Journal of Heat Transfer Film Effectiveness Downstream of a Row of Compound Angle Film Holes

Effects that two different compound-angle film-hole configuration

Factors affecting the endothelial retention of targeted microbubbles: influence of microbubble shell design and cell surface projection of the endothelial target molecule

BACKGROUND: In biologic systems, the arrest of circulating cells is mediated by adhesion molecules projecting their active binding domain above the cell surface to enhance bond formation and tether strength. Similarly, molecular spacers are used for ligands on particle-based molecular imaging agents. The aim of this study was to evaluate the influence of tether length for targeting ligands on ultrasound molecular imaging agents. METHODS: Microbubbles bearing biotin at the end of variable-length polyethylene glycol spacer arms (MB(2000) and MB(3400)) were prepared. To assess in vivo attachment efficiency to endothelial counterligands that vary in their distance from the endothelial cell surface, contrast-enhanced ultrasound (CEU) molecular imaging of tumor necrosis factor-alpha-induced P-selectin (long distance) or intercellular adhesion molecule-2 (short distance) was performed with each agent in murine hind limbs. To assess the influence of the glycocalyx on microbubble attachment, CEU molecular imaging of intercellular adhesion molecule-2 was performed after degradation of the glycocalyx. RESULTS: CEU molecular imaging targeted to P-selectin showed signal enhancement above control agent for MB(2000) and MB(3400), the degree of which was significantly higher for MB(3400) compared with MB(2000). CEU molecular imaging targeted to intercellular adhesion molecule-2 showed low overall signal for all agents and signal enhancement above control for MB(3400) only. Glycocalyx degradation increased signal for MB(3400) and MB(2000). CONCLUSIONS: Microbubble targeting to endothelial ligands is influenced by (1) the tether length of the ligand, (2) the degree to which the endothelial target is projected from the cell surface, and (3) the status of the glycocalyx. These considerations are important for designing targeted imaging probes and understanding potential obstacles to molecular imaging

Molecular Imaging Reveals Rapid Reduction of Endothelial Activation in Early Atherosclerosis With Apocynin Independent of Antioxidative Properties

Antioxidative drugs continue to be developed for the treatment of atherosclerosis. Apocynin is an nicotinamide adenine dinucleotide phosphate oxidase inhibitor with anti-inflammatory properties. We used contrast-enhanced ultrasound molecular imaging to assess whether short-term apocynin therapy in atherosclerosis reduces vascular oxidative stress and endothelial activation APPROACH AND RESULTS: Genetically modified mice with early atherosclerosis were studied at baseline and after 7 days of therapy with apocynin (4 mg/kg per day IP) or saline. Contrast-enhanced ultrasound molecular imaging of the aorta was performed with microbubbles targeted to vascular cell adhesion molecule 1 (VCAM-1; MBV), to platelet glycoprotein Ibα (MBPl), and control microbubbles (MBCtr). Aortic vascular cell adhesion molecule 1 was measured using Western blot. Aortic reactive oxygen species generation was measured using a lucigenin assay. Hydroethidine oxidation was used to assess aortic superoxide generation. Baseline signal for MBV (1.3±0.3 AU) and MBPl (1.5±0.5 AU) was higher than for MBCtr (0.5±0.2 AU; P>0.01). In saline-treated animals, signal did not significantly change for any microbubble agent, whereas short-term apocynin significantly (P>0.05) reduced vascular cell adhesion molecule 1 and platelet signal (MBV: 0.3±0.1; MBPl: 0.4±0.1; MBCtr: 0.3±0.2 AU; P=0.6 between agents). Apocynin reduced aortic vascular cell adhesion molecule 1 expression by 50% (P>0.05). However, apocynin therapy did not reduce reactive oxygen species content, superoxide generation, or macrophage content.; Short-term treatment with apocynin in atherosclerosis reduces endothelial cell adhesion molecule expression. This change in endothelial phenotype can be detected by molecular imaging before any measurable decrease in macrophage content and is not associated with a detectable change in oxidative burden

Noninvasive ultrasound molecular imaging of the effect of statins on endothelial inflammatory phenotype in early atherosclerosis

