Surface Reaction of Electroosmotic Flow-Driven Free Antigens With Immobilized Magnetic-Microbeads-Tagged-Antibodies in Microchannels.

Immunoassays based on reactions between target pathogen (antigen; Ag) and antibody (Ab) are frequently used for Ag detection. An external magnetic field was used to immobilize magnetic microbeads-tagged-antibodies (mMB-Ab) on the surface of a microchannel in the capture zone. The mMB-Ab was subsequently used for Ag detection. The objective of this numerical study, with experimental validation, is to assess the surface reaction between mMB-Ab and Ag in the presence of electro-osmotic flow (EOF). First, immobilization of mMB-Ab complex in the wall of the capture zone was achieved. Subsequently, the Ag was transported by EOF toward the capture zone to bind with the immobilized mMB-Ab. Lastly, mMB-Ab:Ag complex was formed and immobilized in the capture zone. A finite volume solver was used to implement the above steps. The surface reaction between the mMB-Ab and Ag was investigated in the presence of electric fields (E): 150 V/cm-450 V/cm and Ag concentrations: 0.001 M-1000 M. The depletion of mMB-Ab increases with time as the E decreases. Furthermore, as the concentration of Ag decreases, the depletion of mMB-Ab increases with time. These results quantify the detection of Ag using the EOF device; thus, signifying its potential for rapid throughput screening of Ag. This platform technology can lead to the development of portable devices for the detection of target cells, pathogens, and biomolecules for testing water systems, biological fluids, and biochemicals.

Microvascular resistance reserve: diagnostic and prognostic performance in the ILIAS registry.

AIMS: The microvascular resistance reserve (MRR) was introduced as a means to characterize the vasodilator reserve capacity of the coronary microcirculation while accounting for the influence of concomitant epicardial disease and the impact of administration of potent vasodilators on aortic pressure. This study aimed to evaluate the diagnostic and prognostic performance of MRR. METHODS AND RESULTS: A total of 1481 patients with stable symptoms and a clinical indication for coronary angiography were included from the global ILIAS Registry. MRR was derived as a function of the coronary flow reserve (CFR) divided by the fractional flow reserve (FFR) and corrected for driving pressure. The median MRR was 2.97 [Q1-Q3: 2.32-3.86] and the overall relationship between MRR and CFR was good [correlation coefficient (Rs) = 0.88, P < 0.005]. The difference between CFR and MRR increased with decreasing FFR [coefficient of determination (R2) = 0.34; Coef.-2.88, 95% confidence interval (CI): -3.05--2.73; P < 0.005]. MRR was independently associated with major adverse cardiac events (MACE) at 5-year follow-up [hazard ratio (HR) 0.78; 95% CI 0.63-0.95; P = 0.024] and with target vessel failure (TVF) at 5-year follow-up (HR 0.83; 95% CI 0.76-0.97; P = 0.047). The optimal cut-off value of MRR was 3.0. Based on this cut-off value, only abnormal MRR was significantly associated with MACE and TVF at 5-year follow-up in vessels with functionally significant epicardial disease (FFR <0.75). CONCLUSION: MRR seems a robust indicator of the microvascular vasodilator reserve capacity. Moreover, in line with its theoretical background, this study suggests a diagnostic advantage of MRR over other indices of vasodilatory capacity in patients with hemodynamically significant epicardial coronary artery disease.

Temperature-dependent dielectric properties of CsPb2Br5: a 2D inorganic halide perovskite.

Two dimensional (2D) CsPb2Br5have been successfully synthesized via the chemical precipitation method. Detailed structural, morphological, optical, and dielectric studies of these materials have been performed. These 2D CsPb2Br5plates (of thickness around 200-300 nm) are ascribed to a tetragonal lattice system withI4/mcmspace group. The dielectric attributes such as dielectric constant, electrical modulus, loss factor, and the DC, and AC conductivities, are observed to be varying appreciably with temperature over an extensive frequency window of 10 Hz-50 MHz. The Nyquist plots are investigated using the Maxwell-Wagner equivalent circuit model, which shows the impact of grains and grain boundaries on the overall impedance. Both the free charge conductivity and space charge increase with an increment in temperature, as revealed from the modified Cole-Cole plot. The relaxation time and relaxation mechanism of 2D CsPb2Br5are estimated using the Kohlrausch-Williams-Watts equation. Variation in DC conductivity and relaxation time, as a function of temperature, closely resembles Arrhenius' behavior. Value of activation energy calculated from the DC conductivity corroborates with the same derived from relaxation time. The observation of high dielectric constant and nominal dielectric loss for CsPb2Br5perovskite offers enormous potential in energy harvesting and storage devices.

