Bulk Fluid Flow Research Articles

Machine learning-inspired study of dynamical parameters of single vapor bubble under nucleate flow boiling regime

Heat transfer performance of nucleate boiling is interlinked with the departure dynamics of vapor bubbles, which also serves as the basis for heat transfer partitioning schemes and bubble growth models. Given the fast transients and multiple bubble ebullition cycles, boiling experiments lead to voluminous data that are to be analysed for determining the bubble dynamic parameters, and subsequently, the boiling heat transfer rates. Conventional approach of manual handling of such temporal and spatially-resolved experimental data is inherently time-consuming and error-prone. In the backdrop of these limitations, importance of machine learning algorithms gets highlighted in making the entire process automated and accurate as they minimize the need of any human intervention. The present work explores the potential of machine learning techniques towards quantifying the bubble departure characteristics and heat transfer partitioning during nucleate flow boiling. Water-based experiments have been conducted in a vertical channel under varying subcooling levels (ΔTsub = 2, 5, and 8 K) and flow rates (Re = 2400, and 3600). Mask R-CNN machine learning (ML) model is employed to evaluate the temporal variations of dynamical parameters of vapor bubbles and departure characteristics. The bubble departure characteristics as well as the corresponding evaporative and convective heat transfer rates, as retrieved through ML-generated masks, showed a strong dependence on the level of bulk fluid subcooling and flow rates. Heat transfer partitioning analysis revealed a competing interplay between the evaporative and condensation components of overall boiling heat transfer rates. These findings demonstrate the potential of ML techniques towards optimizing the thermal performance of boiling phenomena that have significant implications in a range of critical engineering applications.

A Cautionary Perspective on Hydrogel-Induced Concentration Gradient Generation for Studying Chemotaxis.

The achievement of consistent and static chemical gradients is critically important in the study of diffusion and chemotaxis at the micro- and nanoscales. In this context, a number of groups have reported on hydrogel-based systems for generating concentration gradients. Here, we analyze the behavior of agarose and gelatin-based hydrogels in hybridization chambers of different heights. Our focus is on the issues that are caused by the presence of robust bulk fluid flows in such systems due to the solutes present in the hydrogel and/or the surrounding fluid. We describe the key insights derived from these experiments, offering practical guidelines for establishing gradients using hydrogel-based systems and make the community aware of different variables that can make the experiments nonreproducible and prone to misinterpretations.

Incompressible versus compressible fluid flow models: A case study on furnace tap-hole lancing

Pyrometallurgical furnaces, essential for metal extraction, operate at temperatures exceeding 1600°C and represent complex multiphase systems that challenge direct industrial research. Multiphysics models play a key role in shedding light on their intricate behaviours, supporting the refinement of design and operational strategies. Integral to the operation are the tap-holes, which facilitate the removal of molten products and are routinely opened by lancing, a process comparable to the use of a cutting torch, where high temperatures result from oxygen reacting with an iron lance. When the lance pierces the clay, oxygen gas enters the furnace, which could influence the behaviour of the molten material inside. In this work, a multiphase fluid flow model was used to investigate bulk flow dynamics, with a focus on the effects of the lancing process on the inside of the furnace, immediately behind the tap-hole. Incompressible and compressible multiphase fluid solvers were used and compared with respect their performance - the intention was to assess whether using a compressible solver would yield a different solution to the incompressible one. It was concluded that there are negligible disparities in bulk fluid flow behaviour between the solvers for the case studies examined, indicating that solver selection might be less consequential for certain aspects of oxygen lancing.

Low mass-flow operation of small-scale rotating detonation engine

The primary goal of this research was to utilize a range of oxygen/ethylene mixtures in a small-scale Rotating Detonation Engine (RDE) at low mass flow rates to achieve operational detonation frequencies above the 20 kHz threshold of human hearing. A Micro-RDE was designed with an outer diameter of 28 mm and channel gap of 2 mm that yielded detonations at a wide range of testing conditions. Flow was induced via a Jets-in-Crossflow (JIC) scheme to achieve appropriate mixing of reactants before ignition with a pre-detonator device. Two aerospike nozzles of different diameter were tested to change the backpressure on the device and detonation wave speed and frequency were determined using high-speed imagery. Most successful tests yielded two detonation heads. Wave speeds were between 1100 and 1400 m/s and test frequencies were found to be above 31 kHz, well above the audible frequency. A secondary goal of this investigation was to investigate the mixing process within the RDE. Optical access was achieved by implementing a quartz outerbody. Optical imagery of the detonation channel was captured with a Shimadzu camera for detonations ranging from equivalence ratios (Φ) of 0.2–1.7. The fuel and air mixing processes were imaged at MHz rate revealing the local variations in the equivalence ratio that the bulk fluid flow was predominantly axial.

