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1.  Resistive and reactive changes to the impedance of intracortical microelectrodes can be mitigated with polyethylene glycol under acute in vitro and in vivo settings 
The reactive response of brain tissue to implantable intracortical microelectrodes is thought to negatively affect their recordable signal quality and impedance, resulting in unreliable longitudinal performance. The relationship between the progression of the reactive tissue into a glial scar and the decline in device performance is unclear. We show that exposure to a model protein solution in vitro and acute implantation result in both resistive and capacitive changes to electrode impedance, rather than purely resistive changes. We also show that applying 4000 MW polyethylene glycol (PEG) prevents impedance increases in vitro, and reduces the percent change in impedance in vivo following implantation. Our results highlight the importance of considering the contributions of non-cellular components to the decline in neural microelectrode performance, and present a proof of concept for using a simple dip-coated PEG film to modulate changes in microelectrode impedance.
PMCID: PMC4120760  PMID: 25136315
intracortical microelectrodes; foreign-body reaction; impedance spectroscopy; polyethylene glycols; dip coating
2.  Glial cells, but not neurons, exhibit a controllable response to a localized inflammatory microenvironment in vitro 
The ability to design long-lasting intracortical implants hinges on understanding the factors leading to the loss of neuronal density and the formation of the glial scar. In this study, we modify a common in vitro mixed cortical culture model using lipopolysaccharide (LPS) to examine the responses of microglia, astrocytes, and neurons to microwire segments. We also use dip-coated polyethylene glycol (PEG), which we have previously shown can modulate impedance changes to neural microelectrodes, to control the cellular responses. We find that microglia, as expected, exhibit an elevated response to LPS-coated microwire for distances of up to 150 μm, and that this elevated response can be mitigated by co-depositing PEG with LPS. Astrocytes exhibit a more complex, distance-dependent response, whereas neurons do not appear to be affected by the type or magnitude of glial response within this in vitro model. The discrepancy between our in vitro responses and typically observed in vivo responses suggest the importance of using a systems approach to understand the responses of the various brain cell types in a chronic in vivo setting, as well as the necessity of studying the roles of cell types not native to the brain. Our results further indicate that the loss of neuronal density observed in vivo is not a necessary consequence of elevated glial activation.
PMCID: PMC4231942  PMID: 25452724
intracortical microelectrodes; foreign body response; primary cortical cultures
3.  Islet β-Cell Endoplasmic Reticulum Stress Precedes the Onset of Type 1 Diabetes in the Nonobese Diabetic Mouse Model 
Diabetes  2012;61(4):818-827.
Type 1 diabetes is preceded by islet β-cell dysfunction, but the mechanisms leading to β-cell dysfunction have not been rigorously studied. Because immune cell infiltration occurs prior to overt diabetes, we hypothesized that activation of inflammatory cascades and appearance of endoplasmic reticulum (ER) stress in β-cells contributes to insulin secretory defects. Prediabetic nonobese diabetic (NOD) mice and control diabetes-resistant NOD-SCID and CD1 strains were studied for metabolic control and islet function and gene regulation. Prediabetic NOD mice were relatively glucose intolerant and had defective insulin secretion with elevated proinsulin:insulin ratios compared with control strains. Isolated islets from NOD mice displayed age-dependent increases in parameters of ER stress, morphologic alterations in ER structure by electron microscopy, and activation of nuclear factor-κB (NF-κB) target genes. Upon exposure to a mixture of proinflammatory cytokines that mimics the microenvironment of type 1 diabetes, MIN6 β-cells displayed evidence for polyribosomal runoff, a finding consistent with the translational initiation blockade characteristic of ER stress. We conclude that β-cells of prediabetic NOD mice display dysfunction and overt ER stress that may be driven by NF-κB signaling, and strategies that attenuate pathways leading to ER stress may preserve β-cell function in type 1 diabetes.
PMCID: PMC3314371  PMID: 22442300
4.  Optical Nanosensor Architecture for Cell Signaling Molecules Using DNA Aptamer-Coated Carbon Nanotubes 
ACS nano  2011;5(5):4236-4244.
