Douglas A. Christensen

Extending the two-dimensional FDTD method to hybrid electromagnetic systems with active and passive lumped elements

The finite-difference-time-domain (FDTD) method is extended to include distributed electromagnetic systems with lumped elements (a hybrid system) and voltage and current sources. FDTD equations that include nonlinear elements like diodes and transistors are derived. Calculation of driving-point impedance is described. Comparison of FDTD calculated results with analytical results for several two-dimensional transmission-line configurations illustrates the accuracy of the method. FDTD results for a transistor model and a diode are compared with SPICE calculations. The extended FDTD method should prove useful in the design and analysis of complicated distributed systems with various active, passive, linear, and nonlinear lumped electrical components. >

Factors affecting acoustically triggered release of drugs from polymeric micelles

A custom ultrasonic exposure chamber with real-time fluorescence detection was used to measure acoustically-triggered drug release from Pluronic P-105 micelles under continuous wave (CW) or pulsed ultrasound in the frequency range of 20 to 90 kHz. The measurements were based on the decrease in fluorescence intensity when drug was transferred from the micelle core to the aqueous environment. Two fluorescent drugs were used: doxorubicin (DOX) and its paramagnetic analogue, ruboxyl (Rb). Pluronic P-105 at various concentrations in aqueous solutions was used as a micelle-forming polymer. Drug release was most efficient at 20-kHz ultrasound and dropped with increasing ultrasonic frequency despite much higher power densities. These data suggest an important role of transient cavitation in drug release. The release of DOX was higher than that of Rb due to stronger interaction and deeper insertion of Rb into the core of the micelles. Drug release was higher at lower Pluronic concentrations, which presumably resulted from higher local drug concentrations in the core of Pluronic micelles when the number of micelles was low. At constant frequency, drug release increased with increasing power density. At constant power density and for pulse duration longer than 0.1 s, peak release under pulsed ultrasound was the same as stationary release under CW ultrasound. Released drug was quickly re-encapsulated between the pulses of ultrasound, which suggests that upon leaving the sonicated volume, the non-extravasated and non-internalized drug would circulate in the encapsulated form, thus preventing unwanted drug interactions with normal tissues.

Drug delivery in pluronic micelles: effect of high-frequency ultrasound on drug release from micelles and intracellular uptake

The effect of high-frequency ultrasound on doxorubicin (DOX) release from Pluronic micelles and intracellular DOX uptake was studied for promyelocytic leukemia HL-60 cells, ovarian carcinoma drug-sensitive and multidrug-resistant (MDR) cells (A2780 and A2780/ADR, respectively), and breast cancer MCF-7 cells. Cavitation events initiated by high-frequency ultrasound were recorded by radical trapping. The onset of transient cavitation and DOX release from micelles were observed at much higher power densities than at low-frequency ultrasound (20-100 kHz). Even a short (15-30 s) exposure to high-frequency ultrasound significantly enhanced the intracellular DOX uptake from PBS, RPMI 1640, and Pluronic micelles. The mechanisms of the observed effects are discussed.

Ultrasonic vascular imaging system and method of blood vessel cannulation

An apparatus, method and system for cannulation of blood vessels. The apparatus comprises a sensor assembly including two linear transducer arrays oriented perpendicularly to each other to form a “T” shape to provide substantially simultaneous ultrasound images of at least one blood vessel in a portion of a patients body in two perpendicular planes. The apparatus may also include one or more Doppler transducer elements to transmit and receive one or more Doppler beams at an incident angle beneath one of the transducer arrays and in alignment therewith to determine blood flow direction and velocity within the at least one blood vessel. The sensor assembly may be disposed within an elongated, flexible, protective sheath and secured to a graphically marked cover to facilitate orientation of the sensor assembly on the patient and guidance of a needle towards a desired target vessel during the cannulation procedure. The cover may also include associated structure to cooperate with a reference location element to place, align and secure the sensor assembly to the patients skin at a desired location.

Kinetics of ultrasonic release of doxorubicin from pluronic P105 micelles

The aim of this research was to measure and model the kinetics of acoustic release and subsequent re-encapsulation of Doxorubicin (DOX) from Pluronic P105 micelles. A fluorescence detection ultrasound exposure chamber was used. Experimental data showed that no significant release was observed when DOX loaded in Pluronic P105 micelles was exposed to ultrasound for less than 0.1 s at a power density of 58 mW/cm2 and a frequency of 20 kHz. Above this threshold, the amount of release was shown to increase as the pulse length increased up to 0.6 s. The same experiments showed that it requires at least 0.1 s of no ultrasound for measurable re-encapsulation to occur. Release and re-encapsulation are completed within about 0.6 s of the beginning of the ON and OFF phases of pulsed ultrasound. Several physical models and their corresponding mathematical solutions were analyzed to see which most closely fit the data. The model of zero-order release with first-order re-encapsulation appears to represent data from this polymeric system better than other models. This technique has possible applications in site-specific chemotherapy.

