Aquaporin-4 water channels play a central role in brain water regulation in neurological disorder... more Aquaporin-4 water channels play a central role in brain water regulation in neurological disorders. Aquaporin-4 is abundantly expressed at the astroglial endfeet facing the cerebral vasculature and the pial membrane, and both its expression level and subcellular localization significantly influence brain water transport. However, measurements of aquaporin-4 levels in animal models of brain injury often report opposite trends of change at the injury core and the penumbra. Furthermore, aquaporin-4 channels play a beneficial role in brain water clearance in vasogenic edema, but a detrimental role in cytotoxic edema and exacerbate cell swelling. In light of current evidence, we still do not have a complete understanding of the role of aquaporin-4 in brain water transport. In this review, we propose that the regulatory mechanisms of aquaporin-4 at the transcriptional, translational, and post-translational levels jointly regulate water permeability in the short and long time scale after i...
Spinal microstructures are known to substantially affect cerebrospinal fluid patterns, yet their ... more Spinal microstructures are known to substantially affect cerebrospinal fluid patterns, yet their actual impact on flow resistance has not been quantified. Because the length scale of microanatomical aspects is below medical image resolution, their effect on flow is difficult to observe experimentally. Using a computational fluid mechanics approach, we were able to quantify the contribution of micro-anatomical aspects on cerebrospinal fluid (CSF) flow patterns and flow resistance within the entire central nervous system (CNS). Cranial and spinal CSF filled compartments were reconstructed from human imaging data; microscopic trabeculae below the image detection threshold were added artificially. Nerve roots and trabeculae were found to induce regions of microcirculation, whose location, size and vorticity along the spine were characterized. Our CFD simulations based on volumetric flow rates acquired with Cine Phase Contrast MRI in a normal human subject suggest a 2-2.5 fold increase i...
ABSTRACT Intrathecal drug delivery bypasses the blood brain barrier by infusing therapeutic agent... more ABSTRACT Intrathecal drug delivery bypasses the blood brain barrier by infusing therapeutic agents into the cerebrospinal fluid. Clinical studies have observed rapid distribution of intrathecally infused drugs. We hypothesize that naturally occurring cerebrospinal fluid pulsations inside the spinal canal accelerate drug transport. An experimental model of the human spinal canal was built for infusion tests of a radionucleotide in stagnant and pulsatile flow fields. The distribution of infused Technitium-99m in the spinal canal model was quantified and validated with computational study. The results show that the oscillatory flow of the cerebrospinal fluid accelerates species dispersion in the spinal canal model by a factor of two to four. To demonstrate a clinically relevant application, physiological cerebrospinal fluid pulsations were reproduced in an anatomically consistent computational model and the dispersion of baclofen, an anti-spasticity drug, inside the central nervous system was predicted. The successful characterization of accelerated drug transport due to cerebrospinal fluid pulsations aids in the rational design of intrathecal drug infusion therapies.
Journal of the Air and Waste Management Association, 2011
Fuel-based emission factors for 143 light-duty gasoline vehicles (LDGVs) and 93 heavy-duty diesel... more Fuel-based emission factors for 143 light-duty gasoline vehicles (LDGVs) and 93 heavy-duty diesel trucks (HDDTs) were measured in Wilmington, CA using a zero-emission mobile measurement platform (MMP). The frequency distributions of emission factors of carbon monoxide (CO), nitrogen oxides (NO(x)), and particle mass with aerodynamic diameter below 2.5 microm (PM2.5) varied widely, whereas the average of the individual vehicle emission factors were comparable to those reported in previous tunnel and remote sensing studies as well as the predictions by Emission Factors (EMFAC) 2007 mobile source emission model for Los Angeles County. Variation in emissions due to different driving modes (idle, low- and high-speed acceleration, low- and high-speed cruise) was found to be relatively small in comparison to intervehicle variability and did not appear to interfere with the identification of high emitters, defined as the vehicles whose emissions were more than 5 times the fleet-average values. Using this definition, approximately 5% of the LDGVs and HDDTs measured were high emitters. Among the 143 LDGVs, the average emission factors of NO(x), black carbon (BC), PM2.5, and ultrafine particle (UFP) would be reduced by 34%, 39%, 44%, and 31%, respectively, by removing the highest 5% of emitting vehicles, whereas CO emission factor would be reduced by 50%. The emission distributions of the 93 HDDTs measured were even more skewed: approximately half of the NO(x) and CO fleet-average emission factors and more than 60% of PM2.5, UFP, and BC fleet-average emission factors would be reduced by eliminating the highest-emitting 5% HDDTs. Furthermore, high emissions of BC, PM2.5, and NO(x) tended to cluster among the same vehicles.