Non-invasive evaluation of toxicity in vitreoretinal domain following insertion of sustained release methotrexate micro-implant.

PURPOSE: To evaluate the safety and toxicity profile of a chitosan (CS) and poly(lactic-co-glycolic) acid (PLGA)-based sustained release methotrexate (MTX) intravitreal micro-implant in normal rabbit eyes using non-invasive testing that included electroretinography (ERG), ultrasound biomicroscopy (US), slit-lamp biomicroscopy (SLB), funduscopy, and intraocular pressure (IOP). METHODS: PLGA-coated CS-based micro-implants containing 400 µg of MTX and placebo (without drug) micro-implants were surgically-implanted in the vitreous of the right and the left eyes, respectively, in each of the thirty New Zealand rabbits. ERG, US, SLB, funduscopy, and IOP were assessed in both eyes at pre-determined time points (days: 1, 3, 7, 14, 28 and 56). The safety of micro-implants was assessed by analyzing the ERG data using different statistical models, to quantify and compare the functional integrity of the retina. Further, US, funduscopy, SLB and IOP determined the condition of the retina, the micro-implant and associated intraocular features. RESULTS: Statistical analyses of the ERG data showed unchanged functional integrity of retina between eyes with the PLGA-coated CS-based MTX micro-implant and the placebo micro-implant. US analysis showed that micro-implants were stationary throughout the study. SLB, funduscopy and IOP further confirmed that there were no abnormalities in the intraocular physiology. CONCLUSION: The findings from ERG, US, SLB, funduscopy, and IOP showed no detectable adverse effects caused by our biodegradable micro-implants. These non-invasive techniques appeared to show lack of significant ocular toxicity over time in spite of degradation and changes in morphology of the micro-implants following intraocular implantation.

Influence of Substitutional Groups on the Ordering and Crystallization of Amphiphilic Silsesquioxanes at the Air-Water Interface.

We report on the surface ordering and crystallization sequences in differently organic-substituted amphiphilic polyhedral silsesquioxane (POSS) variants induced by regulated compression at the air-water interface. Such molecular systems floating at the interface serve as a model system to study dynamic crystallization mediated by weak interactions. In situ grazing incidence X-ray scattering (GIXS) measurements, performed at a synchrotron X-ray source using a liquid surface diffractometer and corroborated with Brewster angle microscopy, revealed transformations for the different POSS variants (viz. trisilanol isobutyl POSS (TBPOSS), trisilanol cyclohexyl POSS (TCHPOSS), disilanol octaisobutly POSS (DOBPOSS), and trisilanol isooctyl POSS (TOPOSS)) from a weakly correlated monolayer structure to appreciably different structural and crystalline phases in various packing schemes. GIXS measurements revealed a stable nature of the crystallization of DOBPOSS, varying degrees of metastable crystallization for TCHPOSS and TBPOSS, and complete absence of crystalline phase in TOPOSS molecules. Incidentally, for all POSS variants showing crystalline phases, the motifs always assembled in a triclinic lattice with P1̅ symmetry. For the metastable crystals, preferential surface ordering of the crystallites promotes selective crystalline planes to exhibit preferred tilt angles with respect to the interface. The structural transformations of the differently substituted POSS molecules and their variations therein are attributed to the changing balance of the hydrophobic vs hydrophilic interaction in the layers, which is determined by the anisotropic shape and distribution of substitutional groups over the nanosized core cage of the monomer, steric interaction between nearest dimeric neighbors, as well as the in-plane and out-of-plane assembly of the overlayers.

Thermal crowning mechanism in gold-silica nanocomposites: plasmonic-photonic pairing in archetypal two-dimensional structures.

