Gold nanoparticle interactions in human blood: a model evaluation.

In this study, we investigated gold nanoparticle (AuNP) interactions in blood using thromboelastography as a rapid screening tool to monitor their influence on blood coagulation. 1.2 nM colloidal AuNPs ranging from 12 to 85 nm have no effect in the blood, however, 5 nM AuNPs demonstrate pro-thrombogenic concentration dependent effects with a reduction in clot formation. Size effects exhibit a non-linear trend with 45 and 85 nm particles resulting in a faster pro-thrombotic response. Clot strength decreased with AuNP size with the greatest reduction with 28 nm particles. We assessed AuNP interactions in the blood focusing on their biological activity. AuNP-RGD possessed pro-coagulant activities, while PEG-thiol, human fibrinogen and clopidogrel prevented blood clot formation and influenced platelet activity, and were more efficient when bound to nanocarriers than unbound ligands. Such tests could fill the knowledge gaps in thrombogenicity of NPs between in vitro test methods and predict in vivo haemocompatibility.

In situ Endothelialization: Bioengineering Considerations to Translation.

Improving patency rates of current cardiovascular implants remains a major challenge. It is widely accepted that regeneration of a healthy endothelium layer on biomaterials could yield the perfect blood-contacting surface. Earlier efforts in pre-seeding endothelial cells in vitro demonstrated success in enhancing patency, but translation to the clinic is largely hampered due to its impracticality. In situ endothelialization, which aims to create biomaterial surfaces capable of self-endothelializing upon implantation, appears to be an extremely promising solution, particularly with the utilization of endothelial progenitor cells (EPCs). Nevertheless, controlling cell behavior in situ using immobilized biomolecules or physical patterning can be complex, thus warranting careful consideration. This review aims to provide valuable insight into the rationale and recent developments in biomaterial strategies to enhance in situ endothelialization. In particular, a discussion on the important bio-/nanoengineering considerations and lessons learnt from clinical trials are presented to aid the future translation of this exciting paradigm.

Toxicology of chemically modified graphene-based materials for medical application.

This review article aims to provide an overview of chemically modified graphene, and graphene oxide (GO), and their impact on toxicology when present in biological systems. Graphene is one of the most promising nanomaterials due to unique physicochemical properties including enhanced optical, thermal, and electrically conductive behavior in addition to mechanical strength and high surface-to-volume ratio. Graphene-based nanomaterials have received much attention over the last 5 years in the biomedical field ranging from their use as polymeric conduits for nerve regeneration, carriers for targeted drug delivery and in the treatment of cancer via photo-thermal therapy. Both in vitro and in vivo biological studies of graphene-based nanomaterials help understand their relative toxicity and biocompatibility when used for biomedical applications. Several studies investigating important material properties such as surface charge, concentration, shape, size, structural defects, and chemical functional groups relate to their safety profile and influence cyto- and geno-toxicology. In this review, we highlight the most recent studies of graphene-based nanomaterials and outline their unique properties, which determine their interactions under a range of environmental conditions. The advent of graphene technology has led to many promising new opportunities for future applications in the field of electronics, biotechnology, and nanomedicine to aid in the diagnosis and treatment of a variety of debilitating diseases.

Nitric oxide-eluting nanocomposite for cardiovascular implants.

Cardiovascular implants must resist thrombosis and intimal hyperplasia, but they are prone to such patency limiting conditions during graft implantation and prior to endothelialisation. Nitric oxide (NO) released from the endothelium has a complex protective role in the cardiovascular system, and this study has addressed: (1) in situ NO release profiles from S-nitrosothiols ((S-Nitroso-N-acetylpenicillamine (SNAP) and (S-Nitrosoglutathione (GSNO)) incorporated into polyhedral oligomeric silsesquioxanepoly(carbonate-urea)urethane (POSS-PCU) coronary artery bypass grafts (CABG) in a physiological pulsatile flow, and (2) the determination of their interaction with endothelial progenitor cells (EPCs), smooth muscle cells, platelets, whole blood kinetics. It was found that 1, 2, and 3 wt% SNAP/GSNO incorporated into POSS-PCU-CABG successfully eluted NO, but optimal elution was evident with 2 %-SNAP-POSS-PCU. NO release determined under static conditions using the Griess assay, and in situ measurements under pulsatile flow using amperometric probe was found to differ, thus confirming the significance of monitoring NO-elution under haemodynamic conditions. 2 %-SNAP-POSS-PCU demonstrated anti-thrombogenic kinetics through thromboelastography measurements, while metabolic activity using Alamar Blue™ assay and scanning electron microscopy demonstrated greater adhesion of EPCs and reduced adhesion of platelets.

