Bulk Fluid Flow Research Articles

Rapid pKa estimation using vacuum‐assisted multiplexed capillary electrophoresis (VAMCE) with ultraviolet detection

A rapid approach for estimating the pKa value of small organic molecules was developed using vacuum‐assisted multiplexed capillary electrophoresis (VAMCE) with ultraviolet detection. The VAMCE method employed a 96‐capillary array, arranged in a standard 8 × 12 microtiter plate configuration, with each row of capillaries filled with 12 individual running buffers of equal ionic strength (I = 50 mM) covering a pH range from 2.2 to 10.7. A separate compound was injected hydrodynamically into each row of capillaries allowing the estimation of pKa values for eight compounds in a single run. The application of a vacuum during the separation generated a bulk fluid flow and allowed the electrophoretic separation to be completed within 5 min. The complete VAMCE method, conditioning, and electrophoretic separation was optimized to allow the pKa estimation for between 128 to 168 compounds in an 8‐h period. The VAMCE method provided a reliable approach for estimating pKa values both within‐ and between‐day. The pKa values for a series of 96 compounds estimated by VAMCE agreed well with some of literature pKa values with an average absolute difference of 0.22 log units. © 2005 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:576–589, 2005

A Simple Correlation for Estimating Pressure Drop in Horizontal Wells

Even though it has long been recognized that pressure drop along a horizontal wellbore cannot be neglected, little has been done to estimate the pressure drop with any rigor. The existing models are derived from pipeflow equations, therefore neglecting the presence of radial fluid movement perpendicular to the direction of bulk fluid flow. Recent experimental studies indicate that such a simplistic approach provides an optimistic behavior in a horizontal wellbore. This article presents a realistic representation of the pressure drop in a horizontal wellbore. Equations are derived from rigorous experiments conducted earlier and reported in the literature. They include the effect of radial fluid movement, perforation flow, gas-oil ratio, oil viscosity, bulk flow rate, water saturation and even the presence of asphaltenes in the crude oil. Even though the equations are based on experimental results, predictions apply to field situations. This aspect is verified with certain unpublished field data from USA and Canada.

DNA-templated nanowire fabrication.

DNA-based nanotechnology is a vibrant and expanding field. The specific molecular recognition properties and large aspect ratio of DNA make the molecule a promising template for bottom-up fabrication of nanowires and nanodevices. Fabricating well-defined DNA-templated nanowires requires aligned surface deposition and specific metallization of DNA molecules. DNA localization on surfaces has been achieved by bulk fluid flow or a moving air-water interface, and localization efficiency has been improved by surface modifications that favor DNA-substrate interaction. DNA-templated nanowires have been constructed from gold, silver, copper, palladium, and platinum, and template modifications have allowed the bottom-up construction of a simple electronic nanodevice. These achievements demonstrate the promising feasibility of using bottom-up nanofabrication to create increasingly sophisticated nanodevices.

Numerical and laboratory investigations of electrical resistance tomography for environmental monitoring

Numerical and laboratory studies have been conducted to test the ability of Electrical Resistance Tomography - a technique used to map the electrical resistivity of the subsurface - to delineate contaminant plumes. Two-dimensional numerical models were created to investigate survey design and resolution. Optimal survey design consisted of both downhole and surface electrode sites. Resolution models revealed that while the bulk fluid flow could be outlined, small-scale fingering effects could not be delineated. Laboratory experiments were conducted in a narrow glass tank to validate theoretical models. A visual comparison of fluid flow with ERT images also showed that, while the bulk fluid flow could be seen in most instances, fine-scale effects were indeterminate.

