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Frequency-dependent electroosmosis.

This paper presents a theory for frequency-dependent electroosmosis. It is shown that for a closed capillary the electroosmosis frequency-dependent ratio of DeltaV/DeltaP is constant with increasing frequency until inertial effects become prevalent, at which time DeltaV/DeltaP starts to decrease with increasing frequency. The frequency response of the electroosmosis coupling coefficient is shown to be dependent on the capillary radius. As the capillary radius is made smaller, inertial effects start to occur at higher frequencies. As part of this paper, frequency-dependent electroosmosis is compared to frequency-dependent streaming potentials. In this comparison it is shown that inertial effects start to become more prevalent at higher frequencies for the closed capillary frequency-dependent electroosmosis case than for the frequency-dependent streaming potential case in the same capillary. It is also shown that this difference is due to a second viscosity (transverse) wave that emanates from the velocity zero within the capillary for the electroosmosis case. The second viscosity wave superposes with the viscosity wave that emanates from wall of the capillary to effectively reduce the hydraulic radius of the capillary. Data are presented for a 0.127-mm capillary to support the findings in this paper.

Journal Article↗

Flow behavior of periodical electroosmosis in microchannel for biochips.

This paper presents an analytical solution for periodical electroosmotic flows in two-dimensional uniform microchannel based on Poisson-Boltzmann equations for electric double layer (EDL) and Navier-Stokes equation for incompressible viscous fluid. Analytical results indicate that the velocity of periodical electroosmosis strongly depends on Reynolds number Re=omegah(2)/nu, as well as on EDL properties and applied electric field. Slip velocity of EDL decreases as the Reynolds number increases. Electroosmotic velocity outside the EDL decreases, and lag phase angle of velocity increases as distance away from the channel wall increases. A wavelike velocity profile across the channel is found. An asymptotic solution for low Reynolds number is given in this paper. Periodical electroosmosis with low Reynolds has same velocity amplitude and a pluglike velocity profile as that of steady electroosmosis. Based on Debye-Hückel approximation, this paper also obtains a solution of periodical electroosmosis applicable to cases where the thickness of EDL is of the same order as half of channel width.

Electroosmosis↗

Pore charge distribution considerations in human epidermal membrane electroosmosis.

The aim of this study was to assess the extent to which a model with pores having only net negative charges would adequately describe transdermal electroosmosis in human epidermal membrane (HEM) at neutral pH. Such information would enhance the predictive value of the modified Nernst-Planck model for transdermal iontophoresis, in addition to providing insights regarding the likelihood of significant pore charge distribution in HEM. Baseline results (the control) obtained from 0.1 to 0.4 V anodal and cathodal electroosmosis experiments with synthetic polycarbonate membranes (Nuclepore membranes), using radiolabeled urea and mannitol as the model permeants, demonstrated that such a membrane system can be modeled by the electrokinetic (electroosmosis) theory with the assumption of the pores possessing only negative charges. The studies with HEM were carried out at low voltage (</=0.5 V) where alterations in the barrier properties of HEM were minimal and at higher voltages (>/approximately = 1.0 V) where significant field-induced pore formation in HEM occurred. In both the low and high voltage studies, radiolabeled urea, mannitol, and water were employed as permeants in cathodal and anodal iontophoresis experiments. The results of the low voltage iontophoresis experiments suggest significant pore charge distribution in HEM (a significant deviation between the predictions from the single pore charge type assumption and the experimental data). Under the higher applied voltage conditions (>/approximately = 1.0 V), results from anodal and cathodal electroosmosis studies were consistent with the model in which the HEM has only pores that are net negatively charged.

Algorithms↗

Theoretical examination of electroosmosis control with external radial electric field in capillary electrophoresis.