Nitric oxide donors for cardiovascular implant applications.

In an era of increased cardiovascular disease burden in the ageing population, there is great demand for devices that come in to contact with the blood such as heart valves, stents, and bypass grafts that offer life saving treatments. Nitric oxide (NO) elution from healthy endothelial tissue that lines the vessels maintains haemostasis throughout the vasculature. Surgical devices that release NO are desirable treatment options and N-diazeniumdiolates and S-nitrosothiols are recognized as preferred donor molecules. There is a keen interest to investigate newer methods by which NO donors can be retained within biomaterials so that their release and kinetic profiles can be optimized. A range of polymeric scaffolds incorporating microparticles and nanomaterials are presenting solutions to current challenges, and have been investigated in a range of clinical applications. This review outlines the application of NO donors for cardiovascular therapy using biomaterials that release NO locally to prevent thrombosis and intimal hyperplasia (IH) and enhance endothelialization in the fabrication of next generation cardiovascular device technology.

Self-assembled benzoselenadiazole-capped tripeptide hydrogels with inherent in vitro anti-cancer and anti-inflammatory activity.

Self-assembled benzoselenadiazole (BSe)-capped tripeptide based nanofibrillar hydrogels have been developed with inherent anticancer and anti-inflammatory activity.

A nanocage for nanomedicine: polyhedral oligomeric silsesquioxane (POSS).

Ground-breaking advances in nanomedicine (defined as the application of nanotechnology in medicine) have proposed novel therapeutics and diagnostics, which can potentially revolutionize current medical practice. Polyhedral oligomeric silsesquioxane (POSS) with a distinctive nanocage structure consisting of an inner inorganic framework of silicon and oxygen atoms, and an outer shell of organic functional groups is one of the most promising nanomaterials for medical applications. Enhanced biocompatibility and physicochemical (material bulk and surface) properties have resulted in the development of a wide range of nanocomposite POSS copolymers for biomedical applications, such as the development of biomedical devices, tissue engineering scaffolds, drug delivery systems, dental applications, and biological sensors. The application of POSS nanocomposites in combination with other nanostructures has also been investigated including silver nanoparticles and quantum dot nanocrystals. Chemical functionalization confers antimicrobial efficacy to POSS, and the use of polymer nanocomposites provides a biocompatible surface coating for quantum dot nanocrystals to enhance the efficacy of the materials for different biomedical and biotechnological applications. Interestingly, a family of POSS-containing nanocomposite materials can be engineered either as completely non-biodegradable materials or as biodegradable materials with tuneable degradation rates required for tissue engineering applications. These highly versatile POSS derivatives have created new horizons for the field of biomaterials research and beyond. Currently, the application of POSS-containing polymers in various fields of nanomedicine is under intensive investigation with expectedly encouraging outcomes.

Application of plasma surface modification techniques to improve hemocompatibility of vascular grafts: A review.

Surface modification using plasma processing can significantly change the chemical and physical characteristics of biomaterial surfaces. When used in combination with additional modification techniques such as direct chemical or biochemical methods, it can produce novel biomaterial surfaces, which are anticoagulant, bioactive, and biomimetic in nature. This article reviews recent advances in improving hemocompatibility of biomaterials by plasma surface modification (PSM). The focus of this review is on PSM of the most commonly used polymers for vascular prostheses such as expanded polytetrafluoroethylene (PTFE), polyethylene terephthalate (Dacron(®) ), and next generation of biomaterials, including polyhedral oligomeric silsesquioxane nanocomposite.

Surface modification of POSS-nanocomposite biomaterials using reactive oxygen plasma treatment for cardiovascular surgical implant applications.

In this study, central composite design (CCD) was used to develop predictive models to optimize operating conditions of plasma surface modification. It was concluded that out of the two process variables, power and duration of plasma exposure, the latter was significantly affecting the surface energy (γ(s) ), chemistry, and topography of polyhedral oligomeric silsesquioxane-poly(carbonate-urea)urethane (POSS-PCU) films. On the basis of experimental data, CCD was used to model the γ(s) using a quadratic modeling of the process variables to achieve optimum surface energy to improve the interaction between endothelial cells (ECs). It was found that optimal water θ for EC adhesion and retention, which was reported 55° from supporting literature (equivalent to γ(s) = 51 mN/m), was easily achievable using the following experimental conditions: (1) power output at 30 W for 75 Sec, (2) 90 W for 40 Sec, and (3) 90 W for 55 Sec in oxygen. In vitro cell culture and metabolic activity studies on optimized films [as in (1)] demonstrate increased adhesion, coverage, and growth of human umbilical vein endothelial cells that were confluent over a shorter time period (<24 H) than controls. Such materials enhanced the EC response and promoted endothelialization on optimized films, thus demonstrating their use as bypass graft materials.

