Towards Design Optimization of Compliant Mechanisms: A Hybrid Pseudo-Rigid-Body Model-Finite Element Method Approach and an Accurate Empirical Compliance Equation for Circular Flexure Hinges.

Innovative designs such as morphing wings and terrain adaptive landing systems are examples of biomimicry and innovations inspired by nature, which are actively being investigated by aerospace designers. Morphing wing designs based on Variable Geometry Truss Manipulators (VGTMs) and articulated helicopter robotic landing gear (RLG) have drawn a great deal of attention from industry. Compliant mechanisms have become increasingly popular due to their advantages over conventional rigid-body systems, and the research team led by the second author at Toronto Metropolitan University (TMU) has set their long-term goal to be exploiting these systems in the above aerospace applications. To gain a deeper insight into the design and optimization of compliant mechanisms and their potential application as alternatives to VGTM and RLG systems, this study conducted a thorough analysis of the design of flexible hinges, and single-, four-, and multi-bar configurations as a part of more complex, flexible mechanisms. The investigation highlighted the flexibility and compliance of mechanisms incorporating circular flexure hinges (CFHs), showcasing their capacity to withstand forces and moments. Despite a discrepancy between the results obtained from previously published Pseudo-Rigid-Body Model (PRBM) equations and FEM-based analyses, the mechanisms exhibited predictable linear behavior and acceptable fatigue testing results, affirming their suitability for diverse applications. While including additional linkages perpendicular to the applied force direction in a compliant mechanism with N vertical linkages led to improved factors of safety, the associated increase in system weight necessitates careful consideration. It is shown herein that, in this case, adding one vertical bar increased the safety factor by 100N percent. The present study also addressed solutions for the precise modeling of CFHs through the derivation of an empirical polynomial torsional stiffness/compliance equation related to geometric dimensions and material properties. The effectiveness of the presented empirical polynomial compliance equation was validated against FEA results, revealing a generally accurate prediction with an average error of 1.74%. It is expected that the present investigation will open new avenues to higher precision in the design of CFHs, ensuring reliability and efficiency in various practical applications, and enhancing the optimization design of compliant mechanisms comprised of such hinges. A specific focus was put on ABS plastic and aluminum alloy 7075, as they are the materials of choice for non-load-bearing and load-bearing structural components, respectively.

Cardiac ankyrins in health and disease.

Ankyrins are critical components of ion channel and transporter signaling complexes in the cardiovascular system. Over the past 5 years, ankyrin dysfunction has been linked with abnormal ion channel and transporter membrane organization and fatal human arrhythmias. Loss-of-function variants in the ankyrin-B gene (ANK2) cause "ankyrin-B syndrome" (previously called type 4 long QT syndrome), manifested by a complex cardiac phenotype including ventricular arrhythmias and sudden cardiac death. More recently, dysfunction in the ankyrin-B-based targeting pathway has been linked with a highly penetrant and severe form of human sinus node disease. Ankyrin-G (a second ankyrin gene product) is required for normal expression, membrane localization, and biophysical function of the primary cardiac voltage-gated sodium channel, Na(v)1.5. Loss of the ankyrin-G/Na(v)1.5 interaction is associated with human cardiac arrhythmia (Brugada syndrome). Finally, in the past year ankyrin dysfunction has been associated with more common arrhythmia and cardiovascular disease phenotypes. Specifically, large animal studies reveal striking remodeling of ankyrin-B and associated proteins following myocardial infarction. Additionally, the ANK2 locus has been linked with QT(c) interval variability in the general human population. Together, these findings identify a host of unanticipated and exciting roles for ankyrin polypeptides in cardiac function. More broadly, these findings illustrate the importance of local membrane organization for normal cardiac physiology.

Hypercholesterolemia suppresses inwardly rectifying K+ channels in aortic endothelium in vitro and in vivo.

Inwardly rectifying K+ (Kir) channels are responsible for maintaining endothelial membrane potential and play a key role in endothelium-dependent vasorelaxation. In this study, we show that endothelial Kir channels are suppressed by hypercholesterolemic levels of lipoproteins in vitro and by serum hypercholesterolemia in vivo. Specifically, exposing human aortic endothelial cells to acetylated low-density lipoprotein or very low density lipoprotein resulted in a time- and concentration-dependent decrease in Kir current that correlated with the degree of cholesterol loading. The suppression was fully reversible by cholesterol depletion. Furthermore, a decrease in Kir current resulted in depolarization of endothelial membrane potential. Most important, the flow sensitivity of Kir currents was also impaired by cholesterol loading. Specifically, flow-induced increase in Kir current was suppressed by 70%, and flow-induced hyperpolarization was almost completely abrogated. Furthermore, we show that hypercholesterolemia in vivo also strongly suppresses endothelial Kir currents and causes a shift in endothelial membrane potential, as determined by comparing the currents in aortic endothelial cells freshly isolated from healthy or hypercholesterolemic pigs. Therefore, we suggest that suppression of Kir current is one of the important factors in hypercholesterolemia-induced endothelial dysfunction.

Differentiation of human embryonic stem cells into hepatocytes in 2D and 3D culture systems in vitro.

Human embryonic stem cells (hESCs) have enormous potential as a source of cells for cell replacement therapies and as a model for early human development. In this study we examined the differentiating potential of hESCs into hepatocytes in two- and three-dimensional (2D and 3D) culture systems. Embryoid bodies (EBs) were inserted into a collagen scaffold 3D culture system or cultured on collagen-coated dishes and stimulated with exogenous growth factors to induce hepatic histogenesis. Immunofluorescence analysis revealed the expression of albumin (ALB) and cytokeratin-18 (CK-18). The differentiated cells in 2D and 3D culture system displayed several characteristics of hepatocytes, including expression of transthyretin, alpha-1-antitrypsin, cytokeratin 8, 18, 19, tryptophan-2,3-dioxygenase, tyrosine aminotransferase, glucose-6-phosphatase (G6P), cytochrome P450 subunits 7a1 and secretion of alpha-fetoprotein (AFP) and ALB and production of urea. In 3D culture, ALB and G6P were detected earlier and higher levels of urea and AFP were produced, when compared with 2D culture. Electron microscopy of differentiated hESCs showed hepatocyte-like ultrastructure, including glycogon granules, well-developed Golgi apparatuses, rough and smooth endoplasmic reticuli and intercellular canaliculi. The differentiation of hESCs into hepatocyte-like cells within 3D collagen scaffolds containing exogenous growth factors, gives rise to cells displaying morphological features, gene expression patterns and metabolic activities characteristic of hepatocytes and may provide a source of differentiated cells for treatment of liver diseases.

A placebo controlled, dose-ranging, safety study of allogenic mesenchymal stem cells injected by endomyocardial delivery after an acute myocardial infarction.

AIMS: Although mesenchymal stem cells (MSCs) show promising signs in reducing myocardial infarct (MI) size, the safety of endomyocardial delivery and the most efficacious dose is unknown. METHODS AND RESULTS: Three days after MI, female Yorkshire swine (25-32 kg, age 2 months, n = 32) were randomized to endomyocardial delivery of one of three MSC doses (2.4 x 10(7), 2.4 x 10(8), 4.4 x 10(8) cells) or vehicle control. Animals were sacrificed at 12 weeks. There were no safety issues related to cell delivery and all animals tolerated the procedure. By magnetic resonance imaging infarct size (g) was decreased in the experimental groups and increased in the control group; 2.4 x 10(7): Delta -2.5 +/- 2.5 g, 2.4 x 10(8): -0.9 +/- 2.71 g, 4.4 x 10(8): -1.6 +/- 5.8 g, and control +3.6 +/- 3.4 g (P = 0.002, P = 0.016, and P = 0.055 compared with control, respectively). There was no effect on ejection fraction or left ventricular volumes. By histology there were no toxic effects of MSC delivery, however, few engrafted MSCs were observed. CONCLUSION: Direct MSC delivery into infarcted myocardium was safe and produced a local but not a functional effect. There was no dose-dependent effect. The effect of MSCs on infarct reduction may result from transient residence and subsequent paracrine effects.

One-year clinical outcomes of protected and unprotected left main coronary artery stenting.

AIMS: To evaluate outcomes for left main coronary artery (LMCA) stenting and compare results between protected (left coronary grafted) and unprotected LMCA stenting in the current bare-metal stent era. METHODS: We reviewed outcomes among 142 consecutive patients who underwent protected or unprotected LMCA stenting since 1997. All-cause mortality, myocardial infarction (MI), target-lesion revascularization (TLR), and the combined major adverse clinical event (MACE) rates at one year were computed. RESULTS: Ninety-nine patients (70%) underwent protected and 43 patients (30%) underwent unprotected LMCA stenting. In the unprotected group, 86% were considered poor surgical candidates. Survival at one year was 88% for all patients, TLR 20%, and MACE 32%. At one year, survival was reduced in the unprotected group (72% vs. 95%, P<0.001) and MACE was increased in the unprotected patients (49% vs. 25%, P=0.005). CONCLUSIONS: In the current era, stenting for both protected and unprotected LMCA disease is still associated with high long-term mortality and MACE rates. Stenting for unprotected LMCA disease in a high-risk population should only be considered in the absence of other revascularization options. Further studies are needed to evaluate the role of stenting for unprotected LMCA disease.