Computational Fluid Dynamic Analysis of the Hemodialysis Plastic Cannula.

The jet of fluid returning to the patient through a hemodialysis venous needle has previously been reported as a potential source of endothelial damage which can lead to intimal hyperplasia (IH) in arteriovenous fistulae (AVF). Metal needles are the current standard practice for accessing the vascular system in hemodialysis. However, plastic cannulae have been used in Japan for 30 years. This study utilized computational fluid dynamics to analyze the hemodynamics of blood exiting a plastic cannula and determined the optimal placement and blood flow rate. Transient simulations were run using a 15G Argyle Safety Fistula Cannula with Anti-Reflux Valve inserted into an idealized cephalic vein. The cannula tip was fixed at three different locations within the vein (upper third, middle, and lower third) with blood flow rates of 200 mL/min, 300 mL/min, and 400 mL/min imposed. The high degree of jet break down immediately after exiting the cannula was attributed to the staggered side hole arrangement, position of the cannula in the vein, and the imposed blood flow rate. Elevated levels of wall shear stress which may lead to IH were identified at the site of jet impingement on the vein floor as well as regions of high residency time. The risk of IH may be minimized by enhancing the breakdown of the jet through the use of optimal blood flow rates between 300 and 400 mL/min and ensuring the cannula tip is placed away from the walls of the vein.

Biostability and biological performance of a PDMS-based polyurethane for controlled drug release.

Polymers have been used to deliver therapeutic agents in a range of medical devices with drug eluting stents being the most widespread current application. Although polymers enable controlled release of a therapeutic agent, the polymeric surface has been reported to provide suboptimal biocompatibility and haemocompatibility and it has been suggested that currently used polymers may be at least partly responsible for the late adverse events observed in intravascular stent systems. In this study, the biostability and biological performance of a siloxane-based polyurethane elastomer (E2A) demonstrating excellent long-term biostability in the unloaded state was investigated following incorporation of a therapeutic agent. After implantation in an ovine model for 6 months, samples were assessed using SEM and ATR-FTIR to determine changes in the surface chemical structure and morphology of the materials and tensile testing was used to examine changes in bulk characteristics. Biological response was assessed using in vitro cytotoxicity testing and histological analysis. Results indicated that incorporation of 25mg/g dexamethasone acetate (DexA) into the siloxane-based polyurethane resulted in no significant difference in the biostability and biocompatibility of the material. Some level of cytotoxic potential was exhibited which was believed to result from residual DexA leaching from samples during the extraction process. These findings suggest that E2A is a potential candidate for a delivery vehicle of therapeutic agents in implantable drug delivery applications.

Extracellular matrix remodelling during cell adhesion monitored by the quartz crystal microbalance.

A cell's ability to remodel adsorbed protein layers on surfaces is influenced by the nature of the protein layer itself. Remodelling is often required to accomplish cellular adhesion and extracellular matrix formation which forms the basis for cell spreading, increased adhesion and expression of different phenotypes. The adhesion of NIH3T3 (EGFP) fibroblasts to serum protein (albumin or fibronectin) precoated tantalum (Ta) and oxidised polystyrene (PS(ox)) surfaces was examined using the quartz crystal microbalance with dissipation (QCM-D) monitoring and fluorescence microscopy. The cells were either untreated or treated with cycloheximide to examine the contribution of endogenous protein production during cell adhesion to the QCM-D response over a period of 2h. Following adsorption of albumin onto Ta and PS(ox) there was no difference detected between the response to seeding untreated and cycloheximide treated cells. The QCM-D was able to detect differences in the untreated cellular responses to fibronectin versus serum precoated Ta and PS(ox) substrates, while cycloheximide treatment of the cells produced the same QCM-D response for fibronectin and serum precoatings on each of the materials. This confirmed that the process of matrix remodelling by the cells is dependent on the underlying substrate and the preadsorbed proteins and that the QCM-D response is dominated by changes in the underlying protein layer. Changes in dissipation correspond to the development of the actin cytoskeleton as visualised by actin staining.

The effect of sterilisation on a poly(dimethylsiloxane)/poly(hexamethylene oxide) mixed macrodiol-based polyurethane elastomer.

The effect of various forms of sterilisation on a novel thermoplastic polyurethane elastomer synthesised using poly(hexamethylene oxide) (PHMO) and poly(dimethylsiloxane) (PDMS) macrodiols has been studied. The five sterilisation methods investigated were ethylene oxide (EtO) (single and multiple cycles), gas plasma, steam, vapour phase liquid chemical and gamma-irradiation (single and multiple cycles). Following sterilisation, scanning electron microscopy (SEM) and attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) were used to assess changes in the surface chemical structure and morphology, and gel permeation chromatography (GPC) and tensile testing were used to examine changes in bulk characteristics. Biostability was assessed using subcutaneous implantation of strained samples in sheep for 6 weeks. The results showed that the properties of the commercially available control material, Pellethane 2363-80A, were significantly affected by exposure to gamma-irradiation, steam and multiple cycles of EtO with aging and implantation compounding the effect. Exposure to a gas plasma sterilisation process resulted in significant degradation in both polyurethanes. A vapour phase liquid chemical sterilisation process caused minimal adverse effects. Sterilisation of the PDMS-based polyurethane using EtO, gamma-irradiation and autoclaving resulted in no significant changes in properties. The material's biostability was also unaffected by exposure to each of these sterilisation processes followed by short-term implantation suggesting that this material is a potential candidate for use in a wide range of implantable medical devices sterilised using commercially available processes. Further biostability studies should be performed to assess the longer-term in vivo biostability of the PDMS-based material sterilised using autoclaving and gamma-irradiation.

