Andreas A. Linninger

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

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Publications (138)223.97 Total impact

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    Chih-Yang Hsu · Ben Schneller · Mahsa Ghaffari · Ali Alaraj · Andreas Linninger
    06/2015; 3(2):126-141. DOI:10.3390/technologies3020126
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    Mahsa Ghaffari · Chih-Yang Hsu · Andreas A Linninger
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    ABSTRACT: Unstructured meshes are widely used to delineate the complex geometry of blood vessels in computational fluid dynamics simulation. However, structured parametric meshes can better represent complex geometries with lower grid density thus enabling faster and more precise computations. Current mesh generation methods require user interaction and cannot be used for automatic generation of parametric mesh representations of vascular networks. Our aim is to present a fully automatic algorithm for parametric mesh representation of vascular networks from subject-specific medical images. The methodology requires no user interaction, can create volumetric meshes for non-planar bifurcations and offers full control over the local mesh resolution at the surface and the lumen of the blood vessels. We demonstrate the reliability of our algorithm in terms of mesh quality by evaluating scaled Jacobian and equiangular skewness. The novel method was applied in case studies to reconstruct real image data for the cerebral angioarchitecture. Accurate subject-specific representations of vascular trees are necessary to perform organ-wide hemodynamics for personalized surgical planning of vascular disease.
    12th International Symposium on Process Systems Engineering and 25th European Symposium on Computer Aided Process Engineering, Denmark; 05/2015
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    ABSTRACT: Accurate representation of brain anatomical structure is necessary for performing computational hemodynamics simulation to study intracranial diseases. We show in this work an image processing workflow for physiological representations of a subject-specific whole human head reconstruction from medical images. Our workflow provides cerebral vasculatures, CSF space, grey and white matter, skull and scalp. It provides physicians with a complete visualization of the cerebral anatomy and enables computational hemodynamic studies. Magnetic resonance imaging was acquired for one healthy volunteer. Grey and white matter were segmented from T1 images using cortical reconstruction and volumetric segmentation algorithms. Skull and scalp were segmented using morphological operations of T1 images. The cerebrospinal fluid space was segmented using T2 images. MRA and MRV were first processed with in-house vessel enhancement filters before segmentation. To construct computational meshes for hemodynamic simulations, we developed a parametric meshing algorithm to automatically generate surface and volumetric meshes for the vessels. Figure 1 summarizes our results. Panel A exhibits our segmentation for arteries and veins after image filtering. Our vessel filtering suppresses the non-vessel signals enabling automatic vessel segmentation. Panel B demonstrates our parametric computational mesh generation for cerebral vasculature. Panel C shows all the structures we reconstructed from the medical images. Our parametric meshing of the cerebral vasculature allows for hemodynamic simulation for understanding cerebral vascular disease. Additionally, the inclusion of the other intracranial structures allows us to take into account the interactions of vessels with other human head regions. Accurate subject-specific representations of vascular trees are necessary to perform organ-wide hemodynamics for personalized surgical planning of vascular diseases.
    24th European Stroke Conference (ESC), Vienna, Austria; 05/2015
  • Kevin M Tangen · Ying Hsu · David C Zhu · Andreas A Linninger
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    ABSTRACT: 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 in pressure drop mainly due to arachnoid trabeculae. The timing and phase lag of the CSF pressure and velocity waves along the spinal canal were also computed, and a complete spatio-temporal map encoding CSF volumetric flow rates and pressure was created. Micro-anatomy induced fluid patterns were found responsible for the rapid caudo-cranial spread of an intrathecally administered drug. The speed of rostral drug dispersion is drastically accelerated through pulsatile flow around microanatomy induced vortices. Exploring massive parallelization on a supercomputer, the feasibility of computational drug transport studies was demonstrated. CNS-wide simulations of intrathecal drugs administration can become a practical tool for in silico design, interspecies scaling and optimization of experimental drug trials. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Journal of Biomechanics 03/2015; 48(10). DOI:10.1016/j.jbiomech.2015.02.018 · 2.75 Impact Factor
  • Eric Lueshen · Indu Venugopal · Tejen Soni · Ali Alaraj · Andreas Linninger