Electrokinetic Stretching of Tethered DNA

During electrophoretic separations of DNA in a sieving medium, DNA molecules stretch from a compact coil into elongated conformations when encountering an obstacle and relax back to a coil upon release from the obstacle. These stretching dynamics are thought to play an important role in the separation mechanism. In this article we describe a silicon microfabricated device to measure the stretching of tethered DNA in electric fields. Upon application of an electric field, electro-osmosis generates bulk fluid flow in the device, and a protocol for eliminating this flow by attaching a polymer brush to all silicon oxide surfaces is shown to be effective. Data on the steady stretching of DNA in constant electric fields is presented. The data corroborate the approximate theory of hydrodynamic equivalence, indicating that DNA is not free-draining in the presence of both electric and nonelectric forces. Finally, these data provide the first quantitative test of a Stigter and Bustamante's detailed theory of electrophoretic stretching of DNA without adjustable parameters. The agreement between theory and experiment is good.

Ion concentrations and velocity profiles in nanochannel electroosmotic flows

Ion distributions and velocity profiles for electroosmotic flow in nanochannels of different widths are studied in this paper using molecular dynamics and continuum theory. For the various channel widths studied in this paper, the ion distribution near the channel wall is strongly influenced by the finite size of the ions and the discreteness of the solvent molecules. The classical Poisson–Boltzmann equation fails to predict the ion distribution near the channel wall as it does not account for the molecular aspects of the ion–wall and ion–solvent interactions. A modified Poisson–Boltzmann equation based on electrochemical potential correction is introduced to account for ion–wall and ion–solvent interactions. The electrochemical potential correction term is extracted from the ion distribution in a smaller channel using molecular dynamics. Using the electrochemical potential correction term extracted from molecular dynamics (MD) simulation of electroosmotic flow in a 2.22 nm channel, the modified Poisson–Boltzmann equation predicts the ion distribution in larger channel widths (e.g., 3.49 and 10.00 nm) with good accuracy. Detailed studies on the velocity profile in electro-osmotic flow indicate that the continuum flow theory can be used to predict bulk fluid flow in channels as small as 2.22 nm provided that the viscosity variation near the channel wall is taken into account. We propose a technique to embed the velocity near the channel wall obtained from MD simulation of electroosmotic flow in a narrow channel (e.g., 2.22 nm wide channel) into simulation of electroosmotic flow in larger channels. Simulation results indicate that such an approach can predict the velocity profile in larger channels (e.g., 3.49 and 10.00 nm) very well. Finally, simulation of electroosmotic flow in a 0.95 nm channel indicates that viscosity cannot be described by a local, linear constitutive relationship that the continuum flow theory is built upon and thus the continuum flow theory is not applicable for electroosmotic flow in such small channels.

NANOLEVEL MAGNETIC SEPARATION MODEL CONSIDERING FLOW LIMITATIONS

This work proposes an enhanced nanolevel magnetic separation model considering flow limitations using simplifying assumptions. The theoretical model builds on magnetic heteroflocculation models described in the literature and couples the magnetic and hydrodynamic forces between two spherical particles with different sizes and different magnetic properties under bulk fluid flow conditions. Separator performance figures are presented showing the relationship between input parameters such as applied magnetic field strength, flow rate, and matrix material size and composition, and output parameters such as Peclet number and capture propensity for various contaminant particle sizes. This purely predictive model work may be useful in estimating actual magnetic separator performance and serve as a starting point for experimental work or more accurate mathematical models. This work provides a simplified mathematical model to predict magnetic separator performance based on single magnetic matrix particle and single magnetic contaminant particle interactions. Local maxima, or transition points, between matrix and contaminant particle size and separator performance indicate magnetic separator performance can be optimized by the selection of appropriate magnetic matrix particle size. Evaluation of points of maximum particle capture force using the Peclet number provides limiting conditions for retention of particles under Stokes flow conditions.

Fluid flow induced by nonuniform ac electric fields in electrolytes on microelectrodes. III. Observation of streamlines and numerical simulation.

