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Background: The arteriovenous fistula (AVF) is a requirement for hemodialysis therapy in end-stage kidney disease (ESKD) patients. A consequence of AVF creation is compensatory cardiovascular hemodynamics, which are subsequently associated with cardiac remodeling. Relatedly, cardiovascular mortality and morbidity are elevated in ESKD patients, which worsens in dialysis patients. Currently, no suitable uremic large animal models exist to investigate the underlying mechanisms of AVF-induced cardiac remodeling. Research Question: This study aims to characterize cardiovascular changes secondary to AVF creation, supported by percutaneous transluminal angioplasty (PTA), in a uremic pig model. Methods: Chronic kidney disease (CKD) was induced via renal embolization, followed by AVF creation 28 days later. The AVF was created by anastomosis of the left common carotid artery to the left external jugular vein. AVF stenosis was alleviated 28 days thereafter via PTA, and cardiac MRI was performed at 14-, 28-, and 42-days post-PTA. Results: Increased end-diastolic volumes were observed in the left and right ventricles at day 42 vs 14 (200.8ml to 249.5ml, p=0.0457, and 204.6ml to 260.0ml, p=0.0268 respectively), while systolic function was preserved. Left ventricle (LV) stroke volume and blood flow through the aorta, pulmonary artery, and vena cava were also increased. In perivascular areas of the free wall of the LV at day 42 vs control, senescence markers showed increased p16 expression (fold change 10.21, p=0.0086) and decreased p21 expression (fold change 0.07, p=0.0357). The LV showed perivascular fibrosis (0.2% to 0.59%, p=0.021), via picrosirius red, reduced collagen-type IV expression (fold change 0.81, p=0.0089), and increased MMP2 levels (fold change 14.33, p=0.0213). Cardiomyocyte cross-sectional area was increased (from 800.9 µm 2 to 1250.0 µm 2 , p=0.0296), without CD4+ or CD68+ cell LV infiltration. Conclusion: In conclusion, AVF creation leads to modified left and right ventricular function and increased peripheral flow, potentially mediated by cellular senescence and fibrosis, resulting in progressive cardiac remodeling. This model of uremic kidney disease can now be used to evaluate mechanisms of AVF induced cardiac disease and test the efficacy of therapeutics like senolytics and anti-fibrotic agents.

Worldwide, more than 4 million patients with end-stage kidney disease require hemodialysis through an arteriovenous fistula (AVF). AVFs fail because of venous neointimal hyperplasia (VNH) resulting in venous stenosis formation. A phase 1 randomized trial in patients undergoing upper extremity AVF placement was performed to evaluate the safety and efficacy of autologous adipose–derived mesenchymal stem cells (MSCs) in improving AVF function. The mechanism of action by which MSCs exert their beneficial effects was investigated using AVFs created in mice and pigs treated with allogenic MSCs and xenotransplant using patient MSCs in CD1- Foxn1nu mice. At a median follow-up of 42 months, patients with MSC-treated AVFs had reduced time to maturation with an increase in the vein diameter compared with controls. AVFs treated with allogenic MSCs in mice and pigs had an increase in M2- and M1-like macrophages with a decrease in VNH. Transcriptomic analysis of AVFs treated with allogenic MSCs in mouse and MSC xenotransplants of patients with successful AVFs showed decreased peroxisome proliferator–activated receptor gamma ( Ppar γ) and leptin receptor ( Lepr ) and increased latent transforming growth factor–beta–binding protein 2 ( Ltbp2 ). PPARγ was reduced in CD68 (+) cells from successful AVFs and allogenic MSC-treated mouse AVFs. Venous stenosis and VNH formation were mitigated in AVFs of mice with Ppar γ ablation in immune cells. Conditioned medium from MSCs of responders versus nonresponders had decreased proinflammatory genes, senescence-associated proteins, and monocyte-to-macrophage differentiation induced by phorbol 12-myristate-13-acetate. Periadventitial delivery of MSCs to AVFs promoted positive vascular remodeling through decreased inflammatory responses.

Objectives The impact of body mass index (BMI) on cardiovascular risk in rheumatoid arthritis (RA) is unclear. RA characteristics may influence the association between BMI and risk. Disease activity, which predicts cardiovascular risk, is associated with obesity only among anticitrullinated antibody (ACPA)-positive patients. Biologics alter body composition and mitigate cardiovascular risk in RA. We explored the association of BMI with cardiovascular risk and whether this varied across ACPA status and biologic use. Methods We evaluated 3982 patients from an international observational cohort. Outcomes included (a) first major adverse cardiovascular event (MACE) encompassing myocardial infarction, stroke or cardiovascular death; and (b) all events comprising MACE, angina, revascularisation, transient ischaemic attack, peripheral arterial disease and heart failure. Multivariable Cox models stratified by centre risk evaluated the impact of BMI, ACPA, biologics and their two- and three-way interactions on outcomes. Results We recorded 192 MACE and 319 total events. No main effects of BMI, ACPA or biologics were observed. A three-way interaction between them on MACE (p-interaction<0.001) and all events (p-interaction=0.028) was noted. Among ACPA negative patients, BMI was inversely associated with MACE (HR 0.38 (95% CI 0.25 to 0.57)) and all events (HR 0.67 (0.49 to 0.92)) in biologic users but not non-users (p-for-interaction <0.001 and 0.012). Among ACPA-positive patients, BMI was associated with MACE (HR 1.04 [1.01–1.07]) and all events (HR 1.03 (1.00 to 1.06)) independently of biologic use. Conclusions BMI is inversely associated with cardiovascular risk only among ACPA-negative biologic users. In contrast, BMI is associated with cardiovascular risk in ACPA-positive patients independently of biologic use.