The influence of an external radial electric field (E(R)) on electroosmosis in capillary electrophoresis was studied theoretically. Based on a Stern-like model, three basic equations were deduced, with only two unknown parameters of delta and psi(d) where delta is the distance between the flowing shear interface and the tube wall, while psi(d) is the potential at the starting point of diffuse layer. The new equations reveal that, to effectively regulate the electroosmosis at E(R) <3 x 10(8) V/m, buffer pH should be kept below 5. In a common case of E(R) <10(8) V/m, the buffer pH should be below 4, otherwise the flow direction of the electroosmosis cannot be reversed. A way to increase the working pH range lies in the use of chemically coated rather than bare tubes. As expected, small capillaries and low ionic strength are preferred.

Electrochemistry↗

Scanning electrochemical microscopy of iontophoretic transport in hairless mouse skin. Analysis of the relative contributions of diffusion, migration, and electroosmosis to transport in hair follicles.

Scanning electrochemical microscopy (SECM) is used to measure spatially localized diffusive and iontophoretic transport rates in hairless mouse skin. Molecular fluxes within individual hair follicles are quantified by measuring the rate at which redox-active probe molecules emerge from the follicle. The influence of an applied current on the flux of an anion (ascorbate), a cation (ferrocenylmethyltrimethylammonium), and a neutral molecule (acetaminophen) is used to determine the contributions of diffusion, migration, and electroosmosis to iontophoretic transport. The direction of electroosmotic transport is consistent with hair follicles possessing a net negative charge at neutral pH. Electroosmosis results in a modest increase in the transport rate of the neutral molecule (a factor of approximately 2.4x at an iontophoretic current density of 0.1 mA/cm(2)). Larger enhancements in the flux of the electrically charged species are associated with migration. The electroosmotic flow velocity within hair follicles is established to be 0.5 (+/-0.1) microm/s at 0.1 mA/cm(2), independent of the electrical charge of permeant. The net volume flow rate across skin resulting from electroosmosis in hair follicles is estimated to be 0.3 microL/cm(2)h. The results suggest that hair follicles are a significant pathway for electroosmotic solution flow during iontophoresis. The radius of the hair follicle openings in hairless mouse skin is measured to be 21 +/- 5 microm.

Algorithms↗

Electroosmosis injection of blood serum into biocompatible microcapillary chip fabricated on quartz plate.

A chip which allows the detection of various human health markers from a trace amount of blood has been studied. As a goal, a microcapillary with a 30 x 30 microm cross-section was fabricated using all-dry etching technologies on a 2 x 2 cm SiO2 chip. The coating of the biocompatible 2-methacryloyloxyethylphosphorylcholine (MPC) polymer on the inner quartz wall of the microcapillary demonstrated a sufficiently long adsorption suppression of proteins in the serum on the quartz surface, while rapid stopping occurred for serum injected into the microcapillary with a bare quartz surface. The latter rapid stopping corresponded well to fast electroosmosis flow due to the negatively increasing zeta-potential by the adsorption of proteins on the quartz surface. The electroosmosis pump arranged a downstream of the microcapillary was also developed to inject serum into it. As a preliminary application, a given concentration-standard solution was injected into the ion-sensitive field-effect transistor (ISFET) embedded in the chip, employing the electroosmosis pump arranged downstream of the sensor position. Hence, the pH and Na+ and K+ cation concentrations were measured.

Blood Chemical Analysis↗

Impact of electroosmosis on isotachophoresis in open-tubular fused-silica capillaries: analysis of the evolution of a stationary steady-state zone structure by computer simulation and experimental validation.

A dynamic computer model for simulation of open-tubular capillary electrophoresis that includes in situ calculation of electroosmosis along the fused-silica capillary column has been applied to the characterization of an anionic isotachophoretic system in presence of a cathodic electroosmotic flow. For each column segment, electroosmosis is calculated with the use of a wall mobility, the voltage gradient and the degree of dissociation of the silanol surface groups of the capillary wall. Then, the bulk capillary flow is taken to be the average of all of the segment flows and considered to represent a plug flow. This simple approach enables the combined simulation of the temporal behavior of an isotachophoretic zone structure in presence of electroosmosis. For a model anionic isotachophoretic configuration at pH 6, simulation data reveal the asymptotic formation of a stationary steady-state zone configuration in which electrophoretic and electroosmotic zone displacements are opposite and of equal magnitude. The position of the stationary boundaries are predicted to be dependent on the selected wall pK and mobility values. For two different instruments, qualitative agreement between experimental data and simulation results obtained with a wall pK between 5 and 6 is demonstrated. However, for the two experimental setups, significant differences in electroosmotic pumping (i.e. wall mobility values) are noted.