Advances in Amyloid-β Clearance in the Brain and Periphery: Implications for Neurodegenerative Diseases.

This review examines the role of impaired amyloid-β clearance in the accumulation of amyloid-β in the brain and the periphery, which is closely associated with Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). The molecular mechanism underlying amyloid-β accumulation is largely unknown, but recent evidence suggests that impaired amyloid-β clearance plays a critical role in its accumulation. The review provides an overview of recent research and proposes strategies for efficient amyloid-β clearance in both the brain and periphery. The clearance of amyloid-β can occur through enzymatic or non-enzymatic pathways in the brain, including neuronal and glial cells, blood-brain barrier, interstitial fluid bulk flow, perivascular drainage, and cerebrospinal fluid absorption-mediated pathways. In the periphery, various mechanisms, including peripheral organs, immunomodulation/immune cells, enzymes, amyloid-β-binding proteins, and amyloid-β-binding cells, are involved in amyloid-β clearance. Although recent findings have shed light on amyloid-β clearance in both regions, opportunities remain in areas where limited data is available. Therefore, future strategies that enhance amyloid-β clearance in the brain and/or periphery, either through central or peripheral clearance approaches or in combination, are highly encouraged. These strategies will provide new insight into the disease pathogenesis at the molecular level and explore new targets for inhibiting amyloid-β deposition, which is central to the pathogenesis of sporadic AD (amyloid-β in parenchyma) and CAA (amyloid-β in blood vessels).

Numerical Simulation of Paper-Based Flow Cells during Dynamic Infiltration Phase

Microfluidic electrochemical cells are increasingly being used as power sources for energizing portable electronic devices [1]. Of particular interest is the capillary-driven flow cells because they do not need any type of micropump to establish the flow. In a recent work [2], we developed a general, robust mathematical/numerical model for designing capillary-driven, paper-based, microfluidic flow cells. The model was validated against experimental data available for a novel single-use microfluidic flow cell of this nature called PowerPAD [3]. This flow cell is activated by a drop of water when poured on its sample pad. After dissolving the solid electrolytes stored below the sample pad, the liquid electrolytes produced this way infiltrate the porous electrodes before entering the cellulosic absorbent pad situated below the porous electrodes. Soon after entering the pad, they start flowing in the lateral direction until they are brought into direct contact with each other (at some point in time) so that the electrochemical reactions can take place at the electrodes. The two liquids then continue flowing co-laminarly until the pad becomes fully-saturated and the flow rate drops to zero. The experimental data reported by the inventors of the PowerPAD actually correspond to the fully-saturated case [3]. (Under these conditions the cell works like an ordinary battery when connected to an external load.) They demonstrated that, dependent on the thickness of the absorbent pad, the cell can generate electricity for roughly an hour. In [2], we showed that, for a given electrode, by modifying the microstructure of its absorbent pad (e.g., its porosity or pore-size) and/or its flow structure the runtime of the cell can be extended to roughly three hours so that it can be used for energizing certain portable electronic devices. However, there are other prospective applications in which the power might be needed for merely a few seconds [4]. Remote sensors used for measuring/reporting the pH of acid rains belong to this category. PowerPAD can be used for such short-lived applications, but the mathematical model presented in [2] has to be refined to simulate power generation during the dynamic infiltration process, which is the objective of the present work. As the first step, Darcy’s equation is solved numerically to find the bulk velocity from which the Reynolds number is obtained and used to calculate the mass-transfer coefficient. More importantly, the Richards equations is solved numerically to find the time-dependent saturation field, S(t), which is needed for calculating the mass-transfer coefficient during the infiltration process. Here, the empirical correlation proposed by Barton and Brushett [5] for the Sherwood number (Sh) is modified to incorporate a diffusion-limited term which varies linearly with the saturation field, S(x,y,t); that is: where Re is the Reynolds number and Sc is the Schmidt number. Figure 1a shows the two-dimensional model of PowerPAD used for the simulations, which were performed using the finite-element software package COMSOL; see [2] for the details. According to the imbibition results obtained for the 4h-PAD system [3], the cell is predicted to start generating electricity after t = 0.33 s; see Fig. 1b. The system, however, needs roughly t = 20 s to become fully-saturated. Figure 1c shows the polarization curves for the 4h-PAD system at discrete times, whereas Fig. 1d shows variation of the maximum power as a function of time, up to the fully-saturated time. In these figures the discrete times (5.2, 8, 12, and 20 s) correspond, respectively, to the flow rates 11, 4.5, 0.4, and 0.01 mm3/s. According to Fig. 1d, during the transient phase the maximum power is roughly 50% larger than that for the fully-saturated case. The higher power generation during this initial infiltration process is attributed to the bulk fluid flow through the porous electrodes implying that the mass-transfer coefficients are improved through Re and Sc.

