Antithrombotic Strategies With Left Ventricular Assist Devices.

Long-term outcomes of patients with advanced heart failure treated with durable left ventricular assist devices (LVADs) have been augmented due to improved durability and hemocompatibility on the backbone of pump engineering enhancements. The incidence of hemocompatibility-related adverse events (pump thrombosis, stroke and nonsurgical bleeding events) are device specific and vary by type of engineered pump. A fully magnetically levitated rotor containing LVAD in concert with use of antithrombotic therapy has successfully overcome an increased risk of pump thrombosis and stroke-risk, albeit with only modest reduction in bleeding events. Modifications to antithrombotic strategies have focused on reduced-dose vitamin K antagonist use or use of direct oral anticoagulants with demonstration of safety and progress in reduction of mucosal bleeding episodes with elimination of antiplatelet agents. This review outlines the current landscape of advances in anticoagulation management in LVAD patients, highlighting the need for ongoing research and cautious application of emerging therapies and technologies.

Improving hemocompatibility in tissue-engineered products employing heparin-loaded nanoplatforms.

The enhancement of hemocompatibility through the use of nanoplatforms loaded with heparin represents a highly desirable characteristic in the context of emerging tissue engineering applications. The significance of employing heparin in biological processes is unquestionable, owing to its ability to interact with a diverse range of proteins. It plays a crucial role in numerous biological processes by engaging in interactions with diverse proteins and hydrogels. This review provides a summary of recent endeavors focused on augmenting the hemocompatibility of tissue engineering methods through the utilization of nanoplatforms loaded with heparin. This study also provides a comprehensive review of the various applications of heparin-loaded nanofibers and nanoparticles, as well as the techniques employed for encapsulating heparin within these nanoplatforms. The biological and physical effects resulting from the encapsulation of heparin in nanoplatforms are examined. The potential applications of heparin-based materials in tissue engineering are also discussed, along with future perspectives in this field.

Computational investigation of outflow graft variation impact on hemocompatibility profile in LVADs.

BACKGROUND: Hemocompatibility-related adverse events (HRAE) occur commonly in patients with left ventricular assist devices (LVADs) and add to morbidity and mortality. It is unclear whether the outflow graft orientation can impact flow conditions leading to HRAE. This study presents a simulation-based approach using exact patient anatomy from medical images to investigate the influence of outflow cannula orientation in modulating flow conditions leading to HRAEs. METHODS: A 3D model of a proximal aorta and outflow graft was reconstructed from a computed tomography (CT) scan of an LVAD patient and virtually modified to model multiple cannula orientations (n = 10) by varying polar (cranio-caudal) (n = 5) and off-set (anterior-posterior) (n = 2) angles. Time-dependent computational flow simulations were then performed for each anatomical orientation. Qualitative and quantitative hemodynamics metrics of thrombogenicity including time-averaged wall shear stress (TAWSS), oscillatory shear index (OSI), endothelial cell platelet activation potential (ECAP), particle residence time (PRT), and platelet activation potential (PLAP) were analyzed. RESULTS: Within the simulations performed, endothelial cell activation potential (ECAP) and particle residence time (PRT) were found to be lowest with a polar angle of 85°, regardless of offset angle. However, polar angles that produced parameters at levels least associated with thrombosis varied when the offset angle was changed from 0° to 12°. For offset angles of 0° and 12° respectively, flow shear was lowest at 65° and 75°, time averaged wall shear stress (TAWSS) was highest at 85° and 35°, and platelet activation potential (PLAP) was lowest at 65° and 45°. CONCLUSION: This study suggests that computational fluid dynamic modeling based on patient-specific anatomy can be a powerful analytical tool when identifying optimal positioning of an LVAD. Contrary to previous work, our findings suggest that there may be an "ideal" outflow cannula for each individual patient based on a CFD-based hemocompatibility profile.

Biofunctionalization of surfaces to minimize undesirable effects in cardiovascular assistance devices.