Ultrasonic release of doxorubicin from Pluronic P105 micelles stabilized with an interpenetrating network of N,N-diethylacrylamide.

Pluronic P105 micelles sequester hydrophobic drugs and release them upon insonation with low frequency ultrasound; however these micelles dissolve relatively quickly upon dilution. The objective of this research was to determine whether stabilization of these micelles would compromise their ability to sequester and release drug. P105 micelles were stabilized with an interpenetrating network of poly (N,N-diethylacrylamide), and ultrasonically-activated release of doxorubicin (Dox) was measured by a fluorescence technique. Results showed that stabilized micelles sequestered the Dox and released it upon insonation at 70 kHz. The amount released was not significantly different from that released from P105 micelles (P=0.481), and the drug re-encapsulation upon cessation of insonation was complete. This system has potential for controlled drug delivery to insonated tissues in vivo.

Modeling sources in the FDTD formulation and their use in quantifying source and boundary condition errors

The modeling of voltage and current sources as either added or replaced sources in FDTD simulations is described and their differences discussed in terms of a transmission line analogy. An infinitesimal current element (ICE) is used to illustrate the validation of added source modeling and to study the errors involved with modeling an infinitesimal element within the finite-sized FDTD grid. This model is also used to illustrate the behavior of radiation boundary conditions as their near-field position with respect to the source is varied. We characterize the errors due to modeling and boundary conditions and give guidelines for obtaining acceptable accuracy in simulations. >

Femtomolar sensitivity using a channel-etched thin film waveguide fluoroimmunosensor

A dual channel, evanescent fluoroimmunoassay format is used to detect femtomolar analyte concentrations (i.e. less than 1 part per trillion [w/w]) on an etched channel siliconoxynitride thin film integrated optical waveguide. Two assays are used to demonstrate the dose-response behaviour of the sensor: (1) a direct assay of a fluorescently-labeled protein ligand binding to an immobilized protein receptor, and (2) an indirect sandwich assay of a non-fluorescent protein ligand binding to an immobilized protein receptor, as detected by the binding of a fluorescently-labeled secondary receptor protein. A red-emitting cyanine dye (Cy-5), which minimized background fluorescence and scatter losses of the waveguide, was used in both assays. To our knowledge, this is the first report of femtomolar sensitivity in an immunosensing instrument.

Microbubble Generation in Phase-Shift Nanoemulsions used as Anticancer Drug Carriers.

The paper describes droplet-to-bubble transition in block copolymer stabilized perfluoropentane nanoemulsions. Three physical factors that trigger droplet-to-bubble transition in liquid emulsions and gels were evaluated, namely heat, ultrasound, and injections through fine-gauge needles. Among those listed, ultrasound irradiation was found the most efficient factor. Possible mechanisms of bubble generation and growth discussed in the paper include liquid-to-gas transition inside the individual bubble; bubble coalescence; and diffusion of dissolved air and/or perfluoropentane from small bubbles into larger bubbles (i.e., Oswald ripening). The last two factors result in irreversibility of the droplet-to-bubble transition. In gel matrices, ultrasound-induced droplet-to-bubble transition was substantially inhibited but was catalyzed by large (hundred micron) pre-existing bubbles irradiated by low frequency (hundred kilohertz) ultrasound. The dependence of the droplet-to-bubble transition on initial bubble size is theoretically treated and the role of increase of surface area in promoting bubble coalescence is discussed. Therapeutic implications of observed effects are discussed.

Cavitation Properties of Block Copolymer Stabilized Phase-Shift Nanoemulsions Used as Drug Carriers

Cavitation properties of block copolymer stabilized perfluoropentane nanoemulsions have been investigated. The nanoemulsions were stabilized by two biodegradable amphiphilic block copolymers differing in the structure of the hydrophobic block, poly(ethylene oxide)-co-poly(L-lactide) (PEG-PLLA) and poly(ethylene oxide)-co-polycaprolactone (PEG-PCL). Cavitation parameters were measured in liquid emulsions and gels as a function of ultrasound pressure for unfocused or focused 1-MHz ultrasound. Acoustic droplet vaporization preceded generation of acoustic cavitation in liquid matrices and gels. Both stable and inertial cavitation was observed for focused ultrasound while only stable cavitation was observed for unfocused ultrasound.