Discrete micro-physics interactions determine fracture apertures

An important question arises in relation to a rock-mass that is disrupted by an array of fractures, namely: how to quantify the evolving spatial arrangement of fracture apertures that are a major factor in bulk fluid flow processes. The approach herein employs a discrete micro-physics model of the rock texture, enabling the formulation of analytical expressions that explicitly define the fluids//geomechanics interactions that occur at the micro-scale. The resulting macro-scale responses of the model define the stress, bulk strain, and pressure states that characterise the porous rock. Via extending the discrete model by introducing a planar discontinuity, the fracture-normal bulk strain determines the status of the fracture aperture, as a consequence of the movement of the rock//fracture interface. The micro-physics model shows that a closed fracture cannot change to an open fracture by pressure changes alone; instead, bulk strain must elongate the porous rock in a direction normal to the fracture. Once opened, fracture apertures respond to changes in fluid pressure. A realistic context, within which the required bulk strain occurs, is the discontinuum geomechanics of fractured rock-mass systems, for which previous simulations exhibit a range of emergent local states that relate to the conditions, identified via the micro-physics, as being the essential controls on aperture evolution.Article highlightsDiscrete rock-texture model underpins micro-physics expressions that lead to macro-scale material response of matrix//fractureClosed fracture cannot open without local elongation normal to fracture; high pressure alone does not open fractureOpen fracture changes aperture with changing pressure

Deviation from Darcy Law in Porous Media Due to Reverse Osmosis: Pore-Scale Approach

Shale and tight hydrocarbons are vital to global energy dynamics. The fluid flow in sub-micron pores of tight oil reservoirs varies from bulk fluid flow. The Darcy law is widely accepted to model creeping flow in petroleum reservoirs. However, traditional reservoir modeling approaches fail to account for the sub-micron mechanisms that govern fluid flow. The accuracy of tight oil reservoir simulators has been improved by incorporating the influence of sub-micron effects. However, there are still factors that affect sub-micron fluid mobility that need investigation. The influence of a chemical potential gradient on fluid flow in sub-micron pores was modeled by solving Darcy and the transport and diluted species equations. The findings indicate that when a chemical potential gradient acts in the opposite direction of a hydraulic pressure gradient (reverse osmosis), there exists a limiting pressure threshold below which a non-linear flow pattern deviating from the Darcy equation is observed. Furthermore, the simulation based on tight reservoir pore parameters shows that when the effect of a chemical potential gradient is added, the resultant flux is 8–49% less. Hence, including the effect of the chemical potential gradient will improve the accuracy of sub-micron pressure dynamics and flow velocity.