Extracranial CSF shunt obstruction is one of the most important problems in hydrocephalus patient... more Extracranial CSF shunt obstruction is one of the most important problems in hydrocephalus patient management. Despite ongoing research into better shunt design, robust and reliable detection of shunt malfunction remains elusive. The authors present a novel method of correlating degree of tissue ingrowth into ventricular CSF drainage catheters with internal electrical impedance. The impedance based sensor is able to continuously monitor shunt patency using intraluminal electrodes. Prototype obstruction sensors were fabricated for in-vitro analysis of cellular ingrowth into a shunt under static and dynamic flow conditions. Primary astrocyte cell lines and C6 glioma cells were allowed to proliferate up to 7 days within a shunt catheter and the impedance waveform was observed. During cell ingrowth a significant change in the peak-to-peak voltage signal as well as the root-mean-square voltage level was observed, allowing the impedance sensor to potentially anticipate shunt malfunction long before it affects fluid drainage. Finite element modeling was employed to demonstrate that the electrical signal used to monitor tissue ingrowth is contained inside the catheter lumen and does not endanger tissue surrounding the shunt. These results may herald the development of "next generation" shunt technology that allows prediction of malfunction before it affects patient outcome.
The central nervous system (CNS) is the most difficult target for drug delivery therapies. Despit... more The central nervous system (CNS) is the most difficult target for drug delivery therapies. Despite datasets available describing physiological, biochemical, cellular, and metabolic properties of the CNS, the development of infusion therapies still faces major delivery challenges. There is a need for the integration of data obtained from different experimental modalities to design molecular therapies. In this paper, we propose a novel mathematical method for the integration of datasets to generate useful dosing criteria for infusion therapies. A case study is used to demonstrate the design of gene silencing therapies to down regulate NMDA receptors in the spinal cord for chronic pain management. Based on experimentally derived kinetics for short interfering RNA (siRNA) and magnetic resonance images, the biodistribution and pharmacokinetics of siRNAs were predicted for different infusion modes. This adaptable, multiscale computational platform enables the prediction of dose-response on an organ-wide level. The quantitative integration of valuable datasets with engineering precision is expected to accelerate the clinical implementation of novel therapeutics.
Clinical studies have shown that drugs delivered intrathecally distribute much faster than can be... more Clinical studies have shown that drugs delivered intrathecally distribute much faster than can be accounted for by pure molecular diffusion. However, drug transport inside the cerebrospinal fluid (CSF)-filled spinal canal is poorly understood. In this study, comprehensive experimental and computational studies were conducted to quantify the effect of pulsatile CSF flow on the accelerated drug dispersion in the spinal canal. Infusion tests with a radionucleotide and fluorescent dye under stagnant and pulsatile flow conditions were conducted inside an experimental surrogate model of the human spinal canal. The tracer distributions were quantified optically and by single photon emission computed tomography (SPECT). The experimental results show that CSF flow oscillations substantially enhance fluorescent dye and radionucleotide dispersion in the spinal canal experiment. The experimental observations were interpreted by rigorous computer simulations. To demonstrate the clinical significance, the dispersion of intrathecally infused baclofen, an anti-spasticity drug, was predicted by using patient-specific spinal data and CSF flow measurements. The computational predictions are expected to enable the rational design of intrathecal drug therapies.
Intrathecal drug delivery is an efficient method to administer therapeutic molecules to the centr... more Intrathecal drug delivery is an efficient method to administer therapeutic molecules to the central nervous system. However, even with identical drug dosage and administration mode, the extent of drug distribution in vivo is highly variable and difficult to control. Different cerebrospinal fluid (CSF) pulsatility from patient to patient may lead to different drug distribution. Medical image-based computational fluid dynamics (miCFD) is used to construct a patient-specific model to quantify drug transport as a function of a spectrum of physiological CSF pulsations. Magnetic resonance imaging (MRI) and CINE MRI were performed to capture the patient's central nervous system anatomy and CSF pulsatile flow velocities. An miCFD model was reconstructed from these MRIs and the patient's CSF flow velocities were computed. The effect of CSF pulsatility (frequency and stroke volume) was investigated for a bolus injection of a model drug at the L2 vertebral level. Drug distribution profiles along the entire spine were computed for different heart rates: 43, 60, and 120 bpm, and varied CSF stroke volumes: 1, 2, and 3 mL. To assess toxicity risk for patients with different physiological variables, therapeutic and toxic concentration thresholds for a common anesthetic were derived from experimental studies. Toxicity risk analysis was performed for an injection of a spinal anesthetic for patients with different heart rates and CSF stroke volumes. Both heart rate and CSF stroke volume of the patient strongly influence drug distribution administered intrathecally. Doubling the heart rate (from 60 to 120 bpm) caused a 26.4% decrease in peak concentration in CSF after injection. Doubling the CSF stroke volume diminished the peak concentration after injection by 38.1%. Computations show that potentially toxic peak concentrations due to injection can be avoided by changing the infusion rate. Using slower infusion rates could avoid high peak concentrations in CSF while maintaining drug concentrations above the therapeutic threshold. Our computations identify key variables for patient to patient variability in drug distribution in the spine observed clinically. The speed of drug transport is strongly affected by the frequency and magnitude of CSF pulsations. Toxicity risks associated with an injection can be reduced for a particular patient by adjusting the infusion variables with our rigorous miCFD model.