The application of a nonuniform ac electric field to an electrolyte using coplanar microelectrodes results in steady fluid flow. The flow has its origin in the interaction of the tangential component of the nonuniform field with the induced charge in the electrical double layer on the electrode surfaces. Termed ac electro-osmosis, the flow has been studied experimentally and theoretically using linear analysis. This paper presents experimental observations of the fluid flow profile obtained by superimposing images of particle movement in a plane normal to the electrode surface. These experimental streamlines demonstrate that the fluid flow is driven at the surface of the electrodes. Experimental measurements of the impedance of the electrical double layer on the electrodes are also presented. The potential drop across the double layer at the surface of the electrodes is calculated numerically using a linear double layer model, and also using the impedance of the double layer obtained from experimental data. The ac electro-osmotic flow at the surface of the electrodes is then calculated using the Helmholtz-Smoluchowski formula. The bulk fluid flow driven by this surface velocity is numerically calculated as a function of frequency and good agreement is found between the numerical and experimental streamlines.

Brain Clearance of Alzheimer's Amyloid-β40 in the Squirrel Monkey: A SPECT Study in a Primate Model of Cerebral Amyloid Angiopathy

Squirrel monkey is a valuable model to study pathogenesis of cerebrovascular amyloid angiopathy (CAA). Previous studies suggested that circulating amyloid- β 40 peptide (A β 40) crosses the blood-brain barrier (BBB) and may therefore enhance cerebrovascular amyloidosis in aged squirrel monkeys. In the present study, we used single photon emission computed tomography (SPECT) to determine elimination of 123 I-A β 40 and 99m Tc-DTPA, an extracellular marker, from the brain in squirrel monkeys at different age. Following intracerebral microinfusions, the time-activity brain clearance curves indicated bi-exponential removal of 123 I-A β 40 with an initial rapid washout (1.1 ≤ t 1/2 ≤ 2.7 h). This, plus the observed appearance of 123 I-radioactivity in plasma suggest significant brain-to-blood transport. In contrast, 99m Tc-DTPA was removed slowly by brain interstitial fluid bulk flow (monoexponential decay with 6.8 ≤ t 1/2 ≤ 16.8 h) . A comparison of three middle aged (11-16 years old) vs. two old (22 yrs old) monkeys was consistent with an age-related decline in the BBB capacity to remove 123 I-A β from the brain. This correlated with an age-dependent increase in A β 40/42 cerebrovascular immunoreactivity and amyloid deposition. Thus, vascular clearance plays an important role in reducing A β levels in the squirrel monkey brain and impaired A β 40 elimination across the BBB may contribute to the development of CAA.

Evolution of bulk composition, mineralogy, strain style and fluid flow during an HT–LP metamorphic event: sillimanite zone of the Catalan Coastal Ranges Variscan basement, NE Iberia

Metamorphic rocks in the Osor complex (Guilleries massif, NE Iberian Peninsula) show the following structural and compositional features: strong differentiation into quartz-rich gneissic semipelitic and quartz-absent, mica-rich schistose bands, higher density of igneous (both basic and leucogranitic) and quartz veins in the schistose domains and strong strain partitioning in the pelitic bands. Garnet is present in both kinds of lithologies, showing also differential textural and chemical features interpreted to be dependent on bulk composition, deformation and fluid interaction histories. Textures, mineral composition and thermobarometry suggest the operation of concurrent mechanical, mass transfer and thermal phenomena such as: (1) variations in strain style, (2) fluid infiltration, (3) magmatic injection and (4) HT–LP metamorphic and metasomatic episodes. The following sequence of events is suggested: initially the cooling of syntectonic high- T basic quartz diorite sheets promoted high strain rates, low d P/d T thermobaric evolution, incipient anatexis in the pelitic bands and devolatilization through a pervasive to vein-channelized prograde fluid flow. The prograde flow enhanced an ongoing compositional tectono-metamorphic differentiation and produced metasomatism through depletion of the Osor rocks in alkalis and calcium. Later injection and cooling of peraluminous leucogranitoid sheets, preferentially along pelitic bands, increased the ratio of magmatic/metamorphic components in the fluids and strongly enriched them in alkalis producing a second metasomatic episode. During crystallization of quartz and leucogranitoid veins, the pelitic bands were strongly enriched back again in alkalis, promoting the blastesis of big crystals of post-peak muscovite and albite as well as the retrogression of garnet. The metasomatic mica-rich levels must have been the preferred locus for development of a new deformation style dominated by shear band fabrics in metapelites and related to a release of the gravitational instability originated previously due to crustal thickening. The increasing decompressional component of the retrograde P– T path also suggests that this style of deformation was prevalent during, if not responsible for, a phase of exhumation of the metamorphic complex. It is suggested that similar patterns of thermomechanical and mass transfer phenomena could well be a fundamental characteristic common to all HT–LP metamorphic belts.