A close-packed monolayer of a two-dimensional periodic array of Silica nanospheres (SNs) with gold (Au) crowning, forming a long-ranged archetypal plasmonic-photonic nanocomposite, has been achieved. We investigate the thermal crowning mechanism in such a nanocomposite using electron microscopy and X-ray diffraction techniques. Pre- and post-annealing morphological features reveal gold crowning on top of SNs, at different annealing temperatures for various thicknesses of the sputter-deposited gold. In situ grazing incidence X-ray diffraction was employed to structurally characterize the reconstruction in the Au-layer as a function of the annealing temperature. Finite element methods were used to simulate the interaction between the paired nanocomposites and the incident electromagnetic radiations to elucidate the crowning and nanodrop formation mechanism. This study provides an insight into real-time morphological and structural changes of a dewetting plasmonic film over a photonic basis and explores a robust, reliable, and scalable route to fabricate coupled nanocomposites. Such nanocomposites allow prospective applications in optoelectronics, sensing, catalysis, and surface-enhanced Raman spectroscopy by exploiting the plasmonic-photonic pairing in archetypal two-dimensional structures.

Comparison of Heat Transfer Enhancement Between Magnetic and Gold Nanoparticles During HIFU Sonication.

Long procedure times and collateral damage remain challenges in high-intensity focused ultrasound (HIFU) medical procedures. Magnetic nanoparticles (mNPs) and gold nanoparticles (gNPs) have the potential to reduce the acoustic intensity and/or exposure time required in these procedures. In this research, we investigated relative advantages of using gNPs and mNPs during HIFU thermal-ablation procedures. Tissue-mimicking phantoms containing embedded thermocouples (TCs) and physiologically acceptable concentrations (0.0625% and 0.125%) of gNPs were sonicated at acoustic powers of 5.2 W, 9.2 W, and 14.5 W, for 30 s. It was observed that when the concentration of gNPs was doubled from 0.0625% to 0.125%, the temperature rise increased by 80% for a power of 5.2 W. For a fixed concentration (0.0625%), the energy absorption was 1.7 times greater for mNPs than gNPs for a power of 5.2 W. Also, for the power of 14.5 W, the sonication time required to generate a lesion volume of 50 mm3 decreased by 1.4 times using mNPs, compared with gNPs, at a concentration of 0.0625%. We conclude that mNPs are more likely than gNPs to produce a thermal enhancement in HIFU ablation procedures.

Assessment of Gold Nanoparticle-Mediated-Enhanced Hyperthermia Using MR-Guided High-Intensity Focused Ultrasound Ablation Procedure.

High-intensity focused ultrasound (HIFU) has gained increasing popularity as a noninvasive therapeutic procedure to treat solid tumors. However, collateral damage due to the use of high acoustic powers during HIFU procedures remains a challenge. The objective of this study is to assess the utility of using gold nanoparticles (gNPs) during HIFU procedures to locally enhance heating at low powers, thereby reducing the likelihood of collateral damage. Phantoms containing tissue-mimicking material (TMM) and physiologically relevant concentrations (0%, 0.0625%, and 0.125%) of gNPs were fabricated. Sonications at acoustic powers of 10, 15, and 20 W were performed for a duration of 16 s using an MR-HIFU system. Temperature rises and lesion volumes were calculated and compared for phantoms with and without gNPs. For an acoustic power of 10 W, the maximum temperature rise increased by 32% and 43% for gNPs concentrations of 0.0625% and 0.125%, respectively, when compared to the 0% gNPs concentration. For the power of 15 W, a lesion volume of 0, 44.5 ± 7, and 63.4 ± 32 mm3 was calculated for the gNPs concentration of 0%, 0.0625%, and 0.125%, respectively. For a power of 20 W, it was found that the lesion volume doubled and tripled for concentrations of 0.0625% and 0.125% gNPs, respectively, when compared to the concentration of 0% gNPs. We conclude that gNPs have the potential to locally enhance the heating and reduce damage to healthy tissue during tumor ablation using HIFU.

The mechanism of nanoparticle-mediated enhanced energy transfer during high-intensity focused ultrasound sonication.