To provide information for greenhouse gas reduction policies, the California Air Resources Board ... more To provide information for greenhouse gas reduction policies, the California Air Resources Board (CARB) inventories annual emissions of high-global-warming potential (GWP) fluorinated gases, the fastest growing sector of greenhouse gas (GHG) emissions globally. Baseline 2008 F-gas emissions estimates for selected chlorofluorocarbons (CFC-12), hydrochlorofluorocarbons (HCFC-22), and hydrofluorocarbons (HFC-134a) made with an inventory-based methodology were compared to emissions estimates made by ambient-based measurements. Significant discrepancies were found, with the inventory-based emissions methodology resulting in a systematic 42% under-estimation of CFC-12 emissions from older refrigeration equipment and older vehicles, and a systematic 114% overestimation of emissions for HFC-134a, a refrigerant substitute for phased-out CFCs. Initial, inventory-based estimates for all F-gas emissions had assumed that equipment is no longer in service once it reaches its average lifetime of use. Revised emission estimates using improved models for equipment age at end-of-life, inventories, and leak rates specific to California resulted in F-gas emissions estimates in closer agreement to ambient-based measurements. The discrepancies between inventory-based estimates and ambient-based measurements were reduced from -42% to -6% for CFC-12, and from +114% to +9% for HFC-134a.
Aquaporin-4 water channels play a central role in brain water regulation in neurological disorder... more Aquaporin-4 water channels play a central role in brain water regulation in neurological disorders. Aquaporin-4 is abundantly expressed at the astroglial endfeet facing the cerebral vasculature and the pial membrane, and both its expression level and subcellular localization significantly influence brain water transport. However, measurements of aquaporin-4 levels in animal models of brain injury often report opposite trends of change at the injury core and the penumbra. Furthermore, aquaporin-4 channels play a beneficial role in brain water clearance in vasogenic edema, but a detrimental role in cytotoxic edema and exacerbate cell swelling. In light of current evidence, we still do not have a complete understanding of the role of aquaporin-4 in brain water transport. In this review, we propose that the regulatory mechanisms of aquaporin-4 at the transcriptional, translational, and post-translational levels jointly regulate water permeability in the short and long time scale after i...
Spinal microstructures are known to substantially affect cerebrospinal fluid patterns, yet their ... more Spinal microstructures are known to substantially affect cerebrospinal fluid patterns, yet their actual impact on flow resistance has not been quantified. Because the length scale of microanatomical aspects is below medical image resolution, their effect on flow is difficult to observe experimentally. Using a computational fluid mechanics approach, we were able to quantify the contribution of micro-anatomical aspects on cerebrospinal fluid (CSF) flow patterns and flow resistance within the entire central nervous system (CNS). Cranial and spinal CSF filled compartments were reconstructed from human imaging data; microscopic trabeculae below the image detection threshold were added artificially. Nerve roots and trabeculae were found to induce regions of microcirculation, whose location, size and vorticity along the spine were characterized. Our CFD simulations based on volumetric flow rates acquired with Cine Phase Contrast MRI in a normal human subject suggest a 2-2.5 fold increase i...