Anions↗

Lipid and electroosmosis enhanced transdermal delivery of insulin by electroporation.

Transdermal transport of insulin and extraction of interstitial glucose under anodal iontophoresis (electroosmosis) following electroporation in the presence of 1,2-dimyristoylphophatidylserine (DMPS) was studied. An earlier study showed that DMPS increased the transport of insulin across porcine epidermis under electroporation by approximately fourfold. It was suggested that DMPS increased the lifetime of electropores in the epidermis resulting in an enhanced transport of permeants. When electroosmosis was applied across the epidermis following electroporation with DMPS, the enhancement of insulin transport was approximately 18-fold over electroporation alone. When the same strategy was applied to extract interstitial glucose, the enhancement was approximately 23-fold over electroporation alone. Real-time transdermal insulin transport kinetics was measured using FITC-labeled insulin and a custom-made vertical diffusion apparatus that had a fluorescence cuvette as the receiver compartment. Insulin transport by electroporation alone showed a nonlinear kinetics that is most likely due to the resealing of the electropores with time. The transport kinetics when electroporation was carried out in the presence of DMPS was more linear, confirming earlier studies that suggested the DMPS stabilizes transport paths formed by electroporation. The data suggests that in vivo, noninvasive insulin delivery to therapeutic levels and glucose extraction may be achieved by combining electroporation with anionic lipids and electroosmosis.

Administration, Cutaneous↗

Synergistic effect of anionic lipid enhancer and electroosmosis for transcutaneous delivery of insulin.

A lipid formulation consisting of 1,2-dimyristoyl-sn3-phosphatidylserine (DMPS) in a 0.2% sodium dodecylsulfate (SDS) solution was tested as an in vivo enhancer for the transcutaneous delivery of insulin. The formulation when applied to for 15 min was found to permeabilize porcine epidermis and prolong the permeable state as evidenced by electric resistance measurement. The formulation enhanced the transport of insulin through the epidermis by 40- to 100-fold, as compared to epidermis that was treated with SDS or DMPS alone. Application of electroosmosis across the formulation-treated epidermis enhanced the transport of insulin by an additional 10-fold. Pharmacokinetic studies were carried out in Sprague-Dawley rats. Transcutaneous delivery of insulin with formulation treatment and electroosmosis increased the plasma level of insulin by approximately 10-fold over delivery by formulation treatment alone. With the above protocol plasma insulin concentration remained relatively constant for up to 4h. The synergistic application of anionic lipid formulation and electroosmosis offers a promising non-invasive technique to deliver insulin transcutaneously.

Administration, Cutaneous↗

Effect of electroporation on the electroosmosis across hairless mouse skin in vitro.

The effect of electroporation on the iontophoresis-produced electroosmosis across the skin was evaluated by measuring the permeability of hairless mouse skin, to mannitol, a non-electrolyte, in vitro. Immediately after electroporation by squared pulses (10 times/s) at 100, 150 or 200 V for 1 ms, anodal iontophoretic permeations were determined at 0.4 mA/cm2 for 4 h. The observed iontophoretic permeability of mannitol was higher with electroporation pretreatment than without pretreatment. The enhanced flux of mannitol induced by electroporation, however, was due to increased passive diffusion. The contribution of convective or osmotic flow caused by anodal iontophoresis on skin permeation of mannitol was decreased by the pretreatment. In addition, osmotic flow was decreased with an increase in the applied voltage for electroporation. In contrast, mannitol flux during cathodal iontophoresis at 0.4 mA/cm2 after 150 or 200 V electroporation was higher than without electroporation as well as anodal iontophoresis, but cathodal iontophoretic flux after electroporation was lower than without iontophoresis. The neutral high-molecular compound dextran rhodamine B was also used as a second model. Anodal iontophoresis alone did not increase skin permeability of the compound. However, electroporation pretreatment before anodal iontophoresis enhanced the skin permeation of dextran rhodamine B, which was due to increased osmotic flow induced by this combination. These results suggest that electroporation decreases the electroosmosis produced by iontophoresis, and that electroporation increases skin permeability to neutral low and high model compounds (mannitol and dextran rhodamine B) probably due to an enlarged permeation pathway. Thus, electroporation affects osmotic flow from the anode to cathode during iontophoresis. Therefore, one has to pay attention to the change in electroosmosis produced by iontophoresis for the combined use of electroporation and iontophoresis to attain a high skin-penetration enhancing effect.