In this combined experimental and theoretical research, magnetic nano-particle (mNP) mediated energy transfer due to high intensity-focused ultrasound (HIFU) sonication has been evaluated. HIFU sonications have been performed on phantoms containing three different volume percentages (0%, 0.0047%, and 0.047%) of mNPs embedded in a tissue mimicking material (TMM). A theoretical model has been developed to calculate the temperature rise in the phantoms during HIFU sonication. It is observed from theoretical calculation that the phonon layer at the interface of the mNPs and TMM dominates the attenuation for higher (0.047%) concentration. However, for a lower concentration (0.0047%) of mNPs, intrinsic absorption is the dominating mechanism. Attenuation due to the viscous drag becomes the dominating mechanism for larger size mNPs (>1000 nm). At a higher concentration (0.047%), it is observed from theoretical calculations that the temperature rise is 25% less for gold nano-particles (gNPs) when compared to mNPs. However, at lower concentrations (0.0047% and 0.002%), the difference in temperature rise for the mNPs and gNPs is less than 2%.

Evaluation of Hemodynamics in a Prestressed and Compliant Tapered Femoral Artery Using an Optimization-Based Inverse Algorithm.

The important factors that affect the arterial wall compliance are the tissue properties of the arterial wall, the in vivo pulsatile pressure, and the prestressed condition of the artery. It is necessary to obtain the load-free geometry for determining the physiological level of prestress in the arterial wall. The previously developed optimization-based inverse algorithm was improved to obtain the load-free geometry and the wall prestress of an idealized tapered femoral artery of a dog under varying arterial wall properties. The compliance of the artery was also evaluated over a range of systemic pressures (72.5-140.7 mmHg), associated blood flows, and artery wall properties using the prestressed arterial geometry. The results showed that the computed load-free outer diameter at the inlet of the tapered artery was 6.7%, 9.0%, and 12% smaller than the corresponding in vivo diameter for the 25% softer, baseline, and 25% stiffer arterial wall properties, respectively. In contrast, the variations in the prestressed geometry and circumferential wall prestress were less than 2% for variable arterial wall properties. The computed compliance at the inlet of the prestressed artery for the baseline arterial wall property was 0.34%, 0.19%, and 0.13% diameter change/mmHg for time-averaged pressures of 72.5, 104.1, and 140.7 mmHg, respectively. However, the variation in compliance due to the change in arterial wall property was less than 6%. The load-free and prestressed geometries of the idealized tapered femoral artery were accurately (error within 1.2% of the in vivo geometry) computed under variable arterial wall properties using the modified inverse algorithm. Based on the blood-arterial wall interaction results, the arterial wall compliance was influenced significantly by the change in average pressure. In contrast, the change in arterial wall property did not influence the arterial wall compliance.

Uncertainty Analysis of the Core Body Temperature Under Thermal and Physical Stress Using a Three-Dimensional Whole Body Model.

Heat stress experienced by firefighters is a common consequence of extreme firefighting activity. In order to avoid the adverse health conditions due to uncompensable heat stress, the prediction and monitoring of the thermal response of firefighters is critical. Tissue properties, among other parameters, are known to vary between individuals and influence the prediction of thermal response. Further, measurement of tissue properties of each firefighter is not practical. Therefore, in this study, we developed a whole body computational model to evaluate the effect of variability (uncertainty) in tissue parameters on the thermal response of a firefighter during firefighting. Modifications were made to an existing human whole body computational model, developed in our lab, for conducting transient thermal analysis for a firefighting scenario. In conjunction with nominal (baseline) tissue parameters obtained from literature, and physiologic conditions from a firefighting drill, the Pennes bioheat and energy balance equations were solved to obtain the core body temperature of a firefighter. Subsequently, the uncertainty in core body temperature due to variability in the tissue parameters (input parameters), metabolic rate, specific heat, density, and thermal conductivity was computed using the sensitivity coefficient method. On comparing the individual effect of tissue parameters on the uncertainty in core body temperature, the metabolic rate had the highest contribution (within ±0.20°C) followed by specific heat (within ±0.10°C), density (within ±0.07°C), and finally thermal conductivity (within ±0.01 °C). A maximum overall uncertainty of ±0.23 °C in the core body temperature was observed due to the combined uncertainty in the tissue parameters. Thus, the model results can be used to effectively predict a realistic range of thermal response of the firefighters during firefighting or similar activities.

Ultrasonographical assessment of implanted biodegradable device for long-term slow release of methotrexate into the vitreous.