ABSTRACT Atraumatic and precise drug delivery to arteries and veins remains an unmet need in interventional medicine, with significant implications for managing vascular diseases and long-term patient outcomes. Conventional endovascular methods, such as drug-coated balloons and drug-eluting stents, often damage vessel endothelium and compromise wall integrity, leading to reduced therapeutic efficacy and severe complications including restenosis and thrombosis. To address these limitations, we introduce EndoBot, an untethered soft millirobot designed for atraumatic vessel navigation and localized drug delivery under physiological blood flow. EndoBot achieves this through magnetically actuated corkscrew propulsion and mechanically adaptive surface crawling, exerting low radial pressure (< 1 kPa) to preserve endothelial integrity. We validated its performance in phantom vessels, ex vivo human umbilical veins under normothermic perfusion, and in vivo rat inferior vena cava under fluoroscopic guidance using a human-scale magnetic manipulation platform. Despite dynamic vessel contractions and compressions along non-uniform cross-sections, mechanically adaptive locomotion strategy ensures safe navigation and protects the inner endothelial lining. EndoBot is deployable and retrievable via clinical vascular sheaths and remains stable even under supra-physiological blood flow conditions (> 155 cm/s). Extensive blood compatibility tests demonstrated minimal hemolysis (<0.01%), low platelet activation on the robot surface, and no increased coagulation tendency. For drug delivery, a hydrophobic transfer coating enables EndoBot to gently deposit a stable, flow-resistant drug layer onto the vessel wall without fragmentation. This novel platform enables safer and more effective targeted endovascular drug delivery, paving the way for transformative approaches to address early-stage vascular pathologies and deliver more effective preventive interventions.

Nanoparticle (NP)-based drug delivery systems have received widespread attention due to the excellent physicochemical properties of nanomaterials. Different types of NPs such as lipid NPs, poly(lactic-co-glycolic) acid (PLGA) NPs, inorganic NPs (e.g., iron oxide and Au), carbon NPs (graphene and carbon nanodots), 2D nanomaterials, and biomimetic NPs have found favor as drug delivery vehicles. In this review, we discuss the different types of customized NPs for intravascular drug delivery, nanoparticle behaviors (margination, adhesion, and endothelium uptake) in blood vessels, and nanomaterial compatibility for successful drug delivery. Additionally, cell surface protein targets play an important role in targeted drug delivery, and various vascular drug delivery studies using nanoparticles conjugated to these proteins are reviewed. Finally, limitations, challenges, and potential solutions for translational research regarding NP-based vascular drug delivery are discussed.

Chronic kidney disease (CKD) affects more than 10% of the world’s population. Hemodialysis, along with peritoneal dialysis and renal transplant, is one of the renal replacement therapies offered to patients with CKD/end-stage renal disease (ESRD). To proceed with hemodialysis, vascular access is required. The two means of long-term access are arteriovenous fistula (AVF) and arteriovenous graft (AVG). Multiple therapies have been created to help the long-term patency of AVFs. These therapies are needed as 40% of AVFs fail within the first year and additional intervention is required. Much of the existing research has focused on biomarkers, immune cells, hypoxia, and cell-based therapies. Regeneration therapy using mesenchymal stem cells seeks to investigate other ways that we can treat AVF failure. Mesenchymal stem cells are harvested as two main types, fetal and adult. Fetal cells are harvested at different times in fetal gestation and from multiple sources, placental blood, Whartons jelly, and amniotic stem cell fluid. Taken together, this review summarizes the different preclinical/clinical studies conducted using different types of MSCs towards vascular regenerative medicine and further highlights its potential to be a suitable alternative approach to enhance AVF patency.