ABSTRACT Intrathecal drug delivery bypasses the blood brain barrier by infusing therapeutic agent... more ABSTRACT Intrathecal drug delivery bypasses the blood brain barrier by infusing therapeutic agents into the cerebrospinal fluid. Clinical studies have observed rapid distribution of intrathecally infused drugs. We hypothesize that naturally occurring cerebrospinal fluid pulsations inside the spinal canal accelerate drug transport. An experimental model of the human spinal canal was built for infusion tests of a radionucleotide in stagnant and pulsatile flow fields. The distribution of infused Technitium-99m in the spinal canal model was quantified and validated with computational study. The results show that the oscillatory flow of the cerebrospinal fluid accelerates species dispersion in the spinal canal model by a factor of two to four. To demonstrate a clinically relevant application, physiological cerebrospinal fluid pulsations were reproduced in an anatomically consistent computational model and the dispersion of baclofen, an anti-spasticity drug, inside the central nervous system was predicted. The successful characterization of accelerated drug transport due to cerebrospinal fluid pulsations aids in the rational design of intrathecal drug infusion therapies.
Journal of the Air and Waste Management Association, 2011
Fuel-based emission factors for 143 light-duty gasoline vehicles (LDGVs) and 93 heavy-duty diesel... more Fuel-based emission factors for 143 light-duty gasoline vehicles (LDGVs) and 93 heavy-duty diesel trucks (HDDTs) were measured in Wilmington, CA using a zero-emission mobile measurement platform (MMP). The frequency distributions of emission factors of carbon monoxide (CO), nitrogen oxides (NO(x)), and particle mass with aerodynamic diameter below 2.5 microm (PM2.5) varied widely, whereas the average of the individual vehicle emission factors were comparable to those reported in previous tunnel and remote sensing studies as well as the predictions by Emission Factors (EMFAC) 2007 mobile source emission model for Los Angeles County. Variation in emissions due to different driving modes (idle, low- and high-speed acceleration, low- and high-speed cruise) was found to be relatively small in comparison to intervehicle variability and did not appear to interfere with the identification of high emitters, defined as the vehicles whose emissions were more than 5 times the fleet-average values. Using this definition, approximately 5% of the LDGVs and HDDTs measured were high emitters. Among the 143 LDGVs, the average emission factors of NO(x), black carbon (BC), PM2.5, and ultrafine particle (UFP) would be reduced by 34%, 39%, 44%, and 31%, respectively, by removing the highest 5% of emitting vehicles, whereas CO emission factor would be reduced by 50%. The emission distributions of the 93 HDDTs measured were even more skewed: approximately half of the NO(x) and CO fleet-average emission factors and more than 60% of PM2.5, UFP, and BC fleet-average emission factors would be reduced by eliminating the highest-emitting 5% HDDTs. Furthermore, high emissions of BC, PM2.5, and NO(x) tended to cluster among the same vehicles.
Extracranial CSF shunt obstruction is one of the most important problems in hydrocephalus patient... more Extracranial CSF shunt obstruction is one of the most important problems in hydrocephalus patient management. Despite ongoing research into better shunt design, robust and reliable detection of shunt malfunction remains elusive. The authors present a novel method of correlating degree of tissue ingrowth into ventricular CSF drainage catheters with internal electrical impedance. The impedance based sensor is able to continuously monitor shunt patency using intraluminal electrodes. Prototype obstruction sensors were fabricated for in-vitro analysis of cellular ingrowth into a shunt under static and dynamic flow conditions. Primary astrocyte cell lines and C6 glioma cells were allowed to proliferate up to 7 days within a shunt catheter and the impedance waveform was observed. During cell ingrowth a significant change in the peak-to-peak voltage signal as well as the root-mean-square voltage level was observed, allowing the impedance sensor to potentially anticipate shunt malfunction long before it affects fluid drainage. Finite element modeling was employed to demonstrate that the electrical signal used to monitor tissue ingrowth is contained inside the catheter lumen and does not endanger tissue surrounding the shunt. These results may herald the development of "next generation" shunt technology that allows prediction of malfunction before it affects patient outcome.
The central nervous system (CNS) is the most difficult target for drug delivery therapies. Despit... more The central nervous system (CNS) is the most difficult target for drug delivery therapies. Despite datasets available describing physiological, biochemical, cellular, and metabolic properties of the CNS, the development of infusion therapies still faces major delivery challenges. There is a need for the integration of data obtained from different experimental modalities to design molecular therapies. In this paper, we propose a novel mathematical method for the integration of datasets to generate useful dosing criteria for infusion therapies. A case study is used to demonstrate the design of gene silencing therapies to down regulate NMDA receptors in the spinal cord for chronic pain management. Based on experimentally derived kinetics for short interfering RNA (siRNA) and magnetic resonance images, the biodistribution and pharmacokinetics of siRNAs were predicted for different infusion modes. This adaptable, multiscale computational platform enables the prediction of dose-response on an organ-wide level. The quantitative integration of valuable datasets with engineering precision is expected to accelerate the clinical implementation of novel therapeutics.