Administration, Topical↗

Transdermal iontophoresis: modulation of electroosmosis by polypeptide.

The objective of this research was to further evaluate the relative importance of electrorepulsion and electroosmosis to the mechanism of enhanced transport across the skin during iontophoresis. Specifically, the impact of iontophoresing into the skin positively and negatively charged polypeptides (poly-L-lysines and poly-L-glutamic acids, respectively) on the membrane's permselectivity and hence on the quantity and direction of electroosmotic flow, was examined. Experiments were performed in vitro at pH 7.4 using conventional methodology; electroosmosis during the iontophoresis of the polypeptides into and across the skin was tracked in the usual way via the movement of the polar, uncharged, non-metabolizable marker, D-mannitol. Electrotransport of the cationic polypeptides attenuated electroosmotic flow in the normal anode-to-cathode direction; the degree of inhibition was correlated both with the initial concentration of poly-L-lysine in the anodal chamber and with the molecular weight of the polypeptide employed (from 1 to 25 kilodaltons). Iontophoresis of the anionic poly-L-glutamic acids from the cathode provoked a slight increase in electroosmotic flow in the 'reverse' direction (i.e. from the receptor phase beneath the skin towards the cathode chamber located on the epidermal side of the membrane); this effect, however, was much less dramatic than that produced in the opposite sense by the cationic polypeptides. The results suggest that driving large positively-charged polypeptide molecules into the skin leads to neutralization of the membrane's negativity, a subsequent loss of permselectivity and a concomitant attenuation of electroosmosis in the conventional anode-to-cathode direction. Presumably, the relatively poor iontophoretic permeability of these species (which becomes more and more evident with increasing molecular weight) results in a sufficiently important association of the polypeptide with the skin during the period of current passage. Much less significant effects are realized by the cathodal iontophoresis of poly-anions due to the difficulty of 'pushing' negative ions into an already negatively-charged membrane.

Administration, Cutaneous↗

Iontophoresis enhances the transport of acyclovir through nude mouse skin by electrorepulsion and electroosmosis.

PURPOSE: Iontophoresis was employed for enhancing the transdermal delivery of acyclovir through nude mouse skin in vitro, with the aim of understanding the mechanisms responsible for drug transport, in order to properly set the conditions of therapeutical application. METHODS: Experiments were done in horizontal diffusion cells, using as donor a saturated solution of acyclovir at two different pH values (3.0 and 7.4). Different electrical conditions (current density and polarity) were employed. RESULTS: At pH 3.0, acyclovir anodal transport was due to electrorepulsion, since acyclovir was 20% in the protonated form. In acyclovir anodal iontophoresis at pH 7.4 the main mechanism involved was electroosmosis, since the drug was substantially unionized and the negative charge of the skin at this pH caused the electroosmotic flow to be from anode to cathode. In the case of cathodal iontophoresis at pH 3.0, acyclovir transport was enhanced approx. seven times, due to the presence of an electroosmotic contribution caused by the reversal of the charge of the skin. At pH 7.4 during cathodal iontophoresis acyclovir transport was not enhanced because the electroosmotic flow was in the opposite direction, compared to drug electric transport, i.e. anode to cathode. The increased skin permeability caused by current application was demonstrated to be less important than electrorepulsion and electroosmosis. CONCLUSIONS: Anodal iontophoresis shows potential applicability for enhancing acyclovir transport to the skin, considering that both electric transport and electroosmosis can be used by appropriately setting the pH of the donor.