BACKGROUND: The reactivity of blood with non-endothelial surface is a challenge for long-term Ventricular Assist Devices development, usually made with pure titanium, which despite of being inert, low density and high mechanical resistance it does not avoid the thrombogenic responses. Here we tested a modification on the titanium surface with Laser Induced Periodic Surface Structures followed by Diamond Like Carbon (DLC) coating in different thicknesses to customize the wettability profile by changing the surface energy of the titanium. METHODS: Four different surfaces were proposed: (1) Pure Titanium as Reference Material (RM), (2) Textured as Test Sample (TS), (3) Textured with DLC 0.3µm as (TSA) and (4) Textured with 2.4µm DLC as (TSB). A single implant was positioned in the abdominal aorta of Wistar rats and the effects of hemodynamic interaction were evaluated without anticoagulant drugs. RESULTS: After twelve weeks, the implants were extracted and subjected to qualitative analysis by Scanning Electron Microscopy under low vacuum and X-ray Energy Dispersion. The regions that remained in contact with the wall of the aorta showed encapsulation of the endothelial tissue. TSB implants, although superhydrophilic, have proven that the DLC coating inhibits the adhesion of biological material, prevents abrasive wear and delamination, as observed in the TS and TSA implants. Pseudo- neointimal layers were heterogeneously identified in higher concentration on Test Surfaces.

Anatomical compatibility of a novel total artificial heart-An in-silico study.

BACKGROUND: ShuttlePump is a novel total artificial heart (TAH) recently introduced to potentially overcome the limitations associated with the current state-of-the-art mechanical circulatory support devices intended for adults. In this study, we adapted the outflow cannulation of the previously established ShuttlePump TAH and evaluated the anatomical compatibility using the virtual implantation technique. METHODS: We retrospectively assessed the anatomical compatibility of the ShuttlePump using virtual implantation techniques within 3D-reconstructed anatomies of adult heart failure patients. Additionally, we examined the impact of outflow cannula modification on the hemocompatibility of the ShuttlePump through computational fluid dynamic simulations. RESULTS: A successful virtual implantation in 9/11 patients was achieved. However, in 2 patients, pump interaction with the thoracic cage was observed and considered unsuccessful virtual implantation. A strong correlation (r <-0.78) observed between the measured anatomical parameters and the ShuttlePump volume exceeding pericardium highlights the importance of these measurements apart from body surface area. The numerical simulation revealed that the angled outflow cannulation resulted in a maximum pressure drop of 1.8 mmHg higher than that of the straight outflow cannulation. With comparable hemolysis index, the shear stress thresholds of angled outflow differ marginally (<5%) from the established pump model. Similar washout behavior between the pump models indicate that the curvature did not introduce stagnation zone. CONCLUSION: This study demonstrates the anatomic compatibility of the ShuttlePump in patients with biventricular failure, which was achieved by optimizing the outflow cannulation without compromising hemocompatibility. Nevertheless, clinical validation is critical to ensure the clinical applicability of these findings.

Preoperative anatomical landmarks and longitudinal HeartMate 3 pump position in X-rays: Relevance for adverse events.

BACKGROUND: Left ventricular assist device (LVAD) malposition has been linked to hemocompatibility-related adverse events (HRAEs). This study aimed to identify preoperative anatomical landmarks and postoperative pump position, associated with HRAEs during LVAD support. METHODS: Pre- and postoperative chest X-ray measures (≤14 days pre-implantation, first postoperative standing, 6, 12, 18, and 24 months post-implantation) were analyzed for their association with HRAEs over 24 months in 33 HeartMate 3 (HM3) patients (15.2% female, age 66 (9.5) years). RESULTS: HM3 patients with any HRAE showed significantly lower preoperative distances between left ventricle and thoracic outline (dLVT) (25.3 ± 10.2 mm vs. 40.3 ± 15.5 mm, p = 0.004). A ROC-derived cutoff dLVT ≤ 29.2 mm provided 85.7% sensitivity and 72.2% specificity predicting any HRAE during HM3 support (76.2% (>29.2 mm) vs. 16.7% (≤29.2 mm) freedom from HRAE, p < 0.001) and significant differences in cardiothoracic ratio (0.58 ± 0.04 vs. 0.62 ± 0.04, p = 0.045). Postoperative X-rays indicated lower pump depths in patients with ischemic strokes (9.1 ± 16.2 mm vs. 38.0 ± 18.5 mm, p = 0.007), reduced freedom from any neurological event (pump depth ≤ 28.7 mm: 45.5% vs. 94.1%, p = 0.004), and a significant correlation between pump depth and inflow cannula angle (r = 0.66, p < 0.001). Longitudinal changes were observed in heart-pump width (F(4,60) = 5.61, p < 0.001). CONCLUSION: Preoperative X-ray markers are associated with postoperative HRAE occurrence. Applying this knowledge in clinical practice may enhance risk stratification, guide therapy optimization, and improve HM3 recipient management.