Flow visualization through spacer filled channels by computational fluid dynamics I.: Pressure drop and shear rate calculations for flat sheet geometry

Computational fluid dynamics (CFD) simulations were carried out for fluid flow through rectangular channels filled with several commercially available spacers for membrane modules. Simulation results were compared with literature experimental data. Excellent agreement was found between the experimentally determined dependence of the total drag coefficient on the Reynolds number and the CFD simulations in this work. Analysis of the flow structure through spacer filled channels revealed that bulk of the fluid does not change direction at each mesh as suggested previously in the literature, but that the bulk fluid flows parallel to the spacer filaments. The pressure drop through the channel was found to be largely governed by a loss of fluid momentum caused due to an almost abrupt change in the direction of the velocity vectors across a thin transition plane corresponding to the plane of intersection of the spacer filaments. It was observed that spacers with equal filament diameters usually result in a higher pressure drop across the channel and such symmetric spacers also result in a more uniform shear rate at the top and bottom faces of the test cell. Asymmetric spacers (spacers with unequal filament diameters) resulted in lower pressure drop and also induced unequal shear rate on the top and bottom faces of the test cell. Such unequal shear rates at the top and bottom faces would be expected to have an adverse impact on the membrane module performance because of different mass transfer characteristics for adjacent membrane leaves. It was found that a higher overall bulk turbulent flow would not necessarily result in higher shear rates at the top and bottom faces.

An in vitro investigation of the bulk flow of fluid through apical foramina during simulated tooth extraction: a potential confounder in microbiological studies?

Aim The ‘pumping action’ induced during tooth extraction may cause bacteria suspended in tissue fluids to be transposed from one anatomical compartment to another. Apart from causing bacteraemia, this may lead to inaccuracies in studies evaluating the presence and distribution of bacteria in and around tooth apices. The aim was to investigate the bulk flow of fluid through apical foramina during simulated extraction of teeth in an in vitro model. The influence of the presence or absence of a coronal restoration was also evaluated. Methodology Twenty extracted single‐rooted, human, mature, permanent teeth were used. Standard access cavities were prepared and the root canals located. Standardized micrographs of the apical foramina were obtained and their area (µm2) was calculated by image analysis software. The teeth were then set and sealed into polyvinylsiloxane (rubber base) impression material. Crystal violet dye was inoculated into the coronal half of the root canal system. Tooth extraction movements were simulated in the impression matrix and the leakage of dyes with and without the presence of a coronal restoration was examined. The procedure was repeated, following application of safranin dye in a coronal trough within the simulated rubber base gingival margin at the CEJ. The results were analysed statistically with the independent‐samples t‐test and the McNemar test. Results In the absence of a coronal restoration crystal violet leaked out of the apical foramina in 18/20 teeth; conversely safranin leaked into the teeth through the apical foramina in 11/20 cases when applied to the external root surface. In the presence of an intact coronal restoration crystal violet dye leaked out in 6/20 teeth and conversely safranin leaked into 7/20 teeth. The presence of a coronal restoration significantly reduced (P = 0.002) dye leakage out of the root canal system. No associations were found for leakage of dye into the root canal system when applied externally. In addition, the amount of dye leakage was positively correlated with the area of the apical foramen in the presence of a coronal restoration (P = 0.009). Conclusion The presence of a coronal restoration significantly reduced leakage of dye out of the apical foramen. Microbiological studies on root canals and periapical lesions using extracted teeth should take potential contamination from this source into account.

