Andreas A. Linninger

University of Illinois at Chicago, Chicago, Illinois, United States

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Publications (102)112.17 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    IEEE transactions on bio-medical engineering 07/2014; · 2.15 Impact Factor
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    ABSTRACT: Improvement in cerebral perfusion post endovascular treatment of vasospasm in patients with aneurysmal subarachnoid haemorrhage (aSAH) is typically assessed by comparison of major vessel diameters on digital subtraction angiography (DSA). In this report we sought to assess relative changes in cerebral blood flow by computational DSA transit time (TT) analysis in patients with cerebral vasospasm before/after endovascular treatment.
    Journal of neurointerventional surgery 07/2014; 6 Suppl 1:A27-8. · 1.38 Impact Factor
  • Ian G. Gould, Andreas A. Linninger
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    ABSTRACT: Objective Oxygen tension in the brain is controlled by the microcirculatory supply of red blood cells, but the effect of non-Newtonian blood flow rheology on tissue oxygenation is not well characterized. This paper assesses different biphasic blood flow models for predicting tissue oxygen tension as a function of microcirulatory hemodynamics.Methods Two existing plasma skimming laws are compared against measured RBC distributions in rat and hamster microcirculatory networks. A novel biphasic blood flow model is introduced. The computational models predict tissue oxygenation in the mesentery, cremaster muscle, and the human secondary cortex.ResultsThis investigation shows deficiencies in prior models, including inconsistent plasma skimming trends and insufficient oxygen perfusion due to the high prevalence (33%) of RBC-free microvessels. Our novel method yields physiologically sound RBC distributions and tissue oxygen tensions within one standard deviation of experimental measurements.ConclusionsA simple, novel biphasic blood flow model is introduced with equal or better predictive power when applied to historic raw data sets. It can overcome limitations of prior models pertaining to trifurcations, anastomoses, and loops. This new plasma skimming law eases the computations of bulk blood flow and hematocrit fields in large microcirculatory networks and converges faster than prior procedures.This article is protected by copyright. All rights reserved.
    Microcirculation (New York, N.Y.: 1994) 07/2014; · 2.37 Impact Factor
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    ABSTRACT: The use of digital subtraction angiography (DSA) for semi-quantitative cerebral blood flow (CBF) assessment is a new method. In this report we sought to correlate angiographic transit times (TT) in patients with aneurysmal subarachnoid haemorrhage (aSAH) in relation to Hunt &Hess (H&H) grade.
    Journal of neurointerventional surgery 07/2014; 6 Suppl 1:A64-5. · 1.38 Impact Factor
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    ABSTRACT: Aim: We aimed to magnetically guide and locally confine nanoparticles in desired locations within the spinal canal to achieve effective drug administration for improved treatment of chronic pain, cancers, anesthesia and spasticity. Materials & methods: We developed a physiologically and anatomically consistent in vitro human spine model to test the feasibility of intrathecal magnetic drug targeting. Gold-coated magnetite nanoparticles were infused into the model and targeted to specific regions using external magnetic fields. Experiments and simulations aiming to determine the effect of key parameters, such as magnet strength, duration of magnetic field exposure, magnet location and ferrous implants, on the collection efficiency of superparamagnetic nanoparticles in targeted regions were performed. Results: An 891% increase in nanoparticle collection efficiency within the target region was achieved using intrathecal magnetic drug targeting when compared with the control. Nanoparticle collection efficiency at the target region increased with time and reached a steady value within 15 min. Ferrous epidural implants generated sufficiently high-gradient magnetic fields, even when magnets were placed at a distance equal to the space between a patient's epidermis and spinal canal. Conclusion: Our experiments indicate that intrathecal magnetic drug targeting is a promising technique for concentrating and localizing drugs at targeted sites within the spinal canal for treating diseases affecting the CNS. Original submitted 27 June 2012; Revised submitted 11 March 2013.
    Nanomedicine 07/2013; · 5.26 Impact Factor
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    ABSTRACT: The three-dimensional spatial arrangement of the cortical microcirculatory system is critical for understanding oxygen exchange between blood vessels and brain cells. A three-dimensional computer model of a 3 × 3 × 3 mm(3) subsection of the human secondary cortex was constructed to quantify oxygen advection in the microcirculation, tissue oxygen perfusion, and consumption in the human cortex. This computer model accounts for all arterial, capillary and venous blood vessels of the cerebral microvascular bed as well as brain tissue occupying the extravascular space. Microvessels were assembled with optimization algorithms emulating angiogenic growth; a realistic capillary bed was built with space filling procedures. The extravascular tissue was modeled as a porous medium supplied with oxygen by advection-diffusion to match normal metabolic oxygen demand. The resulting synthetic computer generated network matches prior measured morphometrics and fractal patterns of the cortical microvasculature. This morphologically accurate, physiologically consistent, multi-scale computer network of the cerebral microcirculation predicts the oxygen exchange of cortical blood vessels with the surrounding gray matter. Oxygen tension subject to blood pressure and flow conditions were computed and validated for the blood as well as brain tissue. Oxygen gradients along arterioles, capillaries and veins agreed with in vivo trends observed recently in imaging studies within experimental tolerances and uncertainty.
    Annals of Biomedical Engineering 07/2013; · 3.23 Impact Factor
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    ABSTRACT: Unknown dose regimes are typically assessed on animals prior to clinical trials. Recent advances in the evaluation of new leads’ efficacy have been achieved by pharmacokinetic modeling. Further improvements, including determination of the drug's mechanism of action and organism biodistribution, require an effective methodology for solving parameter estimation challenges. This article solves the problem of rigorously estimating unknown biochemical reaction and transport parameters from in vivo datasets and identifying whole-body physiologically based pharmacokinetic (PBPK) models.A rat blood circulation model was combined with biotransport, biochemical reactions and metabolism of the immunosuppressant Cyclosporin. We demonstrate the proposed methodology on a case study in Sprague-Dawley rats by bolus iv injections of 1.2, 6 and 30 mg/kg. Key pharmacokinetic parameters were determined, including renal and hepatic clearances, elimination half-life, and mass transfer coefficients, to establish drug biodistribution dynamics in all organs and tissues. This multi-scale model satisfies first principles and conservation of mass, species and momentum.Prediction of organ drug bioaccumulation as a function of cardiac output, physiology, pathology or administration route may be possible with the proposed PBPK framework. Successful application of our model-based drug development method may lead to more efficient preclinical trials, accelerated knowledge gain from animal experiments, and shortened time-to-market of new drugs.
    Computers & Chemical Engineering 07/2013; 54:97-110. · 2.09 Impact Factor
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    ABSTRACT: Object Experimental data about the evolution of intracranial volume and pressure in cases of hydrocephalus are limited due to the lack of available monitoring techniques. In this study, the authors validate intracranial CSF volume measurements within the lateral ventricle, while simultaneously using impedance sensors and pressure transducers in hydrocephalic animals. Methods A volume sensor was fabricated and connected to a catheter that was used as a shunt to withdraw CSF. In vitro bench-top calibration experiments were created to provide data for the animal experiments and to validate the sensors. To validate the measurement technique in a physiological system, hydrocephalus was induced in weanling rats by kaolin injection into the cisterna magna. At 28 days after induction, the sensor was implanted into the lateral ventricles. After sealing the skull using dental cement, an acute CSF drainage/infusion protocol consisting of 4 sequential phases was performed with a pump. Implant location was confirmed via radiography using intraventricular iohexol contrast administration. Results Controlled CSF shunting in vivo with hydrocephalic rats resulted in precise and accurate sensor measurements (r = 0.98). Shunting resulted in a 17.3% maximum measurement error between measured volume and actual volume as assessed by a Bland-Altman plot. A secondary outcome confirmed that both ventricular volume and intracranial pressure decreased during CSF shunting and increased during infusion. Ventricular enlargement consistent with successful hydrocephalus induction was confirmed using imaging, as well as postmortem. These results indicate that volume monitoring is feasible for clinical cases of hydrocephalus. Conclusions This work marks a departure from traditional shunting systems currently used to treat hydrocephalus. The overall clinical application is to provide alternative monitoring and treatment options for patients. Future work includes development and testing of a chronic (long-term) volume monitoring system.
    Journal of Neurosurgery Pediatrics 08/2012; 10(4):347-54. · 1.63 Impact Factor
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    ABSTRACT: 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.
    Anesthesia and analgesia 04/2012; 115(2):386-94. · 3.08 Impact Factor
  • Oleksandr Ivanchenko, Nikhil Sindhwani, Andreas A. Linninger
    AIChE Journal 04/2012; 58(4). · 2.49 Impact Factor
  • Andreas A. Linninger
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    ABSTRACT: Recent advances in quantitative imaging allow unprecedented views into cellular chemistry of whole organisms in vivo. These novel imaging modalities enable the quantitative investigation of spatio-temporal reaction and transport phenomena in the living animal or the human body. This article will highlight the significant role that rigorous systems engineering methods can play for interpreting the wealth of in vivo measurements. A methodology to integrate medical imaging modalities with rigorous computational fluid dynamics entitled image-based computational fluid dynamics (iCFD) will be introduced. The quantitative analysis of biological systems with rigorous mathematical methods is expected to accelerate the introduction of novel drugs by providing a rational foundation for the systematic development of new medical therapies. Rigorous engineering methods not only advance biomedical research, but also aid the translation of laboratory research results into the bedside practice.