Acyclovir↗

Electrorepulsion versus electroosmosis: effect of pH on the iontophoretic flux of 5-fluorouracil.

PURPOSE: To delineate the contributions of electrorepulsion and electroosmosis to the iontophoretic flux of 5-FU across porcine skin in vitro. Also, the isoelectric point (pI) of the skin model was determined. METHODS: The electrotransport of 5-FU, anode-to-cathode ("anodal") and cathode-to-anode ("cathodal") was determined as a function of the pH of the electrolyte bathing the skin. RESULTS: At pH 8.5, the drug (pKa approximately 8) is negatively charged and "cathodal", viz. electrorepulsive, transport is much greater than that in the opposite direction. At pH 7.4, where approximately 25% of 5-FU is charged, electrorepulsive and electroosmotic ("anodal") fluxes are balanced. Decreasing the pH to 6, and then 5, reduces the percentage of ionized 5-FU such that "anodal" electroosmosis dominates across the negatively-charged membrane. But, at pH 4, "anodal" and "cathodal" fluxes are again equal suggesting neutralization of the skin (i.e., pI approximately 4). This is confirmed at pH 3, where "cathodal" electroosmosis dominates across the now net-positively charged barrier. CONCLUSIONS: Electrotransport is sensitive, mechanistically, to the properties of the permeant and of the skin; interactions of, for example, the drug or constituents of a formulation, that alter the barrier's net charge, can affect iontophoretic delivery. The pI of porcine ear skin is approximately 4.

Administration, Cutaneous↗

Electroosmosis in Nitella.

The role of electroosmosis was studied directly in Nitella. The cells were mounted in a water-tight barrier between two chambers containing reversible electrodes for the application of potentials, and fitted with calibrated capillaries to measure water movement. No water movement was found when small existing bioelectric potentials were short-circuited through an external connection, nor when external potentials up to 1 or 2 volts were applied (producing currents up to 5 microa). Higher potentials (up to 10 volts) caused small movements of water, toward the negative pole. Larger and often irreversible water movements were produced by potentials up to 20 volts-sometimes persisting after current flow. A variety of evidence suggests that the effects are caused by injury at the cathodal end of the cell, allowing water to be attracted osmotically at the intact end and forced out at the injured end (transosmosis). This injury is reversible under small applied potentials, irreversible after large ones (100 to 200 times the natural bioelectric values). Such water flows persist in low salt concentrations (up to 0.09 M NaCl) but almost completely vanish in isotonic (0.26 M) mannitol. This confirms the osmotic, rather than the electroosmotic nature of the water movement. It is estimated that electroosmosis cannot account for more than 1 per cent of the water movement (or turgor) in Nitella cells. The dead cellulose walls display a small electroosmotic water flow at very high current densities (under 20 volts applied potential).

Electroosmosis↗

Determination of carbamazepine and carbamazepine-10,11-epoxide in human serum and plasma by micellar electrokinetic capillary chromatography in the absence of electroosmosis.

Therapeutic drug monitoring of carbamazepine (CBZ), a widely used antiepileptic drug, is required for optimization of pharmacotherapy with this drug and for assessment of the patient's compliance to therapy. The suitability of employing micellar electrokinetic capillary chromatography (MEKC) in the absence of electroosmosis for the determination of CBZ and its main metabolite carbamazepine-10,11-epoxide (CBZE) in extracts of human serum and plasma is reported. Using micelles formed by dodecyl sulfate, analyses performed in untreated fused-silica capillaries at acidic pH and in commercially available coated capillaries under application of reversed polarity are compared. Uncoated and polyvinyl alcohol coated capillaries proved to be unsuitable for this purpose, whereas capillaries coated with linear polyacrylamide and N-acryloylaminoethoxyethanol and operated at pH 7.6 are shown to provide high-quality and reliable data on a short time scale. Assay performance is discussed via statistical analysis of the data produced from a set of quality control sera that contain up to 14 different drugs and via analysis of patient samples. Intraday and interday imprecision data for concentrations between 4.0 and 84 microM are demonstrated to be < 10%. Run times are shown to be < 50% compared to those observed in conventional MEKC at alkaline pH (i.e., in the presence of electroosmosis).

