S203/pPak2S20/S197 and the subsequent effects on downstream pErk1T202/Y204/pErk2T185/Y187/pErk3S189 and pBadS136 underline its mechanisms of inhibition of VSMCs proliferation and stimulation of apoptosis. Therefore, the phosphor-sites of Pak1S144/S203/Pak2S20/S197 constitute a potential drug-screening target for fighting neointimal hyperplasia restenosis.
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Berberina/análogos & derivados , Traumatismos de las Arterias Carótidas , Músculo Liso Vascular , Ratas , Animales , Hiperplasia/patología , Músculo Liso Vascular/patología , Células Endoteliales/metabolismo , Proliferación Celular , Neointima/metabolismo , Traumatismos de las Arterias Carótidas/patología , Células Cultivadas , Miocitos del Músculo Liso/patología , Movimiento CelularRESUMEN
Coronary stents have saved millions of lives in the last three decades by treating atherosclerosis especially, by preventing plaque protrusion and subsequent aneurysms. They attenuate the vascular SMC proliferation and promote reconstruction of the endothelial bed to ensure superior revascularization. With the evolution of modern stent types, nanotechnology has become an integral part of stent technology. Nanocoating and nanosurface fabrication on metallic and polymeric stents have improved their drug loading capacity as well as other mechanical, physico-chemical, and biological properties. Nanofeatures can mimic the natural nanofeatures of vascular tissue and control drug-delivery. This review will highlight the role of nanotechnology in addressing the challenges of coronary stents and the recent advancements in the field of related medical devices. Different generations of stents carrying nanoparticle-based formulations like liposomes, lipid-polymer hybrid NPs, polymeric micelles, and dendrimers are discussed highlighting their roles in local drug delivery and anti-restenotic properties. Drug nanoparticles like Paclitaxel embedded in metal stents are discussed as a feature of first-generation drug-eluting stents. Customized precision stents ensure safe delivery of nanoparticle-mediated genes or concerted transfer of gene, drug, and/or bioactive molecules like antibodies, gene mimics via nanofabricated stents. Nanotechnology can aid such therapies for drug delivery successfully due to its easy scale-up possibilities. However, limitations of this technology such as their potential cytotoxic effects associated with nanoparticle delivery that can trigger hypersensitivity reactions have also been discussed in this review. This article is categorized under: Implantable Materials and Surgical Technologies > Nanotechnology in Tissue Repair and Replacement Therapeutic Approaches and Drug Discovery > Nanomedicine for Cardiovascular Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies.