Testing microelectronic biofluidic systems

According to the 2005 International Technology Roadmap for Semiconductors, the integration of emerging nondigital CMOS technologies will require radically different test methods, posing a major challenge for designers and test engineers. One such technology is microelectronic fluidic (MEF) arrays, which have rapidly gained importance in many biological, pharmaceutical, and industrial applications. The advantages of these systems, such as operation speed, use of very small amounts of liquid, on-board droplet detection, signal conditioning, and vast digital signal processing, make them very promising. However, testable design of these devices in a mass-production environment is still in its infancy, hampering their low-cost introduction to the market. This article describes analog and digital MEF design and testing method

In-vivo magnetic resonance imaging of hyperpolarized silicon particles

Silicon-based micro and nanoparticles have gained popularity in a wide range of biomedical applications due to their biocompatibility and biodegradability in-vivo, as well as a flexible surface chemistry, which allows drug loading, functionalization and targeting. Here we report direct in-vivo imaging of hyperpolarized 29Si nuclei in silicon microparticles by MRI. Natural physical properties of silicon provide surface electronic states for dynamic nuclear polarization (DNP), extremely long depolarization times, insensitivity to the in-vivo environment or particle tumbling, and surfaces favorable for functionalization. Potential applications to gastrointestinal, intravascular, and tumor perfusion imaging at sub-picomolar concentrations are presented. These results demonstrate a new background-free imaging modality applicable to a range of inexpensive, readily available, and biocompatible Si particles.Comment: Supplemental Material include

Recent advances in the management of chronic stable angina I: Approach to the patient, diagnosis, pathophysiology, risk stratification, and gender disparities

The potential importance of both prevention and personal responsibility in controlling heart disease, the leading cause of death in the USA and elsewhere, has attracted renewed attention. Coronary artery disease is preventable, using relatively simple and inexpensive lifestyle changes. The inexorable rise in the prevalence of obesity, diabetes, dyslipidemia, and hypertension, often in the risk cluster known as the metabolic syndrome, drives the ever-increasing incidence of heart disease. Population-wide improvements in personal health habits appear to be a fundamental, evidence based public health measure, yet numerous barriers prevent implementation. A common symptom in patients with coronary artery disease, classical angina refers to the typical chest pressure or discomfort that results when myocardial oxygen demand rises and coronary blood flow is reduced by fixed, atherosclerotic, obstructive lesions. Different forms of angina and diagnosis, with a short description of the significance of pain and silent ischemia, are discussed in this review. The well accepted concept of myocardial oxygen imbalance in the genesis of angina is presented with new data about clinical pathology of stable angina and acute coronary syndromes. The roles of stress electrocardiography and stress myocardial perfusion scintigraphic imaging are reviewed, along with the information these tests provide about risk and prognosis. Finally, the current status of gender disparities in heart disease is summarized. Enhanced risk stratification and identification of patients in whom procedures will meaningfully change management is an ongoing quest. Current guidelines emphasize efficient triage of patients with suspected coronary artery disease. Many experts believe the predictive value of current decision protocols for coronary artery disease still needs improvement in order to optimize outcomes, yet avoid unnecessary coronary angiograms and radiation exposure. Coronary angiography remains the gold standard in the diagnosis of coronary artery obstructive disease. Part II of this two part series will address anti-ischemic therapies, new agents, cardiovascular risk reduction, options to treat refractory angina, and revascularization

Molecular pathophysiology and pharmacology of the voltage-sensing module of neuronal ion channels

Voltage-gated ion channels (VGICs) are membrane proteins that switch from a closed to open state in response to changes in membrane potential, thus enabling ion fluxes across the cell membranes. The mechanism that regulate the structural rearrangements occurring in VGICs in response to changes in membrane potential still remains one of the most challenging topic of modern biophysics. Na+, Ca2+ and K+ voltage-gated channels are structurally formed by the assembly of four similar domains, each comprising six transmembrane segments. Each domain can be divided into two main regions: the Pore Module (PM) and the Voltage-Sensing Module (VSM). The PM (helices S-5 and S-6 and intervening linker) is responsible for gate opening and ion selectivity; by contrast, the VSM, comprising the first four transmembrane helices (S-1-S-4), undergoes the first conformational changes in response to membrane voltage variations. In particular, the S-4 segment of each domain, which contains several positively charged residues interspersed with hydrophobic amino acids, is located within the membrane electric field and plays an essential role in voltage sensing. In neurons, specific gating properties of each channel subtype underlie a variety of biological events, ranging from the generation and propagation of electrical impulses, to the secretion of neurotransmitters and to the regulation of gene expression. Given the important functional role played by the VSM in neuronal VGICs, it is not surprising that various VSM mutations affecting the gating process of these channels are responsible for human diseases, and that compounds acting on the VSM have emerged as important investigational tools with great therapeutic potential. In the present review we will briefly describe the most recent discoveries concerning how the VSM exerts its function, how genetically inherited diseases caused by mutations occurring in the VSM affects gating in VGICs, and how several classes of drugs and toxins selectively target the VSM