Carbamazepine↗

Contributions of electromigration and electroosmosis to peptide iontophoresis across intact and impaired skin.

d-(Arg)-Kyotorphin iontophoresis was investigated across intact and impaired skins in vitro. Iontophoretic flux increased from 68+/-12 to 538+/-116 nmol cm(-2) h(-1) when the peptide concentration in the anodal compartment was raised from 5 to 40 mM. Electromigration was the principal transport mechanism, accounting for approximately 70% of total peptide delivery. Reducing the number of competing ions in the formulation significantly increased iontophoretic flux but did not affect convective solvent flow. The latter was independent of peptide concentration indicating that skin permselectivity was not modified by kyotorphin transport. Total iontophoretic flux was unaffected when the stratum corneum was removed by tape-stripping (146+/-34 versus 150+/-26 nmol cm(-2) h(-1)). However, the contributions of the different transport mechanisms were significantly altered: (i) electromigration decreased, as more of the charge was carried by anions from the sub-dermal milieu; (ii) electroosmosis was absent; and (iii) passive permeation increased significantly. Transport rates across intact and impaired skin barriers were statistically indistinguishable when the donor electrolyte composition was modified; increased competition from anions was mitigated by the decreased Na+ levels in the formulation. Removal of Cl- ions from the receiver phase further increased peptide delivery, and also increased anodal electroosmosis.

Acetaminophen↗

Iontophoresis: electrorepulsion and electroosmosis.

Over the last 10-15 years, the electrical enhancement of drug delivery across the skin has undergone intense investigation. During this period, considerable amounts of experimental data have been generated, and the successful enhancement of a diverse array of molecules has been achieved. Indeed, the commercial exploitation of the method can be envisaged within the next few years. Despite this progress, however, the mechanistic understanding of iontophoresis remains a challenging scientific question that is yet to be fully resolved. The routes of permeation under the influence of an applied electrical potential, and the molecular interactions of the transporting drug with these pathways, have resisted unequivocal and unambiguous identification. Equally, the relative contributions of electrorepulsion and electroosmosis to the total iontophoretic flux have proven difficult to quantify, due to the difficulty of designing appropriate experiments. The situation is further complicated by the fact that it has now been established that certain lipophilic cations, in particular, can associate strongly with the skin during their iontophoretic delivery, thereby altering the electrical properties of the membrane, and changing the mechanism of transport. In this short communication, the roles of electrorepulsion and electroosmosis have been reconsidered from a simple theoretical point of view, and experimental approaches by which their relative importance may be estimated have been proposed and subjected to initial evaluation.

Administration, Cutaneous↗

Effect of direct control of electroosmosis on peptide and protein separations in capillary electrophoresis.

The separations of peptide and protein mixtures in capillary zone electrophoresis (CZE) at various solution conditions were studied with the direct control of electroosmosis. The zeta potential at the aqueous/capillary interface and the resulted electroosmosis in the presence of an electric field were directly controlled by using an additional electric field applied from outside of the capillary. The controlled electroosmotic flow affected the migration time and zone resolution of peptide and protein mixtures. The changes in the magnitude and polarity of the zeta potential caused the various degrees of peptide and protein adsorption onto the capillary through the electrostatic interactions. The separation efficiencies of peptide and protein mixtures were enhanced due to the reduction in peptide and protein adsorption at the capillary wall. The direct manipulations of the separation efficiency and resolution of peptide and protein mixtures in CZE were demonstrated by simply controlling the zeta potential and the electroosmotic flow with the application of an external electric field.

Adrenocorticotropic Hormone↗