Our group has developed a biodegradable drug delivery device (micro-implant) for long-term slow intraocular release of methotrexate (MTX) that can be implanted in the peripheral vitreous. The purpose of this study was to assess the position of the implanted devices and the status of the adjacent vitreous and peripheral retina over time using B-scan ocular ultrasonography (US). In each of the eight New Zealand rabbits used in this study, a chitosan (CS) and poly-lactic acid (PLA)-based micro-implant containing approximately 400 µg of MTX and a placebo micro-implant without MTX were inserted into the peripheral vitreous of the right and left eyes, respective, employing minimally invasive surgery. B-scan US imaging was performed on all of the rabbits immediately after implant insertion and on two rabbits at each of several pre-determined time points post-insertion (post-insertion days 5, 12, 19, and 33) to evaluate the position of the micro-implants and identify any evident morphological changes in the micro-implants and in the peripheral retina and vitreous during treatment. US imaging revealed stable positioning of the PLA-coated CS-based MTX micro-implant and the placebo micro-implant in the respective eyes throughout the study and lack of any changes in size, shape or sonoreflectivity of the micro-implants or abnormalities of the peripheral vitreous or retina in any of the study eyes. In summary, US did not show any evident morphological changes in the micro-implants, shifts in post-insertion position of the micro-implants, or identifiable changes in the micro-implants or peripheral vitreous and retina of the study eyes.

Diagnostic cutoff for pressure drop coefficient in relation to fractional flow reserve and coronary flow reserve: A patient-level analysis.

OBJECTIVES AND BACKGROUND: Functional assessment of intermediate coronary stenosis during cardiac catheterization is conducted using diagnostic parameters like fractional flow reserve (FFR), coronary flow reserve (CFR), hyperemic stenosis resistance index (HSR), and hyperemic microvascular resistance (HMR). CDP (ratio of pressure drop across a stenosis to distal dynamic pressure), a nondimensional index derived from fundamental fluid dynamic principles, based on a combination of intracoronary pressure, and flow measurements may improve the functional assessment of coronary lesion severity. METHODS: Patient-level data pertaining to 350 intracoronary pressure and flow measurements across coronary stenoses was assessed to evaluate CFR, FFR, HSR, HMR, and CDP. CDP was calculated as (ΔP)/(0.5 × ρ × APV(2)). The density of blood (ρ) was assumed to be 1.05 g/cm(3). The correlation of current diagnostic parameters (CFR, FFR, HSR, and HMR) with CDP was evaluated. The receiver operating characteristic (ROC) curve was used to identify the optimal cut-off point of CDP, corresponding to the clinically used cut-off values (FFR = 0.80 and CFR = 2.0). RESULTS: CDP correlated significantly with FFR (r = 0.81, P < 0.05) and had significant diagnostic efficiency (ROC-area under curve of 86%), specificity (72%) and sensitivity (85%) at FFR < 0.8. The corresponding cut-off value for CDP to detect FFR < 0.8 was at CDP>25.4. CDP also correlated significantly (r = 0.98, P < 0.05) with epicardial-specific parameter, HSR. CONCLUSIONS: CDP, a functional parameter based on both intracoronary pressure and flow measurements, has close agreement (area under ROC curve = 86%) with FFR, the frequently used method of evaluating stenosis severity.

Experimental validation of a nonlinear derating technique based upon Gaussian-modal representation of focused ultrasound beams.

A technique useful for performing derating at acoustic powers where significant harmonic generation occurs is illustrated and validated with experimental measurements. The technique was previously presented using data from simulations. The method is based upon a Gaussian representation of the propagation modes, resulting in simple expressions for the modal quantities, but a Gaussian source is not required. The nonlinear interaction of modes within tissue is estimated from the nonlinear interaction in water, using appropriate amounts of source reduction and focal-point reduction derived from numerical simulations. An important feature of this nonlinear derating method is that focal temperatures can be estimated with little additional effort beyond that required to determine the focal pressure waveforms. Hydrophone measurements made in water were used to inform the derating algorithm, and the resulting pressure waveforms and increases in temperature were compared with values directly measured in tissue phantoms. For a 1.05 MHz focused transducer operated at 80 W and 128 W, the derated pressures (peak positive, peak negative) agreed with the directly measured values to within 11%. Focal temperature rises determined by the derating method agreed with values measured using a remote thermocouple technique with a difference of 17%.