Clinical studies have shown that drugs delivered intrathecally distribute much faster than can be... more Clinical studies have shown that drugs delivered intrathecally distribute much faster than can be accounted for by pure molecular diffusion. However, drug transport inside the cerebrospinal fluid (CSF)-filled spinal canal is poorly understood. In this study, comprehensive experimental and computational studies were conducted to quantify the effect of pulsatile CSF flow on the accelerated drug dispersion in the spinal canal. Infusion tests with a radionucleotide and fluorescent dye under stagnant and pulsatile flow conditions were conducted inside an experimental surrogate model of the human spinal canal. The tracer distributions were quantified optically and by single photon emission computed tomography (SPECT). The experimental results show that CSF flow oscillations substantially enhance fluorescent dye and radionucleotide dispersion in the spinal canal experiment. The experimental observations were interpreted by rigorous computer simulations. To demonstrate the clinical significance, the dispersion of intrathecally infused baclofen, an anti-spasticity drug, was predicted by using patient-specific spinal data and CSF flow measurements. The computational predictions are expected to enable the rational design of intrathecal drug therapies.
Intrathecal drug delivery is an efficient method to administer therapeutic molecules to the centr... more Intrathecal drug delivery is an efficient method to administer therapeutic molecules to the central nervous system. However, even with identical drug dosage and administration mode, the extent of drug distribution in vivo is highly variable and difficult to control. Different cerebrospinal fluid (CSF) pulsatility from patient to patient may lead to different drug distribution. Medical image-based computational fluid dynamics (miCFD) is used to construct a patient-specific model to quantify drug transport as a function of a spectrum of physiological CSF pulsations. Magnetic resonance imaging (MRI) and CINE MRI were performed to capture the patient's central nervous system anatomy and CSF pulsatile flow velocities. An miCFD model was reconstructed from these MRIs and the patient's CSF flow velocities were computed. The effect of CSF pulsatility (frequency and stroke volume) was investigated for a bolus injection of a model drug at the L2 vertebral level. Drug distribution profiles along the entire spine were computed for different heart rates: 43, 60, and 120 bpm, and varied CSF stroke volumes: 1, 2, and 3 mL. To assess toxicity risk for patients with different physiological variables, therapeutic and toxic concentration thresholds for a common anesthetic were derived from experimental studies. Toxicity risk analysis was performed for an injection of a spinal anesthetic for patients with different heart rates and CSF stroke volumes. Both heart rate and CSF stroke volume of the patient strongly influence drug distribution administered intrathecally. Doubling the heart rate (from 60 to 120 bpm) caused a 26.4% decrease in peak concentration in CSF after injection. Doubling the CSF stroke volume diminished the peak concentration after injection by 38.1%. Computations show that potentially toxic peak concentrations due to injection can be avoided by changing the infusion rate. Using slower infusion rates could avoid high peak concentrations in CSF while maintaining drug concentrations above the therapeutic threshold. Our computations identify key variables for patient to patient variability in drug distribution in the spine observed clinically. The speed of drug transport is strongly affected by the frequency and magnitude of CSF pulsations. Toxicity risks associated with an injection can be reduced for a particular patient by adjusting the infusion variables with our rigorous miCFD model.
To provide information for greenhouse gas reduction policies, the California Air Resources Board ... more To provide information for greenhouse gas reduction policies, the California Air Resources Board (CARB) inventories annual emissions of high-global-warming potential (GWP) fluorinated gases, the fastest growing sector of greenhouse gas (GHG) emissions globally. Baseline 2008 F-gas emissions estimates for selected chlorofluorocarbons (CFC-12), hydrochlorofluorocarbons (HCFC-22), and hydrofluorocarbons (HFC-134a) made with an inventory-based methodology were compared to emissions estimates made by ambient-based measurements. Significant discrepancies were found, with the inventory-based emissions methodology resulting in a systematic 42% under-estimation of CFC-12 emissions from older refrigeration equipment and older vehicles, and a systematic 114% overestimation of emissions for HFC-134a, a refrigerant substitute for phased-out CFCs. Initial, inventory-based estimates for all F-gas emissions had assumed that equipment is no longer in service once it reaches its average lifetime of use. Revised emission estimates using improved models for equipment age at end-of-life, inventories, and leak rates specific to California resulted in F-gas emissions estimates in closer agreement to ambient-based measurements. The discrepancies between inventory-based estimates and ambient-based measurements were reduced from -42% to -6% for CFC-12, and from +114% to +9% for HFC-134a.
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Papers by Ying-kuang Hsu