Randomized investigation of increased dialyzer membrane hydrophilicity on hemocompatibility and performance.

BACKGROUND: Hemodialyzers should efficiently eliminate small and middle molecular uremic toxins and possess exceptional hemocompatibility to improve well-being of patients with end-stage kidney disease. However, performance and hemocompatibility get compromised during treatment due to adsorption of plasma proteins to the dialyzer membrane. Increased membrane hydrophilicity reduces protein adsorption to the membrane and was implemented in the novel FX CorAL dialyzer. The present randomized controlled trial compares performance and hemocompatibility profiles of the FX CorAL dialyzer to other commonly used dialyzers applied in hemodiafiltration treatments. METHODS: This prospective, open, controlled, multicentric, interventional, crossover study randomized stable patients on post-dilution online hemodiafiltration (HDF) to FX CorAL 600, FX CorDiax 600 (both Fresenius Medical Care) and xevonta Hi 15 (B. Braun) each for 4 weeks. Primary outcome was ß2-microglobulin removal rate (ß2-m RR). Non-inferiority and superiority of FX CorAL versus comparators were tested. Secondary endpoints were RR and/or clearance of small and middle molecules, and intra- and interdialytic profiles of hemocompatibility markers, with regards to complement activation, cell activation/inflammation, platelet activation and oxidative stress. Further endpoints were patient reported outcomes (PROs) and clinical safety. RESULTS: 82 patients were included and 76 analyzed as intention-to-treat (ITT) population. FX CorAL showed the highest ß2-m RR (76.28%), followed by FX CorDiax (75.69%) and xevonta (74.48%). Non-inferiority to both comparators and superiority to xevonta were statistically significant. Secondary endpoints related to middle molecules corroborated these results; performance for small molecules was comparable between dialyzers. Regarding intradialytic hemocompatibility, FX CorAL showed lower complement, white blood cell, and platelet activation. There were no differences in interdialytic hemocompatibility, PROs, or clinical safety. CONCLUSIONS: The novel FX CorAL with increased membrane hydrophilicity showed strong performance and a favorable hemocompatibility profile as compared to other commonly used dialyzers in clinical practice. Further long-term investigations should examine whether the benefits of FX CorAL will translate into improved cardiovascular and mortality endpoints. TRIAL REGISTRATION: eMPORA III registration on 19/01/2021 at ClinicalTrials.gov (NCT04714281).

Hemocompatibility-related Adverse Events in Patients With Temporary Mechanical Circulatory Support: The Scoring Haemostasis Events and Assessment for Risk (SHEAR) Score.

Evaluation of treatment outcomes in patients supported by temporary mechanical circulatory support (tMCS) currently relies mainly on mortality, which may not sufficiently address other patient benefits or harms. Bleeding and thrombosis are major contributors to mortality. Still, current bleeding scores are not designed for critically ill patients undergoing tMCS, only consider selected populations, and do not account for the high heterogeneity among bleeding and thrombotic adverse events. To improve clinical management, a group of European experts has proposed a revised scoring system based on the MOMENTUM 3 Hemocompatibility Score and the Society of Cardiac Angiography and Interventions (SCAI)classification of cardiogenic shock. The new system termed the Scoring Haemostasis Events and Assessment for Risk (SHEAR) score, is divided into a baseline characterization stage and four escalating scoring stages encompassing all aspects of clinical relevance. This report summarizes the literature on hemocompatibility-related adverse events associated with tMCS, including bleeding, stroke, vascular access complications, hemolysis, thrombosis, and device failure. The SHEAR score provides a simple and rapid bedside scoring system aiming to provide a univocal tool to increase physician awareness of hemocompatibility complications at baseline and beyond, improve clinical research, and enable the capture of device-related complications that will inform relevant outcomes beyond mortality.