Right ventricle-pulmonary circulation dysfunction: a review of energy-based approach.

Patients with repaired or palliated right heart congenital heart disease (CHD) are often left with residual lesions that progress and can result in significant morbidity. However, right ventricular-pulmonary arterial evaluation and the timing of reintvervention is still subjective. Currently, it relies on symptomology, or RV imaging-based metrics from echocardiography or MR derived parameters including right ventricular (RV) ejection fraction (EF), end-systolic pressure (ESP), and end-diastolic volume (EDV). However, the RV is coupled to the pulmonary vasculature, and they are not typically evaluated together. For example, the dysfunctional right ventricular-pulmonary circulation (RV-PC) adversely affects the RV myocardial performance resulting in decreased efficiency. Therefore, comprehensive hemodynamic assessment should incorporate changes in RV-PC and energy efficiency for CHD patients. The ventricular pressure-volume relationship (PVR) and other energy-based endpoints derived from PVR, such as stroke work (SW) and ventricular elastance (Ees), can provide a measure of RV performance. However, a detailed explanation of the relationship between RV performance and pulmonary arterial hemodynamics is lacking. More importantly, PVR is impractical for routine longitudinal evaluation in a clinical setting, because it requires invasive catheterization. As an alternative, analytical methods and computational fluid dynamics (CFD) have been used to compute energy endpoints, such as power loss or energy dissipation, in abnormal physiologies. In this review, we review the causes of RV-PA failure and the limitation of current clinical parameters to quantify RV-PC dysfunction. Then, we describe the advantage of currently available energy-based endpoints and emerging energy endpoints, such as energy loss in the Pas or kinetic energy, obtained from a new non-invasive imaging technique, i.e. 4D phase contrast MRI.

Pulsatile arterial wall-blood flow interaction with wall pre-stress computed using an inverse algorithm.

BACKGROUND: The computation of arterial wall deformation and stresses under physiologic conditions requires a coupled compliant arterial wall-blood flow interaction model. The in-vivo arterial wall motion is constrained by tethering from the surrounding tissues. This tethering, together with the average in-vivo pressure, results in wall pre-stress. For an accurate simulation of the physiologic conditions, it is important to incorporate the wall pre-stress in the computational model. The computation of wall pre-stress is complex, as the un-loaded and un-tethered arterial shape with residual stress is unknown. In this study, the arterial wall deformation and stresses in a canine femoral artery under pulsatile pressure was computed after incorporating the wall pre-stresses. A nonlinear least square optimization based inverse algorithm was developed to compute the in-vivo wall pre-stress. METHODS: First, the proposed inverse algorithm was used to obtain the un-loaded and un-tethered arterial geometry from the unstressed in-vivo geometry. Then, the un-loaded, and un-tethered arterial geometry was pre-stressed by applying a mean in-vivo pressure of 104.5 mmHg and an axial stretch of 48% from the un-tethered length. Finally, the physiologic pressure pulse was applied at the inlet and the outlet of the pre-stressed configuration to calculate the in-vivo deformation and stresses. The wall material properties were modeled with an incompressible, Mooney-Rivlin model derived from previously published experimental stress-strain data (Attinger et al., 1968). RESULTS: The un-loaded and un-tethered artery geometry computed by the inverse algorithm had a length, inner diameter and thickness of 35.14 mm, 3.10 mm and 0.435 mm, respectively. The pre-stressed arterial wall geometry was obtained by applying the in-vivo axial-stretch and average in-vivo pressure to the un-loaded and un-tethered geometry. The length of the pre-stressed artery, 51.99 mm, was within 0.01 mm (0.019%) of the in-vivo length of 52.0 mm; the inner diameter of 3.603 mm was within 0.003 mm (0.08%) of the corresponding in-vivo diameter of 3.6 mm, and the thickness of 0.269 mm was within 0.0015 mm (0.55%) of the in-vivo thickness of 0.27 mm. Under physiologic pulsatile pressure applied to the pre-stressed artery, the time averaged longitudinal stress was found to be 42.5% higher than the circumferential stresses. The results of this study are similar to the results reported by Zhang et al., (2005) for the left anterior descending coronary artery. CONCLUSIONS: An inverse method was adopted to compute physiologic pre-stress in the arterial wall before conducting pulsatile hemodynamic calculations. The wall stresses were higher in magnitude in the longitudinal direction, under physiologic pressure after incorporating the effect of in-vivo axial stretch and pressure loading.