The mathematical description of the bulk fluid flow and that of the content impurity dispersion, obtained by replacing integer order temporal derivatives with general temporal Caputo or general temporal Riemann-Liouville fractional order derivatives, are objective

In the field of fractional calculus applications, there is a tendency to admit that “integer-order derivatives cannot simply be replaced by fractional-order derivatives to develop fractional-order theories”. There are different arguments for that: initialization problem, inconsistency, use of nonsingular or singular kernels, loss of objectivity. In this paper it is shown that the mathematical description of the bulk fluid flow and that of the content impurity spread replacing integer order temporal derivatives with general temporal Caputo or general temporal Riemann-Liouville fractional order derivatives, are objective. More precisely, it is proven that, the mathematical description of the bulk fluid 2D flow and that of the content impurity spread, in a horizontal unconfined aquifer, obtained replacing integer order temporal derivatives with general temporal Caputo or general temporal Riemann-Liouville fractional order derivatives, are objective. It is also proven that, the mathematical description of a Newtonian, incompressible, viscous bulk fluid 3D flow and that of the contained impurity dispersion, obtained replacing integer order temporal derivatives with general temporal Caputo or general temporal Riemann-Liouville fractional order derivatives, are objective. The obtained results show the compatibility of the general temporal Caputo and general temporal Riemann-Liouville fractional order derivatives with the understanding of the “measured time” evolution. In the same time these results reveal that, the objectivity violation, when integer order temporal derivatives are replaced by classic temporal Caputo or classic temporal Riemann-Liouville fractional order derivatives, is originated in the incompatibility of the classic fractional order derivatives, with the understanding of the “measured time” evolution.

CMOS-Based Electrokinetic Microfluidics With Multi-Modal Cellular and Bio-Molecular Sensing for End-to-End Point-of-Care System.

The importance of point-of-care (POC) bio-molecular diagnostics capable of rapid analysis has become abundantly evident after the outbreak of the Covid-19 pandemic. While sensing interfaces for both protein and nucleic-acid based assays have been demonstrated with chip-scale systems, sample preparation in compact form factor has often been a major bottleneck in enabling end-to-end POC diagnostics. Miniaturization of an end-to-end system requires addressing the front-end sample processing, without which, the goal for low-cost POC diagnostics remain elusive. In this paper, we address bulk fluid processing with AC-osmotic based electrokinetic fluid flows that can be fully controlled, processed and automated by CMOS ICs, fabricated in TSMC 65 nm LP process. Here, we combine bulk fluid flow control with bio-molecular sensing, cell manipulation, cytometry, and separation-all of which are controlled with silicon chips for an all-in-one bio-sensing device. We show CMOS controlled pneumatic-free bulk fluid flow with fluid velocities reaching up to 160 μm/s within a microfluidic channel of 100 × 50 μm 2 of cross-sectional area. We incorporate electrode arrays to allow precise control and focused cell flows ( ±2 μm precision) for robust cytometry, and for subsequent separation. We also incorporate a 16-element impedance spectroscopy receiver array for cell and label-free protein sensing. The massive scalability of CMOS-driven microfluidics, manipulation, and sensing can lead to a new design space and a new class of miniaturized sensing technologies.

On the Behavior of Nanoparticles beyond the Nanopore Interface.

Recent advances in solid-state and biological nanopore sensors have produced a deluge of analytical techniques for in situ characterization of bio-nano colloidal dispersions; however, the transport forces governing particle movement into and out of the nanopore are not yet fully understood. Herein, we study the motion of particles outside the smaller opening of an elastomeric size-tunable nanopore and relate this motion to existing transport forces known to act on particles within the pore. Subsequently, we develop a combined optoelectronic approach which allows the comparison of both resistive pulse sensing and single particle tracking-based techniques for particle size characterization and, intriguingly, measurements of the ensemble particle motion induced by a combination of particle electrophoresis as well as pressure-driven and electroosmotic flows through the sensor nanopore. We find evidence suggesting that although bulk fluid flow from the pore tends to drive particle motion, in certain circumstances, electrophoretically driven motion can dominate bulk fluid flow-driven motion even at large distances from the pore opening. By permitting direct observation of the behavior of fluids at the nanopore interface, this approach enables a greater understanding of the transport forces acting on particles as they migrate toward and move through nanopore sensors-with implications for future particle characterization systems and for nanopore methods in general.