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    ABSTRACT: There is an ongoing struggle to develop efficient drug delivery and targeting methods within the central nervous system. One technique known as intrathecal drug delivery, involves direct drug infusion into the spinal canal and has become standard practice for treating many central nervous system diseases due to reduced systemic toxicity from the drug bypassing the blood-brain barrier. Although intrathecal drug delivery boasts the advantage of reduced systemic toxicity compared to oral and intravenous drug delivery techniques, current intrathecal delivery protocols lack a means of sufficient drug targeting at specific locations of interest within the central nervous system. We previously proposed the method of intrathecal magnetic drug targeting in order to overcome the limited targeting capabilities of standard intrathecal drug delivery protocols, while simultaneously reducing the systemic toxicity as well as the amount of drug required to produce a therapeutic effect. Building off of our previous work, this paper presents the concept of implant-assisted intrathecal magnetic drug targeting. Ferritic stainless steel implants were incorporated within the subarachnoid space of our in vitro human spine model, and the targeting magnet was placed at a physiological distance away from the model and implant to mimic the distance between the epidermis and spinal canal. Computer simulations were performed to optimize implant design for generating high gradient magnetic fields and to study how these fields may aid in therapeutic nanoparticle localization. Experiments aiming to determine the effects of different magnetically-susceptible implants placed within an external magnetic field on the targeting efficiency of gold-coated magnetite nanoparticles were then performed on our in vitro human spine model. Our results indicate that implant-assisted intrathecal magnetic drug targeting is an excellent supplementary technique to further enhance the targeting capabilities of our previously established method of intrathecal magnetic drug targeting.
    Journal of Biomedical Nanotechnology 02/2015; 11(2). DOI:10.1166/jbn.2015.1907 · 5.34 Impact Factor
  • Andreas A. Linninger · Ioannis P. Androulakis
    Computers & Chemical Engineering 12/2014; 71:663-664. DOI:10.1016/j.compchemeng.2014.10.003 · 2.78 Impact Factor
  • Martina Heitzig · Andreas A. Linninger · Gürkan Sin · Rafiqul Gani
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    ABSTRACT: The objective of this work is the development of a generic computer-aided modelling framework to support the development of physiologically-based pharmacokinetic models thereby increasing the efficiency and quality of the modelling process. In particular, the framework systematizes the modelling process by identifying the workflow involved and providing the required methods and tools for model documentation, construction, analysis, identification and discrimination. The application and benefits of the developed framework are demonstrated by a case study related to the whole-body physiologically-based pharmacokinetic modelling of the distribution of the drug cyclosporin A in rats and humans. Four alternative candidate models for rats are derived and discriminated based on experimental data. The model candidate that is best represented by the experimental data is scaled-up to a human being applying physiologically-based scaling laws and identifying model parameters that can be re-fitted by the limited experimental data accessible for humans using sensitivity and identifiability analysis techniques.
    Computers & Chemical Engineering 12/2014; 71:677-698. DOI:10.1016/j.compchemeng.2014.07.016 · 2.78 Impact Factor
  • Eric Lueshen · Michael LaRiviere · Bakhtiar Yamini · Andreas Linninger
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    ABSTRACT: Convection-enhanced delivery (CED) has emerged as a promising technique for bypassing the blood-brain barrier to deliver therapeutic agents. However, animal studies and clinical trials that utilize the technique suggest that it may require further optimization before it can be safely used in humans. In particular, while volume of distribution in the target tissue can be controlled, the geometrical spread into a desired target region is highly variable from experiment to experiment. In the present paper we have sought to characterize the non-uniform distribution geometry using fluorescent nanoparticles in both a rat model and computer simulations.
    Computers & Chemical Engineering 12/2014; 71:672-676. DOI:10.1016/j.compchemeng.2014.09.008 · 2.78 Impact Factor
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    Joel Buishas · Ian G Gould · Andreas A Linninger
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    ABSTRACT: Experimental evidence has cast doubt on the classical model of river-like cerebrospinal fluid (CSF) flow from the choroid plexus to the arachnoid granulations. We propose a novel model of water transport through the parenchyma from the microcirculation as driven by Starling forces. This model investigates the effect of osmotic pressure on water transport between the cerebral vasculature, the extracellular space (ECS), the perivascular space (PVS), and the CSF. A rigorous literature search was conducted focusing on experiments which alter the osmolarity of blood or ventricles and measure the rate of CSF production. Investigations into the effect of osmotic pressure on the volume of ventricles and the flux of ions in the blood, choroid plexus epithelium, and CSF are reviewed. Increasing the osmolarity of the serum via a bolus injection completely inhibits nascent fluid flow production in the ventricles. A continuous injection of a hyperosmolar solution into the ventricles can increase the volume of the ventricle by up to 125%. CSF production is altered by 0.231 μL per mOsm in the ventricle and by 0.835 μL per mOsm in the serum. Water flux from the ECS to the CSF is identified as a key feature of intracranial dynamics. A complete mathematical model with all equations and scenarios is fully described, as well as a guide to constructing a computational model of intracranial water balance dynamics. The model proposed in this article predicts the effects the osmolarity of ECS, blood, and CSF on water flux in the brain, establishing a link between osmotic imbalances and pathological conditions such as hydrocephalus and edema.