Biodegradable chitosan and polylactic acid-based intraocular micro-implant for sustained release of methotrexate into vitreous: analysis of pharmacokinetics and toxicity in rabbit eyes.

PURPOSE: The purpose of this study was to evaluate the pharmacokinetics and toxicity of a chitosan (CS) and polylactic acid (PLA) based methotrexate (MTX) intravitreal micro-implant in an animal model using rabbit eyes. METHODS: CS- and PLA-based micro-implants containing 400 µg of MTX were fabricated using lyophilization and dip-coating techniques. The micro-implants were surgically implanted in the vitreous of eight New Zealand rabbits employing minimally invasive technique. The PLA-coated CS-MTX micro-implant was inserted in the right eye and the placebo micro-implant in the left eye of each rabbit. Two rabbits were euthanized at each pre-determined time point post-implantation (days 5, 12, 19, and 33) for pharmacokinetics and histopathology evaluation. RESULTS: A therapeutic concentration of MTX (0.1-1.0 µM) in the vitreous was detected in the rabbit eyes studied for 33 days. The MTX release from the coated micro-implants followed a first order kinetics (R (2) ~ 0.88), implying that MTX release depends on the concentration of MTX in the micro-implant. Histopathological analysis of the enucleated eyes failed to show any signs of infection or tissue toxicity in any of the specimens. CONCLUSION: The PLA-coated CS-MTX micro-implants were able to deliver therapeutic release of MTX for a period of more than 1 month without detectable toxicity in a rabbit model. The micro-implants can be further investigated as a prospective alternative to current treatment protocols of repeated intravitreal MTX injections in intraocular disorders such as primary intraocular lymphoma, and selected cases of non-microbial intraocular inflammation.

Functional diagnostic parameters for arteriovenous fistula.

The inability to detect the arteriovenous fistula (AVF) dysfunction in a timely manner under the current surveillance programs, which are based on either diameter (d), flow rate (Q), or pressure (p) measurements, is one of the major challenges of dialysis treatment. Thus, our aim is to introduce new functional diagnostic parameters that can better predict AVF functionality status. Six AVFs were created between the femoral arteries and veins of three pigs, each pig having two AVFs on either limb. Flow fields and pressure drop (Δp) in AVFs were obtained via numerical analysis utilizing the CT scan and Doppler ultrasound data at 2D (D: days), 7D, and 28D postsurgery. The dataset included 16 (two pigs [four AVFs] for three time points, and one pig [two AVFs] for two time points) repeated measurements over time, and the statistical analysis was done using a mixed model. To evaluate the nature of pressure drop-flow relationships in AVFs, the Δp was correlated with the average velocity at proximal artery (v) and also the corresponding scaled velocity (v*) by the curvature ratio of anastomotic segment. Based on these relationships, two new functional diagnostic parameters, including the nonlinear pressure drop coefficient (Cp ; pressure drop divided by dynamic pressure at proximal artery) and the linear resistance index (R; pressure drop divided by velocity at proximal artery), were introduced. The diagnostic parameters that were calculated based on scaled velocity are represented as R* and Cp *. A marginal (P = 0.1) increase in d from 2D (5.4 ± 0.7 mm) to 7D (6.8 ± 0.7 mm), along with a significant increase in Q (2D: 967 ± 273 mL/min; 7D: 1943 ± 273 mL/min), was accompanied by an almost unchanged Δp over this time period (2D: 16.42 ± 4.6 mm Hg; 7D: 16.40 ± 4.6 mm Hg). However, the insignificant increase in d and Q from 7D to 28D (d = 7.8 ± 0.8 mm; Q = 2181 ± 378 mL/min) was accompanied by the elevation in Δp (24.6 ± 6.5 mm Hg). The functional diagnostic parameters, R and Cp , decreased from 2D (R = 22.4 ± 2.8 mm Hg/m/s; Cp = 12.0 ± 2.6) to 7D (R = 20.8 ± 2.8 mm Hg/m/s; Cp = 8.1 ± 2.6), and then increased from 7D to 28D (R = 35.5 ± 5.7 mm Hg/m/s; Cp = 17.5 ± 3.6) with a marginal significance. However, when the scaled velocity was used to calculate R* and Cp *, the increase in diagnostic parameters from 7D to 28D achieved statistical significance (P < 0.05). In summary, although the differences in the hemodynamic parameters (d, Q, and Δp) from 7D to 28D were insignificant, changes in their combined effects in the form of diagnostic parameters were significant. Therefore, the functional diagnostic parameters are capable of better distinguishing changes in the hemodynamic variations, and thus, could be promising endpoints to diagnose the functionality of AVFs over time.