Robust low-power digital circuit design in nano-CMOS technologies

Device scaling has resulted in large scale integrated, high performance, low-power, and low cost systems. However the move towards sub-100 nm technology nodes has increased variability in device characteristics due to large process variations. Variability has severe implications on digital circuit design by causing timing uncertainties in combinational circuits, degrading yield and reliability of memory elements, and increasing power density due to slow scaling of supply voltage. Conventional design methods add large pessimistic safety margins to mitigate increased variability, however, they incur large power and performance loss as the combination of worst cases occurs very rarely. In-situ monitoring of timing failures provides an opportunity to dynamically tune safety margins in proportion to on-chip variability that can significantly minimize power and performance losses. We demonstrated by simulations two delay sensor designs to detect timing failures in advance that can be coupled with different compensation techniques such as voltage scaling, body biasing, or frequency scaling to avoid actual timing failures. Our simulation results using 45 nm and 32 nm technology BSIM4 models indicate significant reduction in total power consumption under temperature and statistical variations. Future work involves using dual sensing to avoid useless voltage scaling that incurs a speed loss. SRAM cache is the first victim of increased process variations that requires handcrafted design to meet area, power, and performance requirements. We have proposed novel 6 transistors (6T), 7 transistors (7T), and 8 transistors (8T)-SRAM cells that enable variability tolerant and low-power SRAM cache designs. Increased sense-amplifier offset voltage due to device mismatch arising from high variability increases delay and power consumption of SRAM design. We have proposed two novel design techniques to reduce offset voltage dependent delays providing a high speed low-power SRAM design. Increasing leakage currents in nano-CMOS technologies pose a major challenge to a low-power reliable design. We have investigated novel segmented supply voltage architecture to reduce leakage power of the SRAM caches since they occupy bulk of the total chip area and power. Future work involves developing leakage reduction methods for the combination logic designs including SRAM peripherals

Human KATP channelopathies: diseases of metabolic homeostasis

Assembly of an inward rectifier K+ channel pore (Kir6.1/Kir6.2) and an adenosine triphosphate (ATP)-binding regulatory subunit (SUR1/SUR2A/SUR2B) forms ATP-sensitive K+ (KATP) channel heteromultimers, widely distributed in metabolically active tissues throughout the body. KATP channels are metabolism-gated biosensors functioning as molecular rheostats that adjust membrane potential-dependent functions to match cellular energetic demands. Vital in the adaptive response to (patho)physiological stress, KATP channels serve a homeostatic role ranging from glucose regulation to cardioprotection. Accordingly, genetic variation in KATP channel subunits has been linked to the etiology of life-threatening human diseases. In particular, pathogenic mutations in KATP channels have been identified in insulin secretion disorders, namely, congenital hyperinsulinism and neonatal diabetes. Moreover, KATP channel defects underlie the triad of developmental delay, epilepsy, and neonatal diabetes (DEND syndrome). KATP channelopathies implicated in patients with mechanical and/or electrical heart disease include dilated cardiomyopathy (with ventricular arrhythmia; CMD1O) and adrenergic atrial fibrillation. A common Kir6.2 E23K polymorphism has been associated with late-onset diabetes and as a risk factor for maladaptive cardiac remodeling in the community-at-large and abnormal cardiopulmonary exercise stress performance in patients with heart failure. The overall mutation frequency within KATP channel genes and the spectrum of genotype–phenotype relationships remain to be established, while predicting consequences of a deficit in channel function is becoming increasingly feasible through systems biology approaches. Thus, advances in molecular medicine in the emerging field of human KATP channelopathies offer new opportunities for targeted individualized screening, early diagnosis, and tailored therapy