Achieving Independent Control over Surface and Bulk Fluid Flows in Microchambers

To fully realize the potential of microfluidic platforms as useful diagnostic tools, the devices must be sufficiently portable that they function at the point-of-care, as well as remote and resource-poor locations. Using both modeling and experiments, here we develop a standalone fluidic device that is driven by light and operates without the need for external electrical or mechanical pumps. The light initiates a photochemical reaction in the solution; the release of chemical energy from the reaction is transduced into the spontaneous motion of the surrounding fluid. The generated flow is driven by two simultaneously occurring mechanisms: solutal buoyancy that controls the motion of the bulk fluid and diffusioosmosis that regulates motion near the bottom of the chamber. Consequently, the bulk and surface fluid flows can be directed independently of one another. We demonstrate that this exceptional degree of spatiotemporal control provides a new method for autonomously transporting different-sized particles in opposite directions within the chamber. Thus, one device can be used to both separate the particles and drive them to different locations for further processing or analysis. This property is particularly useful for analyzing fluids that contain multiple contaminants or disease agents. Because this system relies on intrinsic hydrodynamic interactions initiated by a portable, small-scale source of light, the device provides the desired level of mobility vital for the next generation of functional fluidic platforms.

Use of computed tomography to assess subcutaneous drug dispersion with recombinant human hyaluronidase PH20 in a swine model

IntroductionSubcutaneous (SC) formulations of therapeutics with recombinant human hyaluronidase PH20 (rHuPH20) are currently approved across various disease indications. The rHuPH20-mediated enzymatic degradation of SC hyaluronan (HA) facilitates bulk fluid flow and dispersion of co-administered therapeutics. However, current methods of quantifying dispersion in the SC space are limited. Here, a novel method is outlined to quantify and follow rapid SC volumetric dispersion of a representative therapeutic fluid in the presence of rHuPH20 using computed tomography (CT). MethodsTen Yucatan miniature swine were randomized to three groups. Animals received simultaneous infusions of contrast agent (CA) alone (left side of the animal) or in combination with rHuPH20 (right side) at infusion rates of 2.5, 5, or 10 mL/min. Spiral CT scans (1.5 mm thickness) were conducted before and after the infusion and at regular time intervals throughout. Scans were used to create three-dimensional (3D) reconstructions of the fluid pockets and analyze surface area, volume, and sphericity. Results3D reconstruction showed increased dispersion of CA with rHuPH20 compared with CA alone, with fenestration and increased dispersion in the craniocaudal and lateromedial directions. The CA with rHuPH20 fluid pockets showed an average increase of 46% in surface area (p = 0.001), a 35% increase in volume (p = 0.001) and a 17% decrease in sphericity post-infusion compared with CA alone at 30 min post-infusion. DiscussionThis exploratory study confirms the value of CT imaging as a non-invasive method of assessing real-time spatial and temporal behavior of SC-administered fluids. This technique could help to assess the dispersion pattern of novel rHuPH20 SC co-formulations.

Calculation of the rate of bulk fluid flow by exponential and logarithmic expressions

A formula is presented to calculate the rate of bulk fluid flow in accord with hydrodynamic flow parameters and physical-chemical characteristics of pumping fluids. The formula was derived based on a model knowledge of fluid flow as a continuous sequence of strains — rotations of fluid fragments by the action of shear stress. Laboratory testing of volumetric flow rate depending on the hydrodynamic flow parameters and physical-chemical properties of liquids performed on a turbulent rheometer and as working fluids used ethanol and gasoline. The power and logarithmic dependences of the volume velocity were also checked using real data from the operation of oilfield pipelines. The results obtained satisfactory agree with the calculated data.

Mathematical description of the bulk fluid flow and that of the contained impurity dispersion which uses Caputo or Riemann-Liouville fractional order partial derivatives is nonobjective

In this paper it is shown that the mathematical description of a Newtonian, incompressible, viscous bulk fluid flow and that of the contained impurity dispersion which uses Caputo or Riemann-Liouville fractional order derivative, having integral representation on finite interval, is nonobjective. This means that, two different observers describing the flow or the contained impurity dispersion with these tools obtain two different results which cannot be reconciled i.e. transformed into each other using only formulas that link the coordinates of a point in two fixed orthogonal reference frames and formulas that link the numbers representing a moment of time in two different choices of the origin of time measuring. This is not an academic curiosity! It is rather a problem: which of the obtained results is correct?