A case of destination therapy for post-fulminant myocarditis with myelodysplastic syndrome.

We encountered a 64-year-old woman who experienced fulminant myocarditis and underwent treatment with veno-arterial extracorporeal membrane oxygenation and Impella CP support. Subsequently, she underwent a device upgrade to Impella 5.5 and received continuous hemodiafiltration for 3 months. During mechanical circulatory support, she developed refractory anemia and thrombocytopenia, leading to a diagnosis of myelodysplastic syndrome. Following the removal of the devices, she no longer required blood transfusions. She received HeartMate 3 left ventricular assist device implantation as a destination therapy indication despite the presence of myelodysplastic syndrome. She was successfully managed by aspirin-free antithrombotic therapy without any hemocompatibility-related adverse events for 4 months after index discharge on foot. We present a patient with a unique and rare presentation, wherein HeartMate 3 was implanted and successfully managed without aspirin to prevent bleeding complications associated with myelodysplastic syndrome.

When all Else Fails, Try This: The HeartMate III Left Ventricle Assist Device.

Heart failure (HF) is a progressive disease. It is estimated that more than 250,000 patients suffer from advanced HF with reduced ejection fraction refractory to medical therapy. With limited donor pool for heart transplant, continue flow left ventricle assist device (LVAD) is a lifesaving treatment option for patients with advanced HF. This review will provide an update on indications, contraindications, and associated adverse events for LVAD support with a summary of the current outcomes data.

Structural Element of Vitamin U-Mimicking Antibacterial Polypeptide with Ultrahigh Selectivity for Effectively Treating MRSA Infections.

Antimicrobial peptides (AMPs) exhibit mighty antibacterial properties without inducing drug resistance. Achieving much higher selectivity of AMPs towards bacteria and normal cells has always been a continuous goal to be pursued. Herein, a series of sulfonium-based polypeptides with different degrees of branching and polymerization were synthesized by mimicking the structure of vitamin U. The polypeptide, G2 -PM-1H+ , shows both potent antibacterial activity and the highest selectivity index of 16000 among the reported AMPs or peptoids (e.g., the known index of 9600 for recorded peptoid in "Angew. Chem. Int. Ed., 2020, 59, 6412."), which can be attributed to the high positive charge density of sulfonium and the regulation of hydrophobic chains in the structure. The antibacterial mechanisms of G2 -PM-1H+ are primarily ascribed to the interaction with the membrane, production of reactive oxygen species (ROS), and disfunction of ribosomes. Meanwhile, altering the degree of alkylation leads to selective antibacteria against either gram-positive or gram-negative bacteria in a mixed-bacteria model. Additionally, both in vitro and in vivo experiments demonstrated that G2 -PM-1H+ exhibited superior efficacy against methicillin-resistant Staphylococcus aureus (MRSA) compared to vancomycin. Together, these results show that G2 -PM-1H+ possesses high biocompatibility and is a potential pharmaceutical candidate in combating bacteria significantly threatening human health.

Antimicrobial Nanostructured Assemblies with Extremely Low Toxicity and Potent Activity to Eradicate Staphylococcus Aureus Biofilms.

Self-assembled cationic polymeric nanostructures have been receiving increasing attention for efficient antibacterial agents. In this work, a new type of antibacterial agents is developed by preparing pH-dependent nanostructured assemblies from cationic copolypeptoid poly(N-allylglycine)-b-poly(N-octylglycine) (PNAG-b-PNOG) modified with cysteamine hydrochloride ((PNAG-g-NH2 )-b-PNOG) driven by crystallization and hydrophobicity of the PNOG blocks. Due to the presence of confined domains arising from crystalline PNOG, persistent spheres and fiber-like assemblies are obtained from the same polymer upon a heating-cooling cycle. This allows for direct comparison of antimicrobial efficiency of nanostructured assemblies with various morphologies that are otherwise similar. Both nanostructured assemblies exhibit extremely low toxicity to human red blood cells, irrespective of the presence of the hydrophobic block. Enhanced antimicrobial performance of the fiber-like micelles compared to the spheres, which result in high selectivity of the fibers, is shown. Notably, the fiber-like micelles show great efficacy in inhibition of the Staphylococcus aureus (S. aureus) biofilm formations and eradication of the mature biofilms, superior to vancomycin. The micelles also show potent in vivo antimicrobial efficacy in a S. aureus infection mouse skin model. With a systematic study, it is demonstrated that both micelles kill the bacteria through a membrane disruption mechanism. These results imply great potential of polypeptoid assemblies as promising excellent candidates for antibacterial treatment and open up new possibilities for the preparation of a new generation of nanostructured antimicrobials.