We report a novel optical biosensor platform using near-infrared (NIR) fluorescent single-walled carbon nanotubes (SWNTs) functionalized with target-recognizing aptamer DNA for noninvasively detecting cell signaling molecules in real-time. Photoluminescence (PL) emission of aptamer-coated SWNTs is modulated upon selectively binding to target molecules, which is exploited to detect insulin using an insulin-binding aptamer (IBA) as a molecular recognition element. We find that nanotube PL quenches upon insulin recognition via a photoinduced charge transfer mechanism with a quenching rate of kq = 5.85×1014 M−1s−1 and a diffusion-reaction rate of kr = 0.129 s−1. Circular dichroism spectra reveal for the first time that IBA strands retain a four-stranded, parallel guanine quadruplex conformation on the nanotubes, ensuring target selectivity. We demonstrate that these IBA-functionalized SWNT sensors incorporated in a collagen extracellular matrix (ECM) can be regenerated by removing bound analytes through enzymatic proteolysis. As proof-of-concept, we show that the SWNT sensors embedded in the ECM promptly detect insulin secreted by cultured pancreatic INS-1 cells stimulated by glucose influx and report a gradient contour of insulin secretion profile. This novel design enables new types of label-free assays and non-invasive, in-situ, real-time detection schemes for cell signaling molecules.
PMCID: PMC3178844  PMID: 21520951
Aptamers; Biosensors; Carbon Nanotubes; Insulin; Near-infrared Fluorescence
5.  Oscillatory glucose flux in INS 1 pancreatic β cells: A self-referencing microbiosensor study 
Analytical biochemistry  2010;411(2):185-193.
Signaling and insulin secretion in β cells have been reported to demonstrate oscillatory modes, with abnormal oscillations associated with type 2 diabetes. We investigated cellular glucose influx in β cells with a self-referencing microbiosensor based on nanomaterials with enhanced performance. Dose-response analysis with glucose and metabolic inhibition studies were used to study oscillatory pattern and transporter kinetics. For the first time, we report a stable and regular oscillatory uptake of glucose (averaged period 2.9±0.6minutes), which corresponds well with an oscillator model. This oscillatory behavior is part of the feedback control pathway involving oxygen, cytosolic Ca2+/ATP, and insulin secretion (periodicity approximately 3 minutes). Glucose stimulation experiments show that the net Michaelis-Menten constant (6.1±1.5mM) is in between GLUT2 and GLUT9. Phloretin inhibition experiments show an EC50 value of 28±1.6μM-phloretin for class I GLUT proteins and a concentration of 40±0.6μM-phloretin caused maximum inhibition with residual non-oscillating flux, suggesting that the transporters not inhibited by phloretin are likely responsible for the remaining non-oscillatory uptake, and that impaired uptake via GLUT2 may be the cause of the oscillation loss in type 2 diabetes. Transporter studies using the SR microbiosensor will contribute to diabetes research and therapy development by exploring the nature of oscillatory transport mechanisms.
PMCID: PMC3081878  PMID: 21167120
glucose oxidase; biosensor; self referencing; diabetes; glycolysis; β cell
6.  The role of multiscale computational approaches for rational design of conventional and nanoparticle oral drug delivery systems 
Multiscale computational modeling of drug delivery systems (DDS) is poised to provide predictive capabilities for the rational design of targeted drug delivery systems, including multi-functional nanoparticles. Realistic, mechanistic models can provide a framework for understanding the fundamental physico-chemical interactions between drug, delivery system, and patient. Multiscale computational modeling, however, is in its infancy even for conventional drug delivery. The wide range of emerging nanotechnology systems for targeted delivery further increases the need for reliable in silico predictions. This review will present existing computational approaches at different scales in the design of traditional oral drug delivery systems. Subsequently, a multiscale framework for integrating continuum, stochastic, and computational chemistry models will be proposed and a case study will be presented for conventional DDS. The extension of this framework to emerging nanotechnology delivery systems will be discussed along with future directions. While oral delivery is the focus of the review, the outlined computational approaches can be applied to other drug delivery systems as well.
PMCID: PMC2676650  PMID: 18019831
Oral drug delivery; multiscale; computational modeling; continuum; computational chemistry; stochastic

Results 1-6 (6)