Cells in New Light: Ion Concentration, Voltage, and Pressure Gradients across a Hydrogel Membrane.

The ionic compositions of the intra- and extracellular environments are distinct from one another, with K+ being the main cation in the cytosol and Na+ being the most abundant cation outside of the cell. Specific ions can permeate into and out of the cell at different rates, bringing about uneven distribution of charges and development of negative electric potential inside the cell. Each healthy cell must maintain a specific ion concentration gradient and voltage. To account for these functions, various ionic pumps and channels located within the cell membrane have been invoked. In this work, we use a porous alginate hydrogel as a model gelatinous network representing the plant cell wall or cytoskeleton of the animal cell. We show that the gel barrier is able to maintain a stable separation of ionic solutions of different ionic strengths and chemical compositions without any pumping activity. For the Na+/K+ concentration gradient sustained across the barrier, a negative electric potential develops within the K+-rich side. The situation is reminiscent of that in the cell. Furthermore, also the advective flow of water molecules across the gel barrier is restricted, despite the gel’s large pores and the osmotic or hydrostatic pressure gradients across it. This feature has important implications for osmoregulation. We propose a mechanism in which charge separation and electric fields developing across the permselective (gel) membrane prevent ion and bulk fluid flows ordinarily driven by chemical and pressure gradients.

Seismic Imaging of Convective Geothermal Flow Systems to Increase Well Productivity

A core feature of convective geothermal resource production is wellbore energy flow Q ~ ρC x T x V. E.g., for wellbore fluid of volume heat capacity ρC ~ 4.3MJ/m3∙oC, temperature T ~ 230oC, and volumetric flow V ~ 50L/s, wellbore heat energy production is Q~ 50MWth ~ 5MWe. Wellbore fluid flow V =2πr0φv0ℓ for open wellbore length ℓ is given in turn by the spatially variable product crustal porosity times crustal fluid velocity v ≡ φv0 at the wellbore radius r0. For a geothermal wellbore to be productive (nominal Q ~ 5MWe), locally variable bulk inflow rates v = φv0 across crustal volumes of dimension ℓ must be adequate to sustain high wellbore flows (nominal V ~ 50L/s). Wide-ranging crustal well productivity statistics show that few crustal wells flow at these rates. This is not surprising as local bulk flow ~ 10-2 m/s needed for production wellbores is decades greater than ambient bulk fluid flow ~ 10-8-10-7m/s characteristic of natural convective geothermal systems. Such rare high flow locales must be found. While existing crustal surveys generally fix resource temperatures T with nominal 500m spatial resolution, as yet no survey technique provides data to locate production-grade flow rates at nominal ℓ ~ 50m spatial resolution. In consequence, many costly unproductive wells are drilled before sites of productive local geothermal fluid bulk flow v = φv0 ~ 10-2 m/s are located. A seismic survey methodology sensitive to crustal flow v = φv0 at ℓ ~25m resolution has evolved from multi-channel seismic reflection technology applied to the production of shale hydrocarbons. The field-proven seismic flow-imaging methodology can be adapted from sedimentary terrains to volcanic terrains through appropriate seismic refraction means for generating effective seismic velocity models for convective geothermal flow volumes. Numerical simulation for characteristic ambient crustal heterogeneous flow distributions v = φv0 at ℓ ~50m resolution shows that travel-time data for seismic source energy refracted from deep geothermal wellbores to surface seismic sensor arrays can replicate the multi-channel seismic flow-imaging capability demonstrated for shale formations. Multi-channel seismic reservoir flow monitor detection and mapping of flow-induced seismic emissions in shale formations can be adapted to achieve similar mapping of convective geothermal flow system structures with v = φv0 ~ 10-2m/s at nominal ℓ ~ 50m resolution. Such seismic emission flow structure maps can greatly reduce the uncertainty and hence the cost of drilling effective production wells at brownfield sites and assessment/development wells at greenfield sites

Mathematical Description of the Groundwater Flow and that of the Impurity Spread, which Use Temporal Caputo or Riemann–Liouville Fractional Partial Derivatives, Is Non-Objective

In this paper, it is shown that the mathematical description of the bulk fluid flow and that of content impurity spread, which uses temporal Caputo or temporal Riemann–Liouville fractional order partial derivatives, having integral representation on a finite interval, in the case of a horizontal unconfined aquifer is non-objective. The basic idea is that different observers using this type of description obtain different results which cannot be reconciled, in other words, transformed into each other using only formulas that link the numbers representing a moment in time for two different choices from the origin of time measurement. This is not an academic curiosity; it is rather a problem to find which one of the obtained results is correct.