    Computers & Chemical Engineering 01/2012; · 2.09 Impact Factor
  • Daniel A. Beneke, Seon B. Kim, Andreas A. Linninger
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    ABSTRACT: Rising energy costs and growing environmental awareness motivate a critical revision of the design of distillation units. Systematic design techniques, such as the rectification body, column profile map, and temperature collocation methods, require exact knowledge of all pinch points in a particular system, because these stationary points delineate the possible composition trajectories realizable in separation columns. This paper demonstrates novel methods for rigorously determining all pinch points for the constant relative volatility, ideal and non-ideal systems. Constant relative volatility and ideal solution systems are transformed into one-dimensional polynomial and nonlinear functions, regardless of the number of the components. A deflation method is proposed to locate all zeros in ideal and non-ideal zeotropic problems. For more challenging non-ideal problems, a novel hybrid sequential niche algorithm is used to solve hard azeotropic problems successfully. Finally, the design implications of these pinch point locations are investigated to show how new separation configurations can be devised. Methodically the paper points out the use of rigorous pinch point computations in conjunction with continuous composition profiles for robust distillation design.
    Chinese Journal of Chemical Engineering. 12/2011; 19(6):911–925.
  • Cierra Hall, Eric Lueshen, Andrej Mošat, Andreas A Linninger
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    ABSTRACT: Drug approval processes require extensive testing and have recently put more emphasis on understanding mechanistic drug action in the body including toxicity and safety.1 Consequently, there is an urgent need in the pharmaceutical industry to develop mechanistic pharmacokinetic (PK) models able to both expedite knowledge gain from experimental trials and, simultaneously, address safety concerns. We previously developed a first principles based whole-body PK model, which incorporated physiological dimensions and drug mass transport. In this follow-up article, we demonstrate how the first principles model in combination with novel physiological scaling laws yields more reliable interspecies and intraspecies extrapolation of drug biodistribution. We show how experimental dose-response data in rats for immunosuppressant cyclosporin are sufficient for predicting the biodistribution of this drug in pigs, monkeys, and humans. The predicted drug concentrations extrapolated by interspecies scaling laws match well with the experimental measurements. These promising results demonstrate that the whole-body PK modeling approach not only elucidates drug mechanisms from a biochemical standpoint, but offers better scaling precision. Better models can substantially accelerate the introduction of drug leads to clinical trials and eventually to the market by offering more understanding of the drug mechanisms, aiding in therapy design, and serving as an accurate dosing tool.
    Journal of Pharmaceutical Sciences 11/2011; 101(3):1221-41. · 3.13 Impact Factor
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    ABSTRACT: 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.
    Annals of Biomedical Engineering 08/2011; · 3.23 Impact Factor
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    ABSTRACT: 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.
    Annals of Biomedical Engineering 07/2011; 39(10):2592-602. · 3.23 Impact Factor
  • Sukhraaj S Basati, Timothy J Harris, Andreas A Linninger
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    ABSTRACT: Knowledge of intracranial ventricular volume is important for the treatment of hydrocephalus, a disease in which cerebrospinal fluid (CSF) accumulates in the brain. Current monitoring options involve MRI or pressure monitors (InSite, Medtronic). However, there are no existing methods for continuous cerebral ventricle volume measurements. In order to test a novel impedance sensor for direct ventricular volume measurements, we present a model that emulates the expansion of the lateral ventricles seen in hydrocephalus. To quantify the ventricular volume, sensor prototypes were fabricated and tested with this experimental model. Fluid was injected and withdrawn cyclically in a controlled manner and volume measurements were tracked over 8 h. Pressure measurements were also comparable to conditions seen clinically. The results from the bench-top model served to calibrate the sensor for preliminary animal experiments. A hydrocephalic rat model was used to validate a scaled-down, microfabricated prototype sensor. CSF was removed from the enlarged ventricles and a dynamic volume decrease was properly recorded. This method of testing new designs on brain phantoms prior to animal experimentation accelerates medical device design by determining sensor specifications and optimization in a rational process.
    IEEE transactions on bio-medical engineering 05/2011; 58(5):1450-5. · 2.15 Impact Factor
  • Jeonghwa Moon, Seon Kim, Andreas A. Linninger
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    ABSTRACT: High-performance processes require a design that operates close to design boundaries and specifications, while still guaranteeing robust performance without design constraint violations. In order to safely approach tighter boundaries of process performance, much attention has been devoted to integrating design and control in which dynamic controllability, as well as the design decisions, are considered simultaneously. However, rigorous methods solving design and control simultaneously lead to challenging mathematical formulations that easily become intractable numerically and computationally. This paper introduces a new mathematical formulation to reduce this combinatorial complexity of integrating design and control. We will show that a substantial reduction in problem size can be achieved using embedded control decisions within specific designs. These embedded control decisions avoid a combinatorial explosion of control configuration, using a full state space model that does not require a pairing of control variables and loops. The current capabilities of the methodology will be demonstrated using a realistic reactor−column flowsheet.