Toward microfluidic integration of respiratory and renal organ support in a single cartridge.

BACKGROUND: Extracorporeal organ assist devices provide lifesaving functions for acutely and chronically ill patients suffering from respiratory and renal failure, but their availability and use is severely limited by an extremely high level of operational complexity. While current hollow fiber-based devices provide high-efficiency blood gas transfer and waste removal in extracorporeal membrane oxygenation (ECMO) and hemodialysis, respectively, their impact on blood health is often highly deleterious and difficult to control. Further challenges are encountered when integrating multiple organ support functions, as is often required when ECMO and ultrafiltration (UF) are combined to deal with fluid overload in critically ill patients, necessitating an unwieldy circuit containing two separate cartridges. METHODS: We report the first laboratory demonstration of simultaneous blood gas oxygenation and fluid removal in single microfluidic circuit, an achievement enabled by the microchannel-based blood flow configuration of the device. Porcine blood is flowed through a stack of two microfluidic layers, one with a non-porous, gas-permeable silicone membrane separating blood and oxygen chambers, and the other containing a porous dialysis membrane separating blood and filtrate compartments. RESULTS: High levels of oxygen transfer are measured across the oxygenator, while tunable rates of fluid removal, governed by the transmembrane pressure (TMP), are achieved across the UF layer. Key parameters including the blood flow rate, TMP and hematocrit are monitored and compared with computationally predicted performance metrics. CONCLUSIONS: These results represent a model demonstration of a potential future clinical therapy where respiratory support and fluid removal are both realized through a single monolithic cartridge.

Development and evaluation of a variable, miniaturized oxygenator for various test methods.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) became an accepted therapy for the treatment of severe acute respiratory distress syndrome and chronic obstructive pulmonary disease. However, ECMO systems are still prone to thrombus formation and decrease of gas exchange over time. Therefore, it is necessary to conduct qualified studies to identify parameters for optimization of ECMO systems, and especially the oxygenator. However, commercially marketed oxygenators are not always appropriate and available for certain research use cases. Therefore, we aimed to design an oxygenator, which is suitable for various test conditions such as blood tests, numerical simulation, and membrane studies, and can be modified in membrane area size and manufactured in laboratory. METHODS: Main design criteria are a homogeneous blood flow without stagnation zones, low pressure drop, manufacturability in the lab, size variability with one set of housing parts and cost-efficiency. Our newly designed oxygenator was tested comparatively regarding blood cell damage, gas transfer performance and pressure drop to prove the validity of the design in accordance with a commercial device. RESULTS: No statistically significant difference between the tested oxygenators was detected and our new oxygenator demonstrated sufficient hemocompatibility. Furthermore, our variable oxygenator has proven that it can be easily manufactured in the laboratory, allows to use various membrane fiber configurations and can be reopened easily and non-destructively for analysis after use, and the original geometry is available for numerical simulations. CONCLUSION: Therefore, we consider this newly developed device as a valuable tool for basic experimental and numerical research on the optimization of oxygenators.

Preclinical evaluation of the fluid dynamics and hemocompatibility of the Corheart 6 left ventricular assist device.