Behavioral and electrophysiological evidence for a neuroprotective role of aquaporin-4 in the 5xFAD transgenic mice model

Aquaporin-4 (AQP4) has been suggested to be involved in the pathogenesis of neurodegenerative diseases including Alzheimer’s disease (AD), which may be due to the modulation of neuroinflammation or the impairment of interstitial fluid bulk flow system in the central nervous system. Here, we show an age-dependent impairment of several behavioral outcomes in 5xFAD AQP4 null mice. Twenty-four-hour video recordings and computational analyses of their movement revealed that the nighttime motion of AQP4-deficient 5xFAD mice was progressively reduced between 20 and 36 weeks of age, with a sharp deterioration occurring between 30 and 32 weeks. This reduction in nighttime motion was accompanied by motor dysfunction and epileptiform neuronal activities, demonstrated by increased abnormal spikes by electroencephalography. In addition, all AQP4-deficient 5xFAD mice exhibited convulsions at least once during the period of the analysis. Interestingly, despite such obvious phenotypes, parenchymal amyloid β (Aβ) deposition, reactive astrocytosis, and activated microgliosis surrounding amyloid plaques were unchanged in the AQP4-deficient 5xFAD mice relative to 5xFAD mice. Taken together, our data indicate that AQP4 deficiency greatly accelerates an age-dependent deterioration of neuronal function in 5xFAD mice associated with epileptiform neuronal activity without significantly altering Aβ deposition or neuroinflammation in this mouse model. We therefore propose that there exists another pathophysiological phase in AD which follows amyloid plaque deposition and neuroinflammation and is sensitive to AQP4 deficiency.

A Preclinical Investigation into the Effects of Aging on Dermal Hyaluronan Properties and Reconstitution Following Recombinant Human Hyaluronidase PH20 Administration.

IntroductionThere is currently no consensus in the literature concerning the impact of aging on the properties of hyaluronan (HA) in the subcutaneous (SC) space. Recombinant human hyaluronidase PH20 (rHuPH20) facilitates SC administration of injected therapeutics by depolymerizing SC HA, facilitating bulk fluid flow, dispersion and absorption. This study assessed the impact of intrinsic aging on HA in the SC space and thus the ability of rHuPH20 to enhance delivery of co-administered therapeutics.MethodsHistologic evaluations of HA levels and degradation were performed on human skin samples from six age groups, aged from 20 to 100 years. HA levels were evaluated by HA staining and degradation by staining samples for HA following incubation with rHuPH20. HA was extracted from samples and HA size determined by gel electrophoresis. Dermal reconstitution was assessed in young (aged 1.5 months) and elderly (aged > 16 months) mice. Baseline dye dispersion was measured at 5 and 20 min post-intradermal dye injection. Following treatment with rHuPH20, dye dispersion was measured again at 2, 24, 48, 72 and 96 h.ResultsDistribution of HA was confined to the interstitial space between adipocytes, with similar pericellular presence and levels of HA found across all age groups. Substantial levels of high-molecular-weight HA were observed in all age groups at baseline. Incubation with a clinically relevant dose of rHuPH20 resulted in degradation of all SC HA and similar degradation profiles independent of age. No difference in dye dispersion time was observed between young and elderly mice across the range of time points assessed, with dye dispersion returning to baseline levels by 24 h after rHuPH20 treatment.ConclusionsSubcutaneous delivery of approved therapeutics facilitated by co-administration with rHuPH20 should not be impacted by intrinsic aging, with this study providing no evidence for an effect of aging on HA distribution, structure or a loss of rHuPH20 efficacy.