Hemodynamic Evaluation of a Centrifugal Left Atrial Decompression Pump for Heart Failure with Preserved Ejection Fraction.

This article discusses a new continuous flow mini pump that has been developed to improve symptoms and prognosis in patients with Heart Failure with Preserved Ejection Fraction (HFpEF), for which there are currently no established treatments. The pump is designed to discharge a reduced percentage of blood volume from the left atrium to the subclavian artery, clamped at the bifurcation with the aortic arch. The overall specifications, design parameters, and hemodynamics of this new device are discussed, along with data from in vitro circulation loop tests and numerical simulations. The article also compares the results for two configurations of the pump with respect to key indicators of hemocompatibility used in blood pump development.

An Overview of In Vitro Drug Release Methods for Drug-Eluting Stents.

The drug release profile of drug-eluting stents (DESs) is affected by a number of factors, including the formulation, design, and physicochemical properties of the utilized material. DES has been around for twenty years and despite its widespread clinical use, and efficacy in lowering the rate of target lesion restenosis, it still requires additional development to reduce side effects and provide long-term clinical stability. Unfortunately, for analyzing these implants, there is still no globally accepted in vitro test method. This is owing to the stent's complexity as well as the dynamic arterial compartments of the blood and vascular wall. The former is the source of numerous biological, chemical, and physical mechanisms that are more commonly observed in tissue, lumen, and DES. As a result, universalizing bio-relevant apparatus, suitable for liberation testing of such complex implants is difficult. This article aims to provide a comprehensive review of the methods used for in vitro release testing of DESs. Aspects related to the correlation of the release profiles in the cases of in vitro and in vivo are also addressed.

Viscoelastic Behavior of Drug-Loaded Polyurethane.

Drug-eluting stents are desirable platforms for local medicine delivery. However, the incorporation of drugs into polymers can influence the mechanical and physicochemical properties of said matrix, which is a topic that is still poorly understood. In fact, this is more noticeable since the apposition is most often accompanied by mechanical stresses on the polymer coating, which can induce therapeutic failure that can result in death. It is therefore necessary to better understand their behavior by examining their properties in conditions such as those in living beings. We studied polyurethane drug carriers made in-house. Diclofenac epolamine was chosen as a model hydrophilic medicine. We used thermal measurements (DMTA) and tensile tests. The aim was to establish the influence of the loading and release of the drug on the physicochemical properties of this polymer in the presence of a stagnant or circulating fluid medium, phosphate-buffered saline (PBS). For the two PU/drug loadings studied, the effect of the initial drug load was more marked. The free volume fraction and the number of pores in the samples increased with the increasing percent of the drug and with release time. The kinetic profiles were accelerated with the loading ratio and with the presence of flow. Young's modulus and ultimate stress were not significantly influenced by the release time. A relevant relationship between the tensile properties and the viscoelastic behavior of the samples was developed. Our results have implications for optimizing the performance of drug coatings for stents.

Improved Aerodynamics of a Hollow-Blade Axial Flow Fan by Controlling the Leakage Flow Rate by Air Injection at the Rotating Shroud.

Axial flow fans are used in many fields in order to ensure the mass and heat transfer from air, chiefly in the heating, ventilation and air conditioning industry (HVAC). A more proper understanding of the airflow behavior through the systems is necessary to manage and optimize the fan operation. Computational fluid dynamics (CFD) represents a real tool providing the ability to access flow structures in areas that measuring equipment cannot reach. Reducing the leakage flow rate, inherent in operation, by synthetic-jet techniques improves performance. This paper presents the CFD results performed on a hollow blade fan developed by our team. The leakage flow is controlled by blowing air from 16 designated circular holes and arranged on the fan shroud. We discuss the results for two rotational speeds (1000 and 2000 rpm) and two injection rates (400 and 800 L/min). The numerical results consistent with the experimental show, for the low rotation speed and high injection ratio, significant gains in power (53%), torque (80%) and leakage flow rate (80%).

Development of a Model Based on Physical Mechanisms for the Explanation of Drug Release: Application to Diclofenac Release from Polyurethane Films.

In this study, we present a method for prediction of the drug-release profile based on the physical mechanisms that can intervene in drug release from a drug-carrier. The application presented here incorporates the effects of drug concentration and Reynolds number defining the circulating flow in the testing vein. The experimental data used relate to the release of diclofenac from samples of non-degradable polyurethane subjected to static and continuous flow. This case includes simultaneously three mechanisms: burst-release, diffusion and osmotic pressure, identified beforehand here as being able to contribute to the drug liberation. For this purpose, authors coded the Sequential Quadratic Programming Algorithm to solve the problem of non-linear optimization. The experimental data used to develop the mathematical model obtained from release studies carried out in water solution at 37 °C, for three concentrations of diclofenac and two water flow rates. We discuss the contribution of mechanisms and kinetics by considering two aforementioned parameters and, following that, we obtain the specific-model and compare the calculated results with the experimental results for the reserved cases. The results showed that drug percentage mostly affect the burst release, however flow rate has affected the osmotic release. In addition, release kinetics of all the mechanisms have increased by increasing the values of two considered parameters.

Numerical study of hemodynamic and diagnostic parameters affected by stenosis in bifurcated artery.