The effect of charged groups on protein interactions with poly(HEMA) hydrogels.

Proteins, lipids and other biomolecules interact strongly with the acrylic-based biomaterials used for contact lenses. Although hydrogels are nominally resistant to protein fouling, many studies have reported considerable amounts of protein bound to poly(2-hydroxyethylmethacrylate) (PHEMA) lenses. This study examined the binding of a series of biomolecules (tear protein analogues, mucin and cholesterol) to poly(methylmethacrylate) (PMMA) and three HEMA-based hydrogels (PHEMA, HEMA plus methacrylic acid (P(HEMA-MAA)), HEMA plus methacrylic acid plus N-vinylpyrrolidone (P(HEMA-MAA-NVP))) by use of a quartz crystal microbalance with dissipation (QCM-D) monitoring. The QCM-D estimates changes in the mass and viscous constant for the adsorbed layer through measurements of frequency and dissipation. Protein interaction with each of the test materials caused a net increase in mass of the material indicating protein binding except for lysozyme interacting with P(HEMA-MAA). A net decrease in mass was observed for lysozyme interacting with P(HEMA-MAA) which may be ascribed to lysozyme collapsing the hydrogel by expelling water. A net mass decrease was observed for cholesterol interacting with each of the hydrogel materials, while a mass increase was observed on PMMA.

Lysozyme interaction with poly(HEMA)-based hydrogel.

Lysozyme interaction with an acrylic-based hydrogel, poly(2-hydroxyethyl methacrylate) co-methacrylic acid (P(HEMA-MAA)), was investigated using a combination of quartz crystal microbalance with dissipation (QCM-D), surface plasmon resonance (SPR) and dual polarisation interferometry (DPI). This combination of techniques demonstrated that lysozyme initially absorbed into the hydrogel matrix and displaced water from the hydrogel while subsequent lysozyme additions were adsorbed onto the surface of the hydrogel material. QCM-D, being sensitive to bound water, showed an overall decrease in mass and stiffening of the layer after lysozyme addition. SPR, a water insensitive technique, showed a net mass increase after addition of lysozyme and buffer rinses. DPI showed that the first exposure of lysozyme to P(HEMA-MAA) was consistent with lysozyme absorption while subsequent lysozyme exposures were consistent with lysozyme adsorption.

Monitoring cell adhesion on tantalum and oxidised polystyrene using a quartz crystal microbalance with dissipation.

The quartz crystal microbalance with dissipation (QCM-D) (Q-Sense AB, Sweden) has been established as a useful tool for evaluating interactions between various biological and non-biological systems, and there has been increasing interest in using the QCM-D technique for cell monitoring applications. This study investigated the potential of the QCM-D to characterise the initial adhesion and spreading of cells in contact with protein precoated biocompatible surfaces. The QCM-D technique is attractive for monitoring cell adhesion and spreading as it allows in situ real-time measurements. The adhesion of NIH3T3 (EGFP) fibroblasts to tantalum (Ta) and oxidised polystyrene (PS(ox)) surfaces precoated with serum proteins was examined using the QCM-D for a period of either 2 or 4 h. Time-lapse photography was performed at 30 min intervals to visually examine cell adhesion and spreading in order to relate cell morphology to the QCM-D response. Following adsorption of albumin, fibronectin or newborn calf serum onto the surfaces, QCM-D measurements showed that cells adhered and spread on the fibronectin and serum coated surfaces, while few cells adhered to the albumin coated surfaces. Cells adhered to albumin coated surfaces had a rounded morphology. The responses to fibronectin and serum precoated surfaces were quite different for each of the underlying substrates indicating that the process of cell adhesion and spreading elicits different responses depending on both the protein coating composition and the influence of the underlying substrate. The different response may be due to extracellular matrix remodelling as well as cytoskeletal changes. Frequency (f) and dissipation (D) changes associated with cell adhesion were less than would be expected from the Sauerbrey relation due to the viscoelastic properties of the cells.

Long-term in vivo biostability of poly(dimethylsiloxane)/poly(hexamethylene oxide) mixed macrodiol-based polyurethane elastomers.