Metal-Fungus interaction: Review on cellular processes underlying heavy metal detoxification and synthesis of metal nanoparticles.

The most adverse outcome of increasing industrialization is contamination of the ecosystem with heavy metals. Toxic heavy metals possess a deleterious effect on all forms of biota; however, they affect the microbial system directly. These heavy metals form complexes with the microbial system by forming covalent and ionic bonds and affecting them at the cellular level and biochemical and molecular levels, ultimately leading to mutation affecting the microbial population. Microbes, in turn, have developed efficient resistance mechanisms to cope with metal toxicity. This review focuses on the vital tolerance mechanisms employed by the fungus to resist the toxicity caused by heavy metals. The tolerance mechanisms have been basically categorized into biosorption, bioaccumulation, biotransformation, and efflux of metal ions. The mechanisms of tolerance to some toxic metals as copper, arsenic, zinc, cadmium, and nickel have been discussed. The article summarizes and provides a detailed illustration of the tolerance means with specific examples in each case. Exposure of metals to fungal cells leads to a response that may lead to the formation of metal nanoparticles to overcome the toxicity by immobilization in less toxic forms. Therefore, fungal-mediated green synthesis of metal nanoparticles, their mechanism of synthesis, and applications have also been discussed. An understanding of how fungus resists metal toxicity can provide insights into the development of adaption techniques and methodologies for detoxification and removal of metals from the environment.

Current Treatment Strategies for Intracranial Aneurysms: An Overview.

Intracranial aneurysm is a leading cause of stroke. Its treatment has evolved over the past 2 decades. This review summarizes the treatment strategies for intracranial aneurysms from 3 different perspectives: open surgery approach, transluminal treatment approach, and new technologies being used or trialed. We introduce most of the available treatment techniques in detail, including contralateral clipping, wrapping and clipping, double catheters assisting coiling and waffle-cone technique, and so on. Data from major trials such as Analysis of Treatment by Endovascular approach of Non-ruptured Aneurysms (ATENA), Internal Subarachnoid Trial (ISAT), Clinical and Anatomical Results in the Treatment of Ruptured Intracranial Aneurysms (CLARITY), and Barrow Ruptured Aneurysm Trial (BRAT) as well as information from other clinical reports and local experience are reviewed to suggest a clinical pathway for treating different types of intracranial aneurysms. It will be a valuable supplement to the current existing guidelines. We hope it could help assisting real-time decision-making in clinical practices and also encourage advancements in managing the disease.

Biomimetic modified clinical-grade POSS-PCU nanocomposite polymer for bypass graft applications: a preliminary assessment of endothelial cell adhesion and haemocompatibility.