    Croatian Medical Journal 10/2014; 55(5):481-97. DOI:10.3325/cmj.2014.55.481 · 1.31 Impact Factor
  • Sukhraaj Basati · Kevin Tangen · Ying hSU · Hanna Lin · David Frim · Andreas Linninger
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    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; DOI:10.1109/TBME.2014.2335171 · 2.35 Impact Factor
  • A Ivanov · C Hsu · A Linninger · S Amin-Hanjani · V Aletich · F Charbel · A Alaraj
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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. DOI:10.1136/neurintsurg-2014-011343.50 · 2.77 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; 22(1). DOI:10.1111/micc.12156 · 2.57 Impact Factor
  • A Ivanov · C Hsu · A Linninger · S Amin-Hanjani · V Aletich · F Charbel · A Alaraj
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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. DOI:10.1136/neurintsurg-2014-011343.124 · 2.77 Impact Factor
  • Seon Kim · Ying Hsu · Andreas Linninger
    03/2014; 2(1):218-237. DOI:10.3390/pr2010218
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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.
    Nanomedicine 07/2013; 9(8). DOI:10.2217/nnm.13.69 · 5.41 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. DOI:10.1016/j.compchemeng.2013.03.026 · 2.78 Impact Factor
  • A A Linninger · I G Gould · T Marinnan · C-Y Hsu · M Chojecki · A Alaraj
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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; 42(8). DOI:10.1007/s10439-013-0828-0 · 3.20 Impact Factor
  • Eric Lueshen · Indu Venugopal · Andreas Linninger
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    ABSTRACT: Intrathecal (IT) drug delivery is a standard technique which involves direct injection of drugs into the cerebrospinal fluid (CSF)-filled space within the spinal canal to treat many diseases of the central nervous system. Currently, in order to reach the therapeutic drug concentration at certain locations within the spinal canal, high drug doses are used. With no method to deliver the large drug doses locally, current IT drug delivery treatments are hindered with wide drug distributions throughout the central nervous system (CNS) which cause harmful side effects. In order to overcome the current limitations of IT drug delivery, we have developed the novel method of intrathecal magnetic drug targeting (IT-MDT). Gold-coated magnetite nanoparticles are infused into a physiologically and anatomically relevant in vitro human spine model and then targeted to a specific site using external magnetic fields, resulting in a substantial increase in therapeutic nanoparticle localization at the site of interest. Experiments aiming to determine the effect of key parameters such as magnet strength, duration of magnetic field exposure, location of magnetic field, and ferrous implants on the collection efficiency of our superparamagnetic nanoparticles in the targeting region were performed. Our experiments indicate that intrathecal magnetic drug targeting and implant-assisted IT-MDT are promising techniques for concentrating and localizing drug-functionalized nanoparticles at required target sites within the spinal canal for potential treatment of diseases affecting the central nervous system.
    ASME 2013 2nd Global Congress on NanoEngineering for Medicine and Biology; 02/2013
  • Ying Hsu · Andreas A. Linninger
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    ABSTRACT: 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 with different experimental modalities to design molecular therapies. In this article, 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 downregulate NMDA receptors in the spinal cord for chronic pain management. Based on experimentally-derived kinetics for short interfering RNA (siRNA) and magnetic resonance (MR) images, the biodistribution and pharmacokinetics of siRNAs were predicted for different infusion modes. This adaptable, multi-scale 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.
    IEEE transactions on bio-medical engineering 02/2013; 60(3). DOI:10.1109/TBME.2013.2244893 · 2.35 Impact Factor
  • Sukhraaj Basati · Bhargav Desai · Ali Alaraj · Fady Charbel · Andreas Linninger
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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. DOI:10.3171/2012.6.PEDS11457 · 1.48 Impact Factor

Publication Stats

1k Citations
223.97 Total Impact Points


  • 1998–2015
    • University of Illinois at Chicago
      • • Department of Bioengineering
      • • Department of Chemical Engineering
      Chicago, Illinois, United States
  • 2007
    • University of Chicago
      Chicago, Illinois, United States
  • 1995–1999
    • Massachusetts Institute of Technology
      • Department of Chemical Engineering
      Cambridge, Massachusetts, United States