The role of electroosmotic flow in transdermal iontophoresis

Iontophoresis enhances transdermal drug delivery by three mechanisms: (a) the ion-electric field interaction provides an additional force which drives ions through the skin; (b) flow of electric current increases permeability of skin; and (c) electroosmosis produces bulk motion of the solvent itself that carries ions or neutral species, with the solvent ‘stream’. The relative importance of electroosmotic flow is the subject of this review. Experimental observations and theoretical concepts are reviewed to clarify the nature of electroosmotic flow and to define the conditions under which electroosmotic flow is an important effect in transdermal iontophoresis. Electroosmotic flow is bulk fluid flow which occurs when a voltage difference is imposed across a charged membrane. Electroosmotic flow occurs in a wide variety of membranes, is always in the same direction as flow of counterions and may either assist or hinder drug transport. Since both human skin and hairless mouse skin are negatively charged above about pH 4, counterions are positive ions and electroosmotic flow occurs from anode to cathode. Thus, anodic delivery is assisted by electroosmosis, but cathodic delivery is retarded. Water carried by ions as ‘hydration water’ does not contribute significantly to electroosmotic flow. Rather electroosmotic flow is caused by an electrical volume force acting on the mobile counterions. The simple ‘limiting law’ theory commonly given in textbooks and some research articles is a very poor approximation for transdermal systems. However, several extensions of the limiting law are compatible with each other and with the available experimental data. One of these theories, the Manning theory, has been incorporated into a theory for the effect of electroosmotic flow on iontophoresis, the latter theory being in good agreement with experiment. Both theory and experimental data indicate that electroosmotic flow increases in importance as the size of the drug ion increases. The ‘ionic’ or Nernst–Planck effect is the largest contributor to flux enhancement for small ions. Increased skin permeability or the skin ‘damage effect’, is a significant factor for both large and small ions, particularly for experiments at high current density. For monovalent ions with Stokes radii larger than about 1 nm, electroosmotic flow is the dominant flow mechanism. Because of electroosmotic flow, transdermal delivery of a large anion (or negatively charged protein) from the anode compartment can be more effective than delivery from the cathode compartment.

Pumping of water with ac electric fields applied to asymmetric pairs of microelectrodes.

Bulk fluid flow induced by an ac electric potential with a peak voltage below the ionization potential of water is described. The potential is applied to an ionic solution with a planar array of electrodes arranged in pairs so that one edge of a large electrode is close to an opposing narrow electrode. During half the cycle, the double layer on the surface of the electrodes charges as current flows between the electrodes. The electrodes charge in a nonuniform manner producing a gradient in potential parallel to the surface of the electrodes. This gradient drives the ions in the double layer across the surface of the electrode and this in turn drags the fluid across the electrode surface. The anisotropic nature of the pairs of electrodes is used to produce a net flow of fluid. The flow produced is approximately uniform at a distance from the electrodes that is greater than the periodicity of the electrode array. The potential and frequency dependence of this flow is reported and compared to a simple model. This method of producing fluid flow differs from electrical and thermal traveling-wave techniques as only a low voltage is required and the electrode construction is much simpler.

Osmotic opening of the blood-brain barrier: principles, mechanism, and therapeutic applications.