BACKGROUND: To date, there are no small internal diameter (<5mm) vascular grafts that are FDA approved for clinical use due to high failure rates from thrombosis and unwanted cell proliferation. The ideal conditions to enhance bioengineered grafts would be the blood contacting lumen of the bypass graft fully covered by endothelial cells (ECs). As a strategy towards this aim, we hypothesized that by immobilising biomolecules on the surface of the polyhedral oligomeric silsesquioxane-poly(carbonate-urea)urethane (POSS-PCU) nanocomposite polymers, which contain binding sites and ligands for cell surface receptors similar to extracellular matrix (ECM) will positively influence the attachment and proliferation of ECs. Since, the surface of POSS-PCU is inert and not directly suitable for immobilisation of biomolecules, plasma graft polymerisation is a suitable method to modify the surface properties ready for immobilisation and biofunctionalisation. METHODS: POSS-PCU was activated by plasma treatment in air/O2 to from hydroperoxides (-OH, -OOH), and then carboxylated via plasma polymerisation of a 30% acrylic acid solution (Poly-AA) using a two-step plasma treatment (TSPT) process. Collagen type I, a major component of ECM, was covalently immobilised to mimic the ECM structures to ECs (5mg/ml) using a two-step chemical reaction using EDC chemistry. Successful immobilisation of poly-AA and collagen on to the nanocomposites was confirmed using Toluidine Blue staining and the Bradford assay. Un-treated POSS-PCU served as a simple control. The impact of collagen grafting on the physical, mechanical and biological properties of POSS-PCU was evaluated via contact angle (θ) measurements, scanning electron microscopy (SEM), atomic force microscopy (AFM), dynamic mechanical thermal analysis (DMTA), ECs adhesion and proliferation followed by platelet adhesion and haemolysis ratio (HR) tests. RESULTS: Poly-AA content on each of the plasma treated nanocomposite films increased on Low, Med and High samples due to more carboxylic acid (-COOH) groups at the surface forming amide (-NH2) bonds. The amount of -COOH groups on each of the Low, Med and High nanocomposites correlated with Poly-AA grafting density at 14.7±0.9, 18.9±0.9, and 34.2±2.4 µg/cm(2). Immobilisation of collagen type I on to nanocomposite surface was also found to increase significantly on the Low, Med and High samples from 22±4, 150±15, and 219±17 µg/cm(2), respectively. The level of ECs and their adhesion efficiency were improved with increasing amounts of grafted collagen I. The maximum adhesion of ECs was found on the highest collagen type I coated nanocomposites. Platelet adhesion and activation also increased with increasing collagen density. The obtained HR values for all of the treated samples were well within the acceptable standards for biomaterials (<5% HR). CONCLUSION: Poly-AA-g-POSS-PCU surfaces offer binding sites for the covalent bonding of collagen type I and other biomolecules such as fibronectin by exposure of RGD cell binding domains and growth factors using EDC cross-linking chemistry. Collagen type I modification can yield accelerated EC growth and enhance the endothelialisation of POSS-PCU nanocomposites, and the amount of immobilised collagen can control the level of platelet adhesion on functionalized POSS-PCU via TSPT and poly acrylic acid (poly-AA) treatment. Such surface modification procedures of polymeric surfaces can improve the patency rate of POSS-PCU nanocomposites as vascular bypass grafts in the preparation of a range of medical devices ready for pre-clinical and in vivo evaluation.

Evolution of covered stents in the contemporary era: clinical application, materials and manufacturing strategies using nanotechnology.

Endovascular stents have revolutionised the field of interventional cardiology. Despite their excellent clinical outcome complications associated with percutaneous stent implantation following the procedure have remained a major drawback in their widespread use. To overcome such limitations, a number of novel endovascular stents have emerged including a covered stent wrapped in a thin membrane sleeve. As well as prevention of complications associated with stenting, covered stents owing to their physical barrier are used as the treatment option of choice for trauma devices during emergency situations and to treat a number of pathological disease states. The aim of this review is to provide the reader with an overall objective outlook in the use of covered stents as a treatment option in a number of vascular complications and addresses their design and materials used in the manufacturing process. In addition, new strategies are highlighted and future prospects with the emergence of novel smart alloys for 3D scaffolds and the use of nanotechnology in the development of nanocomposite materials.

Surface modification of a polyhedral oligomeric silsesquioxane poly(carbonate-urea) urethane (POSS-PCU) nanocomposite polymer as a stent coating for enhanced capture of endothelial progenitor cells.

An unmet need exists for the development of next-generation multifunctional nanocomposite materials for biomedical applications, particularly in the field of cardiovascular regenerative biology. Herein, we describe the preparation and characterization of a novel polyhedral oligomeric silsesquioxane poly(carbonate-urea) urethane (POSS-PCU) nanocomposite polymer with covalently attached anti-CD34 antibodies to enhance capture of circulating endothelial progenitor cells (EPC). This material may be used as a new coating for bare metal stents used after balloon angioplasty to improve re-endothelialization. Biophysical characterization techniques were used to assess POSS-PCU and its subsequent functionalization with anti-CD34 antibodies. Results indicated successful covalent attachment of anti-CD34 antibodies on the surface of POSS-PCU leading to an increased propensity for EPC capture, whilst maintaining in vitro biocompatibility and hemocompatibility. POSS-PCU has already been used in 3 first-in-man studies, as a bypass graft, lacrimal duct and a bioartificial trachea. We therefore postulate that its superior biocompatibility and unique biophysical properties would render it an ideal candidate for coating medical devices, with stents as a prime example. Taken together, anti-CD34 functionalized POSS-PCU could form the basis of a nano-inspired polymer platform for the next generation stent coatings.

Surface modification of biomaterials: a quest for blood compatibility.

