Candidates for smart cardiovascular medical device coatings: A comparative study with endothelial and smooth muscle cells.

Stent-induced vascular injury is manifested by removal of the endothelium and phenotypic changes in the underlying medial smooth muscle cells layer. This results in pathological vascular remodelling primarily contributed to smooth muscle cell proliferation and leads to vessel re-narrowing; neointimal hyperplasia. Current drug-eluting stents release non-selective anti-proliferative drugs such as paclitaxel from the stent surface that not only inhibit growth of smooth muscle cells but also delay endothelial healing, potentially leading to stent thrombosis. This highlights the need for novel bioactive stent coating candidates with the ability to target key events in the pathogenesis of in-stent restenosis. Citric acid, a molecule with anti-coagulant properties, was investigated against L-ascorbic acid, an antioxidant molecule reported to preferentially promote endothelial growth, and paclitaxel, a typically used anti-proliferative stent coating. Citric acid was found to exhibit growth supporting properties on endothelial cells across a range of concentrations that were significantly better than the model stent coating drug paclitaxel and better than the ascorbic acid which inhibited endothelial proliferation at concentrations ≥100 µg/ml. It was demonstrated that a citric acid-paclitaxel combination treatment significantly improves cell viability in comparison to paclitaxel only treated cells, with endothelial cells exhibiting greater cell recovery over smooth muscle cells. Furthermore, cell treatment with citric acid was found to reduce inflammation in a lipopolysaccharide (LPS)-induced in vitro inflammation model by significantly reducing interleukin 6 expression. Thus, this study demonstrates that citric acid is a promising candidate for use as a coating in stents and other endovascular devices.

Lipid Cubic Systems for Sustained and Controlled Delivery of Antihistamine Drugs.

Antihistamines are capable of blocking mediator responses in allergic reactions including allergic rhinitis and dermatological reactions. By incorporating various H1 receptor antagonists into a lipid cubic phase network, these active ingredients can be delivered locally over an extended period of time owing to the mucoadhesive nature of the system. Local delivery can avoid inducing unwanted side effects, often observed after systematic delivery. Lipid-based antihistamine delivery systems are shown here to exhibit prolonged release capabilities. In vitro drug dissolution studies investigated the extent and release rate of two model first-generation and two model second-generation H1 antagonist antihistamine drugs from two monoacyglycerol-derived lipid models. To optimize the formulation approach, the systems were characterized macroscopically and microscopically by small-angle X-ray scattering and polarized light to ascertain the mesophase accessed upon an incorporation of antihistamines of varying solubilities and size. The impact of encapsulating the antihistamine molecules on the degree of mucoadhesivity of the lipid cubic systems was investigated using multiparametric surface plasmon resonance. With the ultimate goal of developing therapies for the treatment of allergic reactions, the ability of the formulations to inhibit mediator release utilizing RBL-2H3 mast cells with the propensity to release histamine upon induction was explored, demonstrating no interference from the lipid excipient on the effectiveness of the antihistamine molecules.

Stent conditioned media for in vitro evaluation of hydrophobic stent coatings.

In vitro cell studies of hydrophobic drugs face difficulties associated with their low aqueous solubility. To study poorly soluble drugs in bio-relevant media, solubilizing agents are frequently used to make stock solutions before final reconstitution in media. This results in drug concentrations that are not representative of in vivo conditions and may pose adverse effects on cells' biological functions. This is especially true of typical hydrophobic stent coatings intended for vascular applications, where poor in vitro to in vivo correlation exists. To this end, a method for preparation of hydrophobic drug suspensions in bio-relevant media via stent conditioned media using paclitaxel (PTX) as a model drug is proposed. Since the drug is present as a suspension, this media was validated for its content uniformity and potency to induce formation of micronuclei, typical of cells undergoing prolonged mitotic arrest. Further, PTX uptake by endothelial cells was quantified and showed that the PTX stent conditioned media (at a theoretical concentration of 100 µM) suppressed cellular growth equivalent to the 0.1 µM DMSO dissolved PTX.

Citric acid functionalized nitinol stent surface promotes endothelial cell healing.

While drug-eluting stents containing anti-proliferative agents inhibit proliferation of smooth muscle cells (SMCs), they also delay the regrowth of the endothelial cells which can result in subsequent development of restenosis. Acidic extracellular environments promote cell anchorage and migration by inducing conformational change in integrins, the main cell adhesion proteins. This study addresses the feasibility of a citric acid (CA) functionalized nitinol stent for improving vascular biocompatibility, specifically enhancing endothelialization. CA functionalized nitinol vascular stents are compared to commercial bare metal (Zilver Flex) and paclitaxel eluting stents (Zilver PTX) in terms of re-endothelialization. To study the effect of stent coatings, a stent conditioned media methodology was developed in an attempt to represent in vivo conditions. Overall, distinct advantages of the CA functionalized nitinol stent over commercial Zilver PTX DES and Zilver Flex BMS stents in terms of endothelial cell adhesion, migration, and proliferation are reported. These novel findings indicate the potential of a CA functionalized stent to serve as a bioactive and therapeutic surface for re-endothelialization, perhaps in combination with a SMC proliferation inhibitor coating, to prevent restenosis.