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    ABSTRACT: Convection-enhanced delivery (CED) is a promising technique to deliver large molecular weight drugs to the human brain for treatment of Parkinson's, Alzheimer's, or brain tumors. Researchers have used agarose gels to study mechanisms of agent transport in soft tissues like brain due to its similar mechanical and transport properties. However, inexpensive quantitative techniques to precisely measure achieved agent distribution in agarose gel phantoms during CED are missing. Such precise measurements of concentration distribution are needed to optimize drug delivery. An optical experimental method to accurately quantify agent concentration in agarose is presented. A novel geometry correction algorithm is used to determine real concentrations from observable light intensities captured by a digital camera. We demonstrate the technique in dye infusion experiments that provide cylindrical and spherical distributions when infusing with porous membrane and conventional single-port catheters, respectively. This optical method incorporates important parameters, such as optimum camera exposure, captured camera intensity calibration, and use of collimated light source for maximum precision. We compare experimental results with numerical solutions to the convection diffusion equation. The solutions of convection-diffusion equations in the cylindrical and spherical domains were found to match the experimental data obtained by geometry correction algorithm.
    IEEE transactions on bio-medical engineering 03/2011; 58(3):626-32. · 2.15 Impact Factor
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    ABSTRACT: A three-dimensional model of the human cerebrospinal fluid (CSF) spaces is presented. Patient-specific brain geometries were reconstructed from magnetic resonance images. The model was validated by comparing the predicted flow rates with Cine phase-contrast MRI measurements. The model predicts the complex CSF flow patterns and pressures in the ventricular system and subarachnoid space of a normal subject. The predicted maximum rostral to caudal CSF flow in the pontine cistern precedes the maximum rostral to caudal flow in the ventricles by about 10% of the cardiac cycle. This prediction is in excellent agreement with the subject-specific flow data. The computational results quantify normal intracranial dynamics and provide a basis for analyzing diseased intracranial dynamics.
    Computers in biology and medicine 02/2011; 41(2):67-75. · 1.27 Impact Factor
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    ABSTRACT: The dynamics of fluid flow in normal pressure hydrocephalus (NPH) are poorly understood. Normally, CSF flows out of the brain through the ventricles. However, ventricular enlargement during NPH may be caused by CSF backflow into the brain through the ventricles. A previous study showed this reversal of flow; in the present study, the authors provide additional clinical data obtained in patients with NPH and supplement these data with computer simulations to better understand the CSF flow and ventricular wall displacement and emphasize its clinical implications. Three NPH patients and 1 patient with aqueductal stenosis underwent cine phase-contrast MR imaging (cine MR imaging) for measurement of CSF flow and ventricle wall movement during the cardiac cycle. These data were compared to data previously obtained in 8 healthy volunteers. The CSF flow measurements were obtained at the outlet of the aqueduct of Sylvius. Calculation of the ventricular wall movement was determined from the complete set of cine MR images obtained axially at the middle of the lateral ventricle. The data were obtained before and after CSF removal with a ventriculoperitoneal shunt with an adjustable valve. To supplement the clinical data, a computational model was used to predict the transmural pressure and flow. In healthy volunteers, net CSF aqueductal flow was 1.2 ml/minute in the craniocaudal direction. In patients with NPH, the net CSF flow was in the opposite direction--the caudocranial direction--before shunt placement. After shunting, the magnitude of the abnormal fluid flow decreased or reversed, with the flow resembling the normal flow patterns observed in healthy volunteers. The authors' MR imaging-based measurements of the CSF flow direction and lateral ventricle volume size change and the results of computer modeling of fluid dynamics lead them to conclude that the directional pattern and magnitude of CSF flow in patients with NPH may be an indication of the disease state. This has practical implications for shunt design and understanding the mechanisms that produce hydrocephalus.
    Journal of Neurosurgery 01/2011; 115(1):159-64. · 3.15 Impact Factor

Publication Stats

622 Citations
112.17 Total Impact Points


  • 1998–2014
    • University of Illinois at Chicago
      • • Department of Bioengineering
      • • Department of Chemical Engineering
      Chicago, Illinois, United States
  • 2007–2009
    • University of Chicago
      • Department of Surgery
      Chicago, IL, United States
  • 2008
    • University of Rhode Island
      Kingston, Rhode Island, United States
  • 2006
    • Michigan State University
      • Department of Psychology
      East Lansing, MI, United States
  • 1995–1996
    • Massachusetts Institute of Technology
      • Department of Chemical Engineering
      Cambridge, MA, United States