Cardiovascular implants must resist thrombosis and intimal hyperplasia to maintain patency. These implants when in contact with blood face a challenge to oppose the natural coagulation process that becomes activated. Surface protein adsorption and their relevant 3D confirmation greatly determine the degree of blood compatibility. A great deal of research efforts are attributed towards realising such a surface, which comprise of a range of methods on surface modification. Surface modification methods can be broadly categorized as physicochemical modifications and biological modifications. These modifications aim to modulate platelet responses directly through modulation of thrombogenic proteins or by inducing antithrombogenic biomolecules that can be biofunctionalised onto surfaces or through inducing an active endothelium. Nanotechnology is recognising a great role in such surface modification of cardiovascular implants through biofunctionalisation of polymers and peptides in nanocomposites and through nanofabrication of polymers which will pave the way for finding a closer blood match through haemostasis when developing cardiovascular implants with a greater degree of patency.

Small calibre polyhedral oligomeric silsesquioxane nanocomposite cardiovascular grafts: influence of porosity on the structure, haemocompatibility and mechanical properties.

There is a significant worldwide demand for a small calibre vascular graft for use as a bypass or replacement conduit. An important feature in determining the success of a graft is the wall structure, which includes porosity, pore size and pore interconnectivity, as these play a crucial role in determining the long-term patency of a bypass graft. In this study we fabricate a small diameter (<5mm) vascular graft from polyhedral oligomeric silsesquioxane-poly(carbonate urea)urethane (POSS-PCU) via an extrusion, phase inversion method using an automated, custom built machine. Through the dispersion of a porogen, sodium bicarbonate (NaHCO(3)), in controlled concentrations (0-55%) we were able to produce grafts with well-defined pore morphologies. The impact of NaHCO(3) concentration on the structure of the graft wall and its influence on the mechanical and haemocompatibility properties are evaluated here. Scanning electron microscopy and mercury porosimetry were used to characterise graft structure. Atomic force microscopy elucidated any changes in surface morphology. The addition of NaHCO(3) improved the pore interconnectivity and increasing the concentration of NaHCO(3) led to grafts with rougher surfaces and larger pore sizes. The ultimate tensile strength and suture retention decreased with increasing concentrations of NaHCO(3), while graft compliance increased. To evaluate haemocompatibility platelets and peripheral blood mononuclear cells (PBMC) were incubated on a range of different graft samples. Platelet adhesion, PBMC surface receptor expression (CD14, CD86, CD69 and HLA-DR) and cytokine release (PF4, IL-1ß, IL-6, IL-10, TNFα) were all measured. Increasing numbers of platelets adhered to grafts produced with no NaHCO(3), which exhibited a smooth surface morphology, and PBMC adherent on these grafts expressed higher levels of CD14 and CD86. Whilst the different graft samples induced varying levels of cytokine secretion in vitro, no distinct pattern suggesting a non-trivial relationship was observed.

Development of conductive polymer with carbon nanotubes for regenerative medicine applications.

Multi-wall carbon nanotube (MWCNT)/polymer composites are hybrid materials that combine numerous mechanical, electrical and chemical properties and thus, constitute ideal biomaterials for a wide range of regenerative medicine applications. Although, complete dispersion of MWCNT in a polymer matrix has rarely been achieved, in this study we have studied the dispersibility of MWCNT in POSS-PCU, a novel polymer based on polyprolactone and polycarbonate polyurethane (PCU) with an incorporated polyhedral oligomeric silsesquioxane (POSS). Furthermore, we developed a computational model that can visualise MWCNTs in order to predict the range of dispersibility and provide a 3-D mathematical model that can predict the chemical concentration for ideal nanocomposites.

A study of the dynamic interaction of surfactants with graphite and carbon nanotubes using Fmoc-amino acids as a model system.

We have studied the dynamic interaction of surfactants with carbon surfaces by using a series of Fmoc- (N-(fluorenyl-9-methoxycarbonyl)) terminated amino acid derivatives (Fmoc-X, where X is glycine, tyrosine, phenylalanine, tryptophan, or histidine) as a model system. In these systems, highly conjugated fluorenyl groups and aromatic amino acid side chains interact with the carbon surface, while carboxylate groups provide an overall negative charge. Ideal carbon surfaces were selected which possessed either predominantly macroscale (graphite) or nanoscale features (multiwalled carbon nanotube (MWNT) mats). The adsorption equilibrium for the Fmoc-X solutions with the graphitic surfaces was well-described by the Freundlich model. When a library containing various Fmoc-X compounds were exposed to a target graphite surface, Fmoc-tryptophan was found to bind preferentially at the expense of the other components present, leading to a substantial difference in the observed binding behavior compared to individual adsorption experiments. This approach therefore provides a straightforward means to identify good surfactants within a library of many candidates. Finally, the fully reversible nature of Fmoc-X binding was demonstrated by switching the surface chemistry of carbon substrate through sequential exposure to surfactants with increasing binding energies.