Enhanced capture of magnetic microbeads using combination of reduced magnetic field strength and sequentially switched electroosmotic flow--a numerical study.

Magnetophoretic immunoassay is a widely used technique in lab-on-chip systems for detection and isolation of target cells, pathogens, and biomolecules. In this method, target pathogens (antigens) bind to specific antibodies coated on magnetic microbeads (mMBs) which are then separated using an external magnetic field for further analysis. Better capture of mMB is important for improving the sensitivity and performance of magnetophoretic assay. The objective of this study was to develop a numerical model of magnetophoretic separation in electroosmotic flow (EOF) using magnetic field generated by a miniaturized magnet and to evaluate the capture efficiency (CE) of the mMBs. A finite-volume solver was used to compute the trajectory of mMBs under the coupled effects of EOF and external magnetic field. The effect of steady and time varying (switching) electric fields (150-450 V/cm) on the CE was studied under reduced magnetic field strength. During switching, the electric potential at the inlet and outlet of the microchannel was reversed or switched, causing reversal in flow direction. The CE was a function of the momentum of the mMB in EOF and the applied magnetic field strength. By switching the electric field, CE increased from 75% (for steady electric field) to 95% for lower electric fields (150-200 V/cm) and from 35% to 47.5% for higher electric fields (400-450 V/cm). The CE was lower at higher EOF electric fields because the momentum of the mMB overcame the external magnetic force. Switching allowed improved CE due to the reversal and decrease in EOF velocity and increase in mMB residence time under the reduced magnetic field strength. These improvements in CE, particularly at higher electric fields, made sequential switching of EOF an efficient separation technique of mMBs for use in high throughput magnetophoretic immunoassay devices. The reduced size of the magnet, along with the efficient mMB separation technique of switching can lead to the development of portable device for detection of target cells, pathogens, and biomolecules.

Functional diagnosis of coronary stenoses using pressure drop coefficient: a pilot study in humans.

OBJECTIVES AND BACKGROUND: Myocardial fractional flow reserve (FFR) in conjunction with coronary flow reserve (CFR) is used to evaluate the hemodynamic severity of coronary lesions. However, discordant results between FFR and CFR have been observed in intermediate coronary lesions. A functional parameter, pressure drop coefficient (CDP; ratio of pressure drop to distal dynamic pressure), was assessed using intracoronary pressure drop (dp) and average peak velocity (APV). The CDP is a nondimensional ratio, derived from fundamental fluid dynamic principles. We sought to evaluate the correlation of CDP with FFR, CFR, and hyperemic stenosis resistance (HSR: ratio of pressure drop to APV) in human subjects. METHODS: Twenty-seven patients with reversible perfusion defects based on SPECT were consented for the study before cardiac catheterization. Distal coronary pressure and APV were measured simultaneously for each coronary lesion using a Combowire(©) during cardiac catheterization. Reference diameter, minimal lumen diameter, and %AS were obtained by quantitative coronary angiography. Maximum hyperemia was induced by IV adenosine (140 µg/kg/min). CDP was calculated as, (Δp)/(0.5 × ρ × APV(2) ). The density of blood (ρ) was assumed to be 1.05 gm/cm(3) . RESULTS: The functional index, CDP, when correlated simultaneously with FFR and CFR, was found to have a significant correlation (r = 0.61; P < 0.05). Similarly a significant correlation was achieved when CDP was correlated with HSR (r = 0.91; P < 0.001). This is consistent with the definition of CDP, which is a functional parameter that includes both pressure and flow information. CONCLUSIONS: CDP, a nondimensional parameter combining simultaneous measurements of pressure drop and velocity data, can accurately define the severity of coronary stenoses and could prove advantageous clinically.