1. Osmotic opening of the blood-brain barrier by intracarotid infusion of a hypertonic arabinose or mannitol solution is mediated by vasodilatation and shrinkage of cerebrovascular endothelial cells, with widening of the interendothelial tight junctions to an estimated radius of 200 A. The effect may be facilitated by calcium-mediated contraction of the endothelial cytoskeleton. 2. The marked increase in apparent blood-brain barrier permeability to intravascular substances (10-fold for small molecules) following the osmotic procedure is due to both increased diffusion and bulk fluid flow across the tight junctions. The permeability effect is largely reversed within 10 min. 3. In experimental animals, the osmotic method has been used to grant wide access to the brain of water-soluble drugs, peptides, antibodies, boron compounds for neutron capture therapy, and viral vectors for gene therapy. The method also has been used together with anticancer drugs to treat patients with metastatic or primary brain tumors, with some success and minimal morbidity.

An experimental study of the reactive surface area of the Fontainebleau sandstone as a function of porosity, permeability, and fluid flow rate

Reactive surface areas of Fontainebleau sandstone were measured as a function of porosity, permeability, and bulk fluid flow rate. Reactive surface areas were obtained by comparing the steady-state outlet Si concentration of flow-through experiments performed on sandstone cores with quartz dissolution rates normalized to BET surface areas obtained from ground cleaned samples of this sandstone. All experiments were performed at 80°C and far from equilibrium conditions using a 0.1 M NaCl + 0.01 M NaOH input solution having an in situ pH of 10.4. Measured reactive surface areas increase from ∼20 to ∼170 cm −1 with increasing porosity from 5.1 to 16.6%, respectively. These surface areas are similar to those predicted either by assuming the sandstone consists of a idealized spherical pore array or by using the Canals and Meunier (1995) intergrown sphere model. These geometric models, therefore, likely provide reasonable estimates of the reactive surface area of non-fractured porous media. Permeability measured in situ increases exponentially with increasing porosity, in good agreement with previous measurements. Both permeability and reactive surface area increased with increasing bulk flow rate. However, reactive surface area attained a steady-state at high flow rates whereas permeability increased continuously. This increase is probably due to a widening of connecting pore channels in response to increasing pore fluid pressure.

Mass transfer in gas-sparged ultrafiltration: upward slug flow in tubular membranes

Gas sparging is recognized as an effective way to increase permeate flux in ultrafiltration processes. This paper discusses the mechanism of flux enhancement in ultrafiltration processes by gas sparging, in the special case of upward slug flow in tubular membrane module. An attempt is made to model gas sparged ultrafiltration with a view to predicting permeate flux in such processes. The model is based on dividing the region near the gas slug into three different zones depending on the nature of flow in the vicinity of the membrane. These different zones are (a) the film zone, where there is falling film flow, (b) wake zone, which is a region of free turbulence, and (c) liquid slug zone, where the flow could be either streamline or turbulent depending on the bulk fluid flow. The mass transfer coefficients for each of these zones can be determined for a particular feed solution, and from these, the averaged permeate flux for gas sparged ultrafiltration can be calculated. The model was tested for ultrafiltration of 167 kDa dextran. A reasonably good agreement between experimental and theoretically predicted data was obtained. The discrepancies observed are discussed. Simulations were run in order to examine the effects of operational parameters on permeate flux. The results suggest that gas sparging is more effective at higher transmembrane pressure, and increasing the liquid flow rate has opposite effects in single phase flow and gas-sparged ultrafiltration.

Observation of thick biofilm accumulation and structure in porous media and corresponding hydrodynamic and mass transfer effects

A series of flat plate, porous media reactor studies was performed to characterize the development and structure of thick biofilms in porous media and the subsequent effects on porous media hydrodynamics and mass transport variables including average pore velocity, hydrodynamic dispersivity, and (dye tracer) breakthrough curve features. Biofilms composed of either a mucoid strain of Pseudomonas aeruginosa or a non-mucoid strain of Ps. aeruginosa were established in the reactors over a 2-3 week period. Analysis of porous media biofilms was performed using a combination of image analysis, photography, microbial vital stains, enumerations, and microscopy. Bulk fluid flow and flow channel distribution in the porous media/biofilm matrix were monitored by imaging a pulse of nigrosine dye. Hydrodynamics of the systems were determined by evaluating fluorescein dye breakthrough curves. Destructive sampling of the flat plate reactors at the end of each study provided additional information on the distribution and cell density of the porous media biofilms. Imaging results indicated the creation and closure of flow channels within the biofilm/porous media matrix for both mucoid and non-mucoid strains. Both systems exhibited accelerated tracer breakthrough and slightly increased hydrodynamic dispersivity as the biofilm matrix developed. Gray scale analysis of nigrosine pulses, along with fluorescein dye studies, suggests that biofilm development transforms the flow regime within the reactor from well defined porous media flow with a symmetric breakthrough curve to a skewed breakthrough curve with accelerated time to breakthrough.