BACKGROUND: Corheart 6 (Corheart) is a newly developed magnetically levitated continuous-flow left ventricular assist device currently undergoing multicenter clinical trials in China. Featuring a small size, minimal weight, and low power consumption, the Corheart aims to improve pump hemocompatibility, reduce adverse events, and enhance the quality of life of heart failure patients. METHODS: Computational simulations assessed flow field, shear stress, and washout, while in vitro and in vivo experiments were performed to further demonstrate hemocompatibility. RESULTS: Numerical results show that the flow path in the Corheart blood pump is well designed. There is no significantly high shear stress in the majority of the flow domain. Short secondary flow paths and small pump size (small priming volume) provide good washing (0.049 and 0.165 s to remove 55% and 95% old blood, respectively), allowing low hemolysis levels both in computational and in vitro hemolysis tests (in vitro hemolysis index ranges from 0.00092 ± 0.00006 g/100 L to 0.00134 ± 0.00019 g/100 L). Good hemocompatibility was further evidenced by ten 60-day sheep implants tested with relatively low flow rates of 2.0 ± 0.2 L/min; the results showed no hemolysis or thrombosis. CONCLUSIONS: Numerical and experimental results shed light on the fluid dynamics characteristics and hemocompatibility of the Corheart. It is believed that the Corheart will provide more promising possibilities for minimally invasive implantation techniques and for those patients with a small body surface area.

Procoagulant Activity of Umbilical Cord-Derived Mesenchymal Stromal Cells' Extracellular Vesicles (MSC-EVs).

Many cell types, including cancer cells, release tissue factor (TF)-exposing extracellular vesicles (EVs). It is unknown whether MSC-EVs pose a thromboembolism risk due to TF expression. Knowing that MSCs express TF and are procoagulant, we hypothesize that MSC-EVs also might. Here, we examined the expression of TF and the procoagulant activity of MSC-EVs and the impact of EV isolation methods and cell culture expansion on EV yield, characterization, and potential risk using a design of experiments methodology. MSC-EVs were found to express TF and have procoagulant activity. Thus, when MSC-derived EVs are employed as a therapeutic agent, one might consider TF, procoagulant activity, and thromboembolism risk and take steps to prevent them.

Polymeric Heart Valves Will Displace Mechanical and Tissue Heart Valves: A New Era for the Medical Devices.

The development of a novel artificial heart valve with outstanding durability and safety has remained a challenge since the first mechanical heart valve entered the market 65 years ago. Recent progress in high-molecular compounds opened new horizons in overcoming major drawbacks of mechanical and tissue heart valves (dysfunction and failure, tissue degradation, calcification, high immunogenic potential, and high risk of thrombosis), providing new insights into the development of an ideal artificial heart valve. Polymeric heart valves can best mimic the tissue-level mechanical behavior of the native valves. This review summarizes the evolution of polymeric heart valves and the state-of-the-art approaches to their development, fabrication, and manufacturing. The review discusses the biocompatibility and durability testing of previously investigated polymeric materials and presents the most recent developments, including the first human clinical trials of LifePolymer. New promising functional polymers, nanocomposite biomaterials, and valve designs are discussed in terms of their potential application in the development of an ideal polymeric heart valve. The superiority and inferiority of nanocomposite and hybrid materials to non-modified polymers are reported. The review proposes several concepts potentially suitable to address the above-mentioned challenges arising in the R&D of polymeric heart valves from the properties, structure, and surface of polymeric materials. Additive manufacturing, nanotechnology, anisotropy control, machine learning, and advanced modeling tools have given the green light to set new directions for polymeric heart valves.

Targeted Drug Administration onto Cancer Cells Using Hyaluronic Acid-Quercetin-Conjugated Silver Nanoparticles.

Quercetin (QtN) displays low systemic bioavailability caused by poor water solubility and instability. Consequently, it exerts limited anticancer action in vivo. One solution to increase the anticancer efficacy of QtN is the use of appropriate functionalized nanocarriers that preferentially target and deliver the drug to the tumor location. Herein, a direct advanced method was designed to develop water-soluble hyaluronic acid (HA)-QtN-conjugated silver nanoparticles (AgNPs). HA-QtN reduced silver nitrate (AgNO3) while acting as a stabilizing agent to produce AgNPs. Further, HA-QtN#AgNPs served as an anchor for folate/folic acid (FA) conjugated with polyethylene glycol (PEG). The resulting PEG-FA-HA-QtN#AgNPs (further abbreviated as PF/HA-QtN#AgNPs) were characterized both in vitro and ex vivo. Physical characterizations included UV-visible (UV-Vis) spectroscopy, Fourier transform infrared (FTIR) spectroscopy, transmission electron microscopy (TEM), particle size (PS) and zeta potential (ZP) measurements, and biopharmaceutical evaluations. The biopharmaceutical evaluations included analyses of the cytotoxic effects on the HeLa and Caco-2 cancer cell lines using the MTT assay; cellular drug intake into cancer cells using flow cytometry and confocal microscopy; and blood compatibility using an automatic hematology analyzer, a diode array spectrophotometer, and an enzyme-linked immunosorbent assay (ELISA). The prepared hybrid delivery nanosystem was hemocompatible and more oncocytotoxic than the free, pure QtN. Therefore, PF/HA-QtN#AgNPs represent a smart nano-based drug delivery system (NDDS) and could be a promising oncotherapeutic option if the data are validated in vivo.