Stenosis in the bifurcated coronary artery has attracted wide attention among the researchers. Many investigations have been carried out by means of Computational Fluid Dynamics (CFD) to better understand the physical mechanism inside the stenotic bifurcated artery. However, the main focus of the existing publications is limited to the variation of hemodynamic parameters affected by the stenosis and bifurcation structure. The present study aims to make further evaluations of stenosis development and diagnostic lesion assessments based on the critical values of hemodynamic and practical diagnostic parameters. The bifurcated coronary artery with initial stenosis source has been studied in 2 D unsteady model. Different locations of initial stenosis source have been found to greatly affect the orientation of the further stenosis development. In addition, different stenosis severities (diameter stenosis: 30%, 50% and 70%), different stenosis lengths (3 mm, 6 mm and 9 mm) and different pulse rates (75 bpm, 100 bpm and 120 bpm) as controlling parameters have been investigated.

A New Hemodynamic Ex Vivo Model for Medical Devices Assessment.

BACKGROUND: In-stent restenosis (ISR) remains a major public health concern associated with an increased morbidity, mortality, and health-related costs. Drug-eluting stents (DES) have reduced ISR, but generate healing-related issues or hypersensitivity reactions, leading to an increased risk of late acute stent thrombosis. Assessments of new DES are based on animal models or in vitro release systems, which have several limitations. The role of flow and shear stress on endothelial cell and ISR has also been emphasized. The aim of this work was to design and first evaluate an original bioreactor, replicating ex vivo hemodynamic and biological conditions similar to human conditions, to further evaluate new DES. METHODS: This bioreactor was designed to study up to 6 stented arteries connected in bypass, immersed in a culture box, in which circulated a physiological systolo-diastolic resistive flow. Two centrifugal pumps drove the flow. The main pump generated pulsating flows by modulation of rotation velocity, and the second pump worked at constant rotation velocity, ensuring the counter pressure levels and backflows. The flow rate, the velocity profile, the arterial pressure, and the resistance of the flow were adjustable. The bioreactor was placed in an incubator to reproduce a biological environment. RESULTS: A first feasibility experience was performed over a 24-day period. Three rat aortic thoracic arteries were placed into the bioreactor, immersed in cell culture medium changed every 3 days, and with a circulating systolic and diastolic flux during the entire experimentation. There was no infection and no leak. At the end of the experimentation, a morphometric analysis was performed confirming the viability of the arteries. CONCLUSIONS: We designed and patented an original hemodynamic ex vivo model to further study new DES, as well as a wide range of vascular diseases and medical devices. This bioreactor will allow characterization of the velocity field and drug transfers within a stented artery with new functionalized DES, with experimental means not available in vivo. Another major benefit will be the reduction of animal experimentation and the opportunity to test new DES or other vascular therapeutics in human tissues (human infrapopliteal or coronary arteries collected during human donation).

2-Aryl-N-acyl indole derivatives as liver X receptor (LXR) agonists.

Structure-activity relationship studies on a series of Boc-indole derivatives as LXR agonists are described. Compound 1 was identified as an LXR agonist through structure-based virtual screening followed by high-throughput gene profiling. Replacement of the indan linker portion in 1 with an open-chain linker resulted in compounds with similar or improved in vitro potency and cellular functional activity. The Boc group at the N-1 position of the indole moiety can be replaced with a benzoyl group. The SAR studies led to the identification of compound 8, a potent LXRbeta agonist with an EC50 of 12 nM in the cofactor recruitment assay.

Discovery and structure-activity relationship studies of indole derivatives as liver X receptor (LXR) agonists.

A structurally novel liver X receptor (LXR) agonist (1) was identified from internal compound collection utilizing the combination of structure-based virtual screening and high-throughput gene profiling. Compound 1 increased ABCA1 gene expression by eightfold and SREBP1c by threefold in differentiated THP-1 macrophage cell lines. Confirmation of its agonistic activity against LXR was obtained in the co-factor recruitment and reporter transactivation assays. Structure-activity relationship studies on compound 1 are described.

Discovery and SAR of a novel selective and orally bioavailable nonpeptide classical competitive inhibitor class of protein-tyrosine phosphatase 1B.

Reversible phosphorylation and dephosphorylation of key proteins on tyrosine residues are important parts of intracellular signaling triggered by hormones and other agents. Recent knock-out studies in mice have identified PTP1B as a potential target for the treatment of diabetes and obesity. As a consequence, a number of academic and industrial groups are aggressively pursuing the development of selective PTP1B inhibitors. In addition, other protein-tyrosine phosphatases (PTPs) appear to be critically involved in major diseases such as cancer and autoimmunity. Given the diversity of PTPs and their potential as drug targets in different diseases, we have taken a broad approach to develop active site-directed selective inhibitors of specific members of this family of enzymes. Using a high throughput screening, we have previously identified 2-(oxalylamino)benzoic acid 3a as a relatively weak but classical competitive inhibitor of several PTPs.(4) On the basis of our early studies, indicating that 3a might be used as a starting point for the synthesis of selective PTP inhibitors, we now present our efforts in expansion of this concept and provide here a number of new chemical scaffolds for the development of inhibitors of different members of the PTP family. Although the core structure of these inhibitors is charged, good oral bioavailability has been observed in rat for some compounds. Furthermore, we have observed enhancement of 2-deoxy-glucose accumulation in C2C12 cells with prodrug analogues.