Observation of thick biofilm accumulation and structure in porous media and corresponding hydrodynamic and mass transfer effects

A series of flat plate, porous media reactor studies was performed to characterize the development and structure of thick biofilms in porous media and the subsequent effects on porous media hydrodynamics and mass transport variables including average pore velocity, hydrodynamic dispersivity, and (dye tracer) breakthrough curve features. Biofilms composed of either a mucoid strain of Pseudomonas aerugtnosa or a non-mucoid strain of Ps. aeruginosa were established in the reactors over a 2–3 week period. Analysis of porous media biofilms was performed using a combination of image analysis, photography, microbial vital stains, enumerations, and microscopy. Bulk fluid flow and flow channel distribution in the porous medralbiofilm matrix were monitored by imaging a pulse of nigrosine dye. Hydrodynamics of the systems were determined by evaluating fluorescein dye breakthrough curves. Destructive sampling of the flat plate reactors at the end of each study provided additional information on the distribution and cell density of the porous media biofilms. Imaging results indicated the creation and closure of flow channels within lie biofilm/porous media matrix for both mucoid and non-mucoid strains. Both systems exhibited accelerated tracer breakthrough and slightly increased hydrodynamic dispersivity as the biofilm matrix developed. Gray scale analysts of nigrosine pulses, along with fluorescein dye studies, suggests that biofilm development transforms the flow regime within the reactor from well defined porous media flow with a symmetric breakthrough curve to a skewed breakthrough curve with accelerated time to breakthrough.

Chronic interstitial infusion of protein to primate brain: determination of drug distribution and clearance with single-photon emission computerized tomography imaging.

High-flow interstitial infusion into the brain, which uses bulk fluid flow to achieve a relatively homogeneous drug distribution in the extracellular space of the brain, has the potential to perfuse large volumes of brain. The authors report reproducible long-term delivery of 111In-diethylenetriamine pentaacetic acid-apotransferrin (111In-DTPA-Tf) (molecular mass 81 kD) to Macaca mulatta brain and monitoring with single-photon emission computerized tomography (SPECT). The 111In-DTPA-Tf was infused at 1.9 microl/minute over 87 hours into the frontal portion of the centrum semiovale using a telemetry-controlled, fully implanted pump. On Days 1, 3, 4, 8, 11, and 15 after beginning the infusion, planar and SPECT scans of 111In-DTPA-Tf were obtained. Spread of protein in the brain ranged from 2 to 3 cm and infusion volumes ranged from 3.9 to 6.7 cm3. Perfusion of over one-third of the white matter of the infused hemisphere was achieved. From brain SPECT images of (99m)Tc-hexamethylpropyleneamine oxime, which was administered intravenously before each 111In scan, the authors also found that blood perfusion in the infused region was reduced by less than 5% relative to corresponding noninfused regions. Histological examination at 30 days revealed only mild gliosis limited to the area immediately surrounding the needle tract. These findings indicate that long-term interstitial brain infusion is effective for the delivery of drugs on a multicentimeter scale in the primate brain. The results also indicate that it should be possible to perfuse targeted regions of the brain for extended intervals to investigate the potential utility of neurotrophic factors, antitumor agents, and other materials for the treatment of central nervous system disorders.