Vascular access is an indispensable component of haemodialysis therapy for end-stage kidney disease patients. The arteriovenous fistula (AVF) is most common, but importantly, two-year failure rates are greater than fifty percent. AVF failure can occur due to a lack of suitable vascular remodelling, and inappropriate inflammation preventing maturation, or alternatively neointimal hyperplasia and vascular stenosis preventing long-term use. A comprehensive mechanistic understanding of these processes is still lacking, but recent studies highlight an essential role for inflammation from uraemia and the AVF itself. Inflammation affects each cell in the cascade of AVF failure, the endothelium, the infiltrating immune cells, and the vascular smooth muscle cells. This review examines the role of inflammation in each cell step by step and the influence on AVF failure. Inflammation resulting in AVF failure occurs initially via changes in endothelial cell activation, permeability, and vasoprotective chemokine secretion. Resultingly, immune cells can extravasate into the subendothelial space to release inflammatory cytokines and cause other deleterious changes to the microenvironment. Finally, all these changes modify vascular smooth muscle cell function, resulting in excessive and unchecked hyperplasia and proliferation, eventually leading to stenosis and the failure of the AVF. Finally, the emerging therapeutic options based off these findings are discussed, including mesenchymal stem cells, small-molecule inhibitors, and far-infrared therapies. Recent years have clearly demonstrated a vital role for inflammation in deciding the fate of the AVF, and future works must be centred on this to develop therapies for a hitherto unacceptably underserved patient population.

Background: Percutaneous transluminal angioplasty (PTA) is the first-line treatment for arteriovenous fistula (AVF) failure and immaturation. High rate of restenosis occurs post PTA procedure caused by venous neointimal hyperplasia (VNH), and decrease the durability of it. Failed AVF showed increased gene expression of Ier3. Poly lactic- co -glycolic acid nanoparticles (PLGA) loaded with 1,25-dihydroxyvitamin D 3 (1,25 NP) can inhibit Ier3 gene expression. Hypothesis: Adventitial delivery of 1,25 NP in hydrogel will reduce venous stenosis in a murine PTA model. Methods: Male C57BL/6J mice underwent partial nephrectomy at day -42 and arteriovenous fistula (AVF) creation at day -14. At day 0, mice were randomized to vehicle group (PTA + PLGA hydrogel) or treatment group (PTA + 1,25 NP hydrogel). Mice were euthanized at day 3 for gene expression analysis and at day 21 for histopathological analysis. Doppler ultrasound was performed weekly to evaluate AVF patency and function. Results: At day 3, PTA + 1,25 NP treated vessels had a significant decrease in the gene expression of Ier3 compared to controls. At day 21, 1,25 NP treated outflow veins had increased lumen vessel area, apoptosis, and higher peak systolic velocity, but decrease in neointimal area/media area ratio, fibroblasts, pro-inflammatory macrophages (M1), fibrosis (picrosirius red staining) and cellular proliferation. Conclusion: Adventitial delivery of 1,25 NP plus PTA has the ability to reduce restenosis and VNH formation. This protective effect is related to inhibition of Ier3 gene expression which modulates vascular inflammation and fibrosis post PTA.

Chitosan (CS) and two-dimensional nanomaterial (2D nanomaterials)-based scaffolds have received widespread attention in recent times in biomedical applications due to their excellent synergistic potential. CS has garnered much attention as a biomedical scaffold material either alone or in combination with some other material due to its favorable physiochemical properties. The emerging 2D nanomaterials, such as black phosphorus (BP), molybdenum disulfide (MoS2), etc., have taken huge steps towards varying biomedical applications. However, the implementation of a CS-2D nanomaterial-based scaffold for clinical applications remains challenging for different reasons such as toxicity, stability, etc. Here, we reviewed different types of CS scaffold materials and discussed their advantages in biomedical applications. In addition, a different CS nanostructure, instead of a scaffold, has been described. After that, the importance of 2D nanomaterials has been elaborated on in terms of physiochemical properties. In the next section, the biomedical applications of CS with different 2D nanomaterial scaffolds have been highlighted. Finally, we highlighted the existing challenges and future perspectives of using CS-2D nanomaterial scaffolds for biomedical applications. We hope that this review will encourage a more synergistic biomedical application of the CS-2D nanomaterial scaffolds and their utilization clinical applications.

Arterial stiffness predicts cardiovascular disease, the leading cause of death worldwide. Ultrasound elastography methods that measure wave velocity have promise for evaluating the stiffness of blood vessels in vivo. However, vessel geometry modulates wave velocity by inducing geometric dispersion. Here, we compare Young's modulus E estimates obtained using in vivo wave velocity measurements and techniques that either do or do not consider geometry to ex vivo reference E values from mechanical testing . An acoustic radiation force was applied to generate propagating waves in the right common carotid artery (N = 9) and external jugular vein (N = 10) of anesthetized pigs. Vessels were imaged with ultrafast ultrasound to measure wave motion. Group velocity cg was estimated from wave motion using a Radon transform. E was estimated from cg using a bulk media assumption which neglects geometry, as well as the Moens–Korteweg equation and a semi-analytical finite element model, which consider geometry. Pigs were euthanized and vessels were excised. Ring-shaped samples were extracted and tested in a uniaxial tension setup to obtain reference E values for comparison with E values obtained from wave-based techniques. Techniques considering geometry exhibited higher correlation with reference E values, underscoring the need to incorporate geometry for accurate vascular elastography assessments.