In-vivo mechanical characterization of coronary atherosclerotic plaques in living swine using intravascular laser speckle imaging.

The ability to evaluate the viscoelastic properties of coronary arteries is crucial for identifying mechanically unstable atherosclerotic plaques. Here, we demonstrate for the first time in living swine, the capability of intravascular laser speckle imaging (ILSI) to measure an index of coronary plaque viscoelasticity, τ, using a human coronary to swine xenograft model. Cardiac motion effects are evaluated by comparing the EKG-non-gated τ ¯ N G , and EKG-gated τ ¯ G among different plaque types. Results show that both τ ¯ N G and τ ¯ G are significantly lower in necrotic-core plaques compared with stable lesions. Discrete-point pullback measurements demonstrate the capability of ILSI for rapid mechanical characterization of coronary segments under physiological conditions, in-vivo.

Dose ranging, expanded acute toxicity and safety pharmacology studies for intravenously administered functionalized graphene nanoparticle formulations.

Graphene nanoparticle dispersions show immense potential as multifunctional agents for in vivo biomedical applications. Herein, we follow regulatory guidelines for pharmaceuticals that recommend safety pharmacology assessment at least 10-100 times higher than the projected therapeutic dose, and present comprehensive single dose response, expanded acute toxicology, toxicokinetics, and respiratory/cardiovascular safety pharmacology results for intravenously administered dextran-coated graphene oxide nanoplatelet (GNP-Dex) formulations to rats at doses between 1 and 500 mg/kg. Our results indicate that the maximum tolerable dose (MTD) of GNP-Dex is between 50 mg/kg ≤ MTD < 125 mg/kg, blood half-life < 30 min, and majority of nanoparticles excreted within 24 h through feces. Histopathology changes were noted at ≥250 mg/kg in the heart, liver, lung, spleen, and kidney; we found no changes in the brain and no GNP-Dex related effects in the cardiovascular parameters or hematological factors (blood, lipid, and metabolic panels) at doses < 125 mg/kg. The results open avenues for pivotal preclinical single and repeat dose safety studies following good laboratory practices (GLP) as required by regulatory agencies for investigational new drug (IND) application.

In vitro hematological and in vivo vasoactivity assessment of dextran functionalized graphene.

The intravenous, intramuscular or intraperitoneal administration of water solubilized graphene nanoparticles for biomedical applications will result in their interaction with the hematological components and vasculature. Herein, we have investigated the effects of dextran functionalized graphene nanoplatelets (GNP-Dex) on histamine release, platelet activation, immune activation, blood cell hemolysis in vitro, and vasoactivity in vivo. The results indicate that GNP-Dex formulations prevented histamine release from activated RBL-2H3 rat mast cells, and at concentrations ≥ 7 mg/ml, showed a 12-20% increase in levels of complement proteins. Cytokine (TNF-Alpha and IL-10) levels remained within normal range. GNP-Dex formulations did not cause platelet activation or blood cell hemolysis. Using the hamster cheek pouch in vivo model, the initial vasoactivity of GNP-Dex at concentrations (1-50 mg/ml) equivalent to the first pass of a bolus injection was a brief concentration-dependent dilation in arcade and terminal arterioles. However, they did not induce a pro-inflammatory endothelial dysfunction effect.

Physicochemical characterization of a novel graphene-based magnetic resonance imaging contrast agent.

We report the synthesis and characterization of a novel carbon nanostructure-based magnetic resonance imaging contrast agent (MRI CA); graphene nanoplatelets intercalated with manganese (Mn(2+)) ions, functionalized with dextran (GNP-Dex); and the in vitro assessment of its essential preclinical physicochemical properties: osmolality, viscosity, partition coefficient, protein binding, thermostability, histamine release, and relaxivity. The results indicate that, at concentrations between 0.1 and 100.0 mg/mL, the GNP-Dex formulations are hydrophilic, highly soluble, and stable in deionized water, as well as iso-osmolar (upon addition of mannitol) and iso-viscous to blood. At potential steady-state equilibrium concentrations in blood (0.1-10.0 mg/mL), the thermostability, protein-binding, and histamine-release studies indicate that the GNP-Dex formulations are thermally stable (with no Mn(2+) ion dissociation), do not allow non-specific protein adsorption, and elicit negligible allergic response. The r 1 relaxivity of GNP-Dex was 92 mM(-1)s(-1) (per-Mn(2+) ion, 22 MHz proton Larmor frequency); ~20- to 30-fold greater than that of clinical gadolinium (Gd(3+))- and Mn(2+)-based MRI CAs. The results open avenues for preclinical in vivo safety and efficacy studies with GNP-Dex toward its development as a clinical MRI CA.

Imaging the subcellular structure of human coronary atherosclerosis using micro-optical coherence tomography.

Progress in understanding, diagnosis, and treatment of coronary artery disease (CAD) has been hindered by our inability to observe cells and extracellular components associated with human coronary atherosclerosis in situ. The current standards for microstructural investigation, histology and electron microscopy are destructive and prone to artifacts. The highest-resolution intracoronary imaging modality, optical coherence tomography (OCT), has a resolution of ~10 µm, which is too coarse for visualizing most cells. Here we report a new form of OCT, termed micro-optical coherence tomography (µOCT), whose resolution is improved by an order of magnitude. We show that µOCT images of cadaver coronary arteries provide clear pictures of cellular and subcellular features associated with atherogenesis, thrombosis and responses to interventional therapy. These results suggest that µOCT can complement existing diagnostic techniques for investigating atherosclerotic specimens, and that µOCT may eventually become a useful tool for cellular and subcellular characterization of the human coronary wall in vivo.