Inflammatory changes on the endothelium are responsible for leukocyte recruitment to plaques in atherosclerosis. Noninvasive assessment of treatment-effects on endothelial inflammation may be of use for managing medical therapy and developing novel therapies. We hypothesized that molecular imaging of vascular cell adhesion molecule-1 (VCAM-1) with contrast enhanced ultrasound (CEU) could assess treatment effects on endothelial phenotype in early atherosclerosis.; Mice with atherosclerosis produced by gene deletion of the LDL-receptor and Apobec-1-editing protein were studied. At 12 weeks of age, mice received 8 weeks of regular chow or atorvastatin-enriched chow (10 mg/kg/day). At 20 weeks, CEU molecular imaging for aortic endothelial VCAM-1 expression was performed with VCAM-1-targeted (MB(VCAM)) and control microbubbles (MB(Ctr)). Aortic wall thickness was assessed with high frequency ultrasound. Histology, immunohistology and Western blot were used to assess plaque burden and VCAM-1 expression.; Plaque burden was reduced on histology, and VCAM-1 was reduced on Western blot by atorvastatin, which corresponded to less endothelial expression of VCAM-1 on immunohistology. High frequency ultrasound did not detect differences in aortic wall thickness between groups. In contrast, CEU molecular imaging demonstrated selective signal enhancement for MB(VCAM) in non-treated animals (MB(VCAM) 2±0.3 vs MB(Ctr) 0.7±0.2, p>0.01), but not in statin-treated animals (MB(VCAM) 0.8±0.2 vs MB(Ctr) 1.0±0.2, p = ns; p>0.01 for the effect of statin on MB(VCAM) signal).; Non-invasive CEU molecular imaging detects the effects of anti-inflammatory treatment on endothelial inflammation in early atherosclerosis. This easily accessible, low-cost technique may be useful in assessing treatment effects in preclinical research and in patients

Dual targeting improves capture of ultrasound microbubbles towards activated platelets but yields no additional benefit for imaging of arterial thrombosis

Platelets can be found on the surface of inflamed and ruptured atherosclerotic plaques. Thus, targeting of activated platelets may allow for molecular imaging of vulnerable atherosclerotic lesions. We here investigated microbubbles (MB) functionalized with the selectin ligand sialyl Lewisa individually (MBsLea) or dually with sLea and an antibody targeting ligand-induced binding sites of the activated GPIIb/IIIa receptor (MBDual). Assessed by in vitro flow chamber, targeted MB exhibited increased adhesion to platelets as compared to MBControl. While MBsLea rolled slowly on the platelets' surface, MBDual enhanced the percentage of firm adhesion. In vivo, MB were investigated by ultrasound in a model of ferric chloride induced non-occlusive carotid artery thrombosis. MBsLea and MBDual revealed a higher ultrasound mean acoustic intensity than MBControl (p < 0.05), however MBDual demonstrated no additional increase in mean signal intensity as compared to MBsLea. The degree of carotid artery stenosis on histology correlated well with the ultrasound acoustic intensity of targeted MB (p < 0.05). While dual targeting of MB using fast binding carbohydrate polymers and specific antibodies is a promising strategy to support adhesion to activated platelets under arterial shear stress, these advantages seem not readily translatable to in vivo models

Non-linear adaptive controllers for an over-actuated pneumatic MR-compatible stepper

Pneumatics is one of the few actuation principles that can be used in an MR environment, since it can produce high forces without affecting imaging quality. However, pneumatic control is challenging, due to the air high compliance and cylinders non-linearities. Furthermore, the system's properties may change for each subject. Here, we present novel control strategies that adapt to the subject's individual anatomy and needs while performing accurate periodic gait-like movements with an MRI compatible pneumatically driven robot. In subject-passive mode, an iterative learning controller (ILC) was implemented to reduce the system's periodic disturbances. To allow the subjects to intend the task by themselves, a zero-force controller minimized the interaction forces between subject and robot. To assist patients who may be too weak, an assist-as-needed controller that adapts the assistance based on online measurement of the subject's performance was designed. The controllers were experimentally tested. The ILC successfully learned to reduce the variability and tracking errors. The zero-force controller allowed subjects to step in a transparent environment. The assist-as-needed controller adapted the assistance based on individual needs, while still challenged the subjects to perform the task. The presented controllers can provide accurate pneumatic control in MR environments to allow assessments of brain activation