Study of biocompatibility, cytotoxic activity in vitro of a tetrazole-containing derivative of 2-amino-4,6-di(aziridin-1-yl)-1,3,5-triazine.

The hydrolytic stability, hemocompatibility, antioxidant properties and in vitro cytotoxic activity of {5-[(4,6-di(aziridin-1-yl)-1,3,5-triazin-2-yl)amino]-2,2-dimethyl-1,3-dioxan-5-yl}methyl 2-(5-phenyl-2H-tetrazol-2-yl)acetate have been studied. 1H NMR spectroscopy showed that this tetrazole-containing derivative of 1,3,5-triazine is stable in neutral (pH 7) and alkaline (pH 10) media; hydrolysis of the dioxane cycle occurs in an acidic environment (pH 3). It has been established that {5-[(4,6-di(aziridin-1-yl)-1,3,5-triazin-2-yl)amino]-2,2-dimethyl-1,3-dioxan-5-yl}methyl-2-(5-phenyl-2H-tetrazol-2-yl)acetate is hemocompatible, exhibits antioxidant properties, but does not show antiradical activity over the entire range of concentrations. In turn, the study of cytotoxic activity in vitro showed that the tetrazole-containing derivative of 1,3,5-triazine has an effect on the cell lines of human alveolar basal epithelium adenocarcinoma A549 (IC50 41.3 µmol l-1), human ovarian teratocarcinoma PA-1 (IC50 10.6 µmol l-1), hepatocarcinoma Huh7 (IC50 19.9 µmol l-1), cervical cancer HeLa (IC50 3.7 µmol l-1), and human embryonic kidney HEK293 (IC50 15.8 µmol l-1). It was suggested one of the possible mechanism of substance 2 cytotoxicity via HIF pathway inhibition.

Proactive Hemocompatibility Platform Initiated by PAMAM Dendrimer Adapting to Key Components in Coagulation System.

Surface modification manipulates the application performance of materials, and thrombosis caused by material contact is a key risk factor of biomaterials failure in blood-contacting/implanting devices. Therefore, building a safe and effective hemocompatibility platform is still urgent. Owing to the unique properties of polyamidoamine (PAMAM) dendrimers, in this study, modified surfaces with varying dendrimer densities were interacted with elements maintaining blood homeostasis. These included the plasma proteins bovine serum albumin and fibrinogen, cells in blood (platelets and erythrocyte), as well as endothelial cells (ECs), and the objective was to evaluate the blood compatibility of the chosen materials. Whole blood test and dynamic blood circulation experiment by the arteriovenous shunt mode of rabbit were also conducted, based on the complexity and fluidity of blood. The PAMAM-modified substrates, particularly that with a high density of PAMAM (N1.0), adsorbed proteins with lessened fibrinogen adsorption, reduced platelet activation and aggregation, and suppressed clotting in whole blood and dynamic blood testing. Furthermore, the designed PAMAM dendrimer densities were safe and showed negligible erythrocyte lysis. Concurrently, PAMAM modification could maintain EC growth and did not trigger the release of procoagulant factors. These results suggest that the PAMAM-modified materials are compatible for maintaining blood homeostasis. Thus, PAMAM dendrimers can work as excellent surface modifiers for constructing a hemocompatibility platform and even a primer layer for desired functional design, promoting the service performance of blood-contacting devices.