The long-term biostability of a novel thermoplastic polyurethane elastomer (Elast-Eon 2 80A) synthesized using poly(hexamethylene oxide) (PHMO) and poly(dimethylsiloxane) (PDMS) macrodiols has been studied using an in vivo ovine model. The material's biostability was compared with that of three commercially available control materials, Pellethane 2363-80A, Pellethane 2363-55D and Bionate 55D, after subcutaneous implantation of strained compression moulded flat sheet dumbbells in sheep for periods ranging from 3 to 24 months. Scanning electron microscopy, attenuated total reflectance-Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy were used to assess changes in the surface chemical structure and morphology of the materials. Gel permeation chromatography, differential scanning calorimetry and tensile testing were used to examine changes in bulk characteristics of the materials. The results showed that the biostability of the soft flexible PDMS-based test polyurethane was significantly better than the control material of similar softness, Pellethane 80A, and as good as or better than both of the harder commercially available negative control polyurethanes, Pellethane 55D and Bionate 55D. Changes observed in the surface of the Pellethane materials were consistent with oxidation of the aliphatic polyether soft segment and hydrolysis of the urethane bonds joining hard to soft segment with degradation in Pellethane 80A significantly more severe than that observed in Pellethane 55D. Very minor changes were seen on the surfaces of the Elast-Eon 2 80A and Bionate 55D materials. There was a general trend of molecular weight decreasing with time across all polymers and the molecular weights of all materials decreased at a similar relative rate. The polydispersity ratio, Mw/Mn, increased with time for all materials. Tensile tests indicated that UTS increased in Elast-Eon 2 80A and Bionate 55D following implantation under strained conditions. However, ultimate strain decreased and elastic modulus increased in the explanted specimens of all three materials when compared with their unimplanted unstrained counterparts. The results indicate that a soft, flexible PDMS-based polyurethane synthesized using 20% PHMO and 80% PDMS macrodiols has excellent long-term biostability compared with commercially available polyurethanes.

In vivo biostability of polyurethane-organosilicate nanocomposites.

Organically modified layered silicates were incorporated into a polyether soft-segment polyurethane to form composites of at least delaminated morphology. The primary organic modifier was a quaternary ammonium compound; however, one composite included an alternative amino undecanoic acid-modified silicate. The composites' biostability was assessed in an in vivo ovine model over a period of 6 weeks. Attenuated total reflectance-Fourier transform infrared analysis and semi-quantitative scanning electron microscopy image rating indicate a significant enhancement of the base polyurethane biostability with the inclusion of silicate at 3 wt.%. The potential effect at 15 wt.% was confounded by probable leaching of the quaternary ammonium compound affecting the tissue response. The amino undecanoic acid composite compared favourably with the quaternary ammonium compound composite of equivalent silicate loading, and offers the promise of a more favourable tissue response.

Non-degradable polymer nanocomposites for drug delivery.

INTRODUCTION: The need to optimize therapeutic outcomes while minimizing side effects is a major driving force for research and development in the controlled drug delivery field. Polymer nanocomposites (NCs) are an emerging class of materials with remarkable potential for controlled drug delivery. There are a range of release mechanisms that characterize polymer NC systems, and these may be perturbed not only by the addition of nanofillers, but also by the type of drug and the interactions of the drug with the components of the system. AREAS COVERED: The focus of this review is on non-degradable polymer NC systems. In particular, the types of drug delivery approach from these polymer NCs and the theoretical models developed to describe those approaches are discussed. The importance of component interactions and factors affecting drug delivery from polymer NCs is also addressed. EXPERT OPINION: Despite the remarkable potential and extensive research being conducted on polymer NCs for use in drug delivery, commercialization and large-scale production are limited by the cost and difficulty in consistently producing fully exfoliated NCs. A continuing challenge for the field is to understand better the key interactions and structure-property relationships arising from different polymer, filler and drug combinations.

The modulation of platelet and endothelial cell adhesion to vascular graft materials by perlecan.

Controlled neo-endothelialisation is critical to the patency of small diameter vascular grafts. Endothelialisation and platelet adhesion to purified endothelial cell-derived perlecan, the major heparan sulfate (HS) proteoglycan in basement membranes, were investigated using in vivo and in vitro assays. Expanded polytetrafluoroethylene (ePTFE) vascular grafts were coated with perlecan and tested in an ovine carotid interposition model for a period of 6 weeks and assessed using light and scanning microscopy. Enhanced endothelial cell growth and reduced platelet adhesion were observed on the perlecan coated grafts when compared to uncoated controls implanted in the same sheep (n=5). Perlecan was also found to stimulate endothelial cell proliferation in vitro over a period of 6 days in the presence of plasma proteins and fibroblastic growth factor 2 (FGF-2), however in the absence of FGF-2 endothelial cell growth could not be maintained during this period. Perlecan was found to be anti-adhesive for platelets, however after removal of the HS chains attached to perlecan, platelet adhesion and aggregation were supported. These results suggest a role for HS chains of perlecan in improving graft patency by selectively promoting endothelial cell proliferation while modulating platelet adhesion.