James M. Anderson

Surface modification of liposomes for selective cell targeting in cardiovascular drug delivery.

Cardiovascular disease processes such as atherosclerosis, restenosis, and inflammation are typically localized to discrete regions of the vasculature, affording great opportunity for targeted pharmacological treatment. Liposomes are potentially advantageous targeted drug carriers for such intravascular applications. To facilitate their use as drug delivery vehicles, we have considered three components of liposome design: (i) identification of candidate cell surface receptors for targeting; (ii) identification of ligands that maintain binding specificity and affinity; and (iii) prevention of rapid nonspecific clearance of liposomes into the reticuloendothelial organs. In this report, we describe our work in developing liposomal surface modifications that address both targeting and clearance. An arginine-glycine-aspartic acid (RGD) containing peptide was used as a model ligand to target liposomes to the integrin GPIIb-IIIa on activated platelets. Additionally, oligodextran surfactants incorporated into liposomes provided insight into the effect of vesicle perturbations on liposome clearance, and the importance of molecular geometry in designing oligosaccharide surface modifications. Together these studies demonstrate the feasibility of using peptides to guide liposomes to desired receptors, and illustrate the influence of vesicle stability on liposome interactions in vivo. Furthermore, they underscore the importance of simultaneously considering both targeting specificity and vesicle longevity in the design of effective targeted drug delivery systems.

Intracoronary ultrasound—defined plaque composition: Computer-aided plaque characterization and correlation with histologic samples obtained during directional coronary atherectomy

The ability to classify lesion composition accurately may be important for selecting or guiding interventional therapy and for understanding the pathophysiologic basis of individual lesions. To assess the usefulness of ultrasound in classifying lesions, intracoronary ultrasound images were obtained from 44 atherosclerotic lesions in patients before directional atherectomy. Lesions were classified by visual analysis and by computer-assisted gray-level statistics. Atherectomy samples were evaluated histologically for elastosis and calcium and quantitatively by morphometric analysis for various tissue components. The computer-assisted quantitative classification agreed well with the findings on visual analysis. Visual and computer-assisted quantitative ultrasound images were found to have distinctive histologic features. Lesions with predominantly echogenic plaque had a larger fraction of dense fibrous, elastic, or calcified tissue. Lesions with predominantly echolucent soft plaque had a greater fraction of loose fibrous, smooth-muscle, thrombotic, or necrotic elements. Thus intracoronary ultrasound allows accurate classification of lesion composition in patients.

Morphologic characteristics of adsorbed human plasma proteins on vascular grafts and biomaterials.

Protein adsorption on the surfaces of clinically significant prosthetic vascular graft materials from human whole blood was independent of plasma concentration as determined morphologically by use of immunogold labels. Some proteins, such as fibrinogen, adsorbed in a multilayer pattern on expanded polytetrafluoroethylene and had a preference for particular surface features of the polymer. Other proteins, such as Hageman factor (factor XII), showed diffuse adsorption patterns. Physiologically significant proteins that have not been well studied, such as immunoglobulin G and factor VIII, adsorbed readily to the surface of expanded polytetrafluoroethylene. This finding may be significant since adsorbed proteins may activate coagulation mechanisms and immunologic responses, including platelet and monocyte adhesion and activation. Any human blood protein for which an antibody has been developed can be studied by use of this technique.

Shear stress modulates the thickness and architecture of Candida albicans biofilms in a phase-dependent manner.

Biofilm formation plays an integral role in catheter‐associated bloodstream infections caused by Candida albicans. Biofilms formed on catheters placed intravenously are exposed to shear stress caused by blood flow. In this study, we investigated whether shear stress affects the ability of C. albicans to form biofilms. Candida biofilms were formed on catheter discs and exposed to physiological levels of shear stress using a rotating disc system (RDS). Control biofilms were grown under conditions of no flow. Tetrazolium (XTT) assay and dry weight (DW) measurements were used to quantify metabolic activity and biofilm mass respectively. Confocal scanning laser microscopy (CSLM) was used to evaluate architecture and biofilm thickness. After 90u2003min, cells attached under no‐flow exhibited significantly greater XTT activity and DW than those under shear. However, by 24u2003h, biofilms formed under both conditions had similar XTT activities and DW. Interestingly, thickness of biofilms formed under no‐flow was significantly greater after 24u2003h than of those formed under shear stress, demonstrating that shear exposure results in thinner, but denser biofilms. These studies suggest that biofilm architecture is modulated by shear in a phase‐dependent manner.

Chapter 19 Cardiovascular device retrieval and evaluation

Abstract The essential components of cardiovascular device retrieval and evaluation are included in this chapter. The goals, perspectives, and strategies for cardiovascular device retrieval and evaluation are presented. Factors determining appropriate retrieval and evaluation procedures and techniques for the assessment of host and device responses and interactions are noted. The specific aims or purposes of techniques, specimens, and fixatives for the evaluation of retrieved cardiovascular devices are included to provide perspective and assist in decision-making processes. Special emphasis is placed on the retrieval and evaluation of vascular prostheses, heart valve prostheses, vetricular assist devices (VADs) and intravascular and other cardiovascular devices.

Thrombotic events and markers of oxidation and inflammation in hemodialysis.

The goal of this study was to determine whether antioxidant therapy with vitamin E would alter the rate of vascular access complications or other macrovascular complications in hemodialysis (HD) patients. A secondary goal of the study was to explore the relationship between baseline pretreatment markers of oxidative stress (the advanced glycation end product pentosidine and basal levels of vitamin Eα and γ) and the subsequent development of access failure. Thirty‐five stable patients treated by HD were recruited for the study. Patients were provided with vitamin E (800u2003IU) or placebo capsules to be taken daily. Clinical variables, vascular access function (flow meter access flow measurements), and circulating blood markers were obtained initially and every 3 months throughout the study. Vitamin Eα levels rose in treated patients from 12.7u2003±u20034.4 to 25.1u2003±u200315.1u2003µg/mL at 3 months and 28.6u2003±u200314.8u2003µg/mL at 6 months. Vitamin Eγ levels fell in treated patients from 3.9u2003±u20031.7 to 2.3u2003±u20031.5u2003µg/mL at 3 months and 1.7u2003µg/mL at 6 months. Patients who subsequently developed repeated thrombotic vascular access events were characterized by higher baseline pentosidine content of circulating proteins. Patients who developed a myocardial infarction had higher pentosidine, lower vitamin Eα, and much lower vitamin Eγ than patients who did not develop thrombotic events. These findings lead to the speculation that the anti‐inflammatory effects of vitamin Eγ may play a more important role in thrombotic vascular events than the antioxidant effects of vitamin Eα. Additional studies of these interactions are in progress.