George M. Whitesides

Harvard University, Cambridge, Massachusetts, United States

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Publications (776)6419.53 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: This work describes a 3D, paper-based assay that can isolate sub-populations of cells based on their invasiveness (i.e., distance migrated in a hydrogel) in a gradient of concentration of oxygen (O2). Layers of paper impregnated with a cell-compatible hydrogel are stacked and placed in a plastic holder to form the invasion assay. In most assays, the stack comprises a single layer of paper containing mammalian cells suspended in a hydrogel, sandwiched between multiple layers of paper containing only hydrogel. Cells in the stack consume and produce small molecules; these molecules diffuse throughout the stack to generate gradients in the stack, and between the stack and the bulk culture medium. Placing the cell-containing layer in different positions of the stack, or modifying the permeability of the holder to oxygen or proteins, alters the profile of the gradients within the stack. Physically separating the layers after culture isolates sub-populations of cells that migrated different distances, and enables their subsequent analysis or culture. Using this system, three independent cell lines derived from A549 cancer cells are shown to produce distinguishable migration behavior in a gradient of oxygen. This result is the first experimental demonstration that oxygen acts as a chemoattractant for cancer cells.
    Biomaterials 06/2015; 52. · 8.31 Impact Factor
  • George M. Whitesides
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    ABSTRACT: Chemistry is in a period of change, from an era focused on molecules and reactions, to one in which manipulations of systems of molecules and reactions will be essential parts of controlling larger systems. This Essay traces paths from the past to possible futures. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    Angewandte Chemie International Edition 02/2015; · 11.34 Impact Factor
  • Jerome M Fox, George M Whitesides
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    ABSTRACT: Spreading fires are noisy (and potentially chaotic) systems in which transitions in dynamics are notoriously difficult to predict. As flames move through spatially heterogeneous environments, sudden shifts in temperature, wind, or topography can generate combustion instabilities, or trigger self-stabilizing feedback loops, that dramatically amplify the intensities and rates with which fires propagate. Such transitions are rarely captured by predictive models of fire behavior and, thus, complicate efforts in fire suppression. This paper describes a simple, remarkably instructive physical model for examining the eruption of small flames into intense, rapidly moving flames stabilized by feedback between wind and fire (i.e., "wind-fire coupling"-a mechanism of feedback particularly relevant to forest fires), and it presents evidence that characteristic patterns in the dynamics of spreading flames indicate when such transitions are likely to occur. In this model system, flames propagate along strips of nitrocellulose with one of two possible modes of propagation: a slow, structured mode, and a fast, unstructured mode sustained by wind-fire coupling. Experimental examination of patterns in dynamics that emerge near bifurcation points suggests that symptoms of critical slowing down (i.e., the slowed recovery of the system from perturbations as it approaches tipping points) warn of impending transitions to the unstructured mode. Findings suggest that slowing responses of spreading flames to sudden changes in environment (e.g., wind, terrain, temperature) may anticipate the onset of intense, feedback-stabilized modes of propagation (e.g., "blowup fires" in forests).
    Proceedings of the National Academy of Sciences 02/2015; · 9.81 Impact Factor
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    ABSTRACT: Magnetic levitation (MagLev) enables rapid and non-destructive quality control of plastic parts. The feasibility of MagLev as a method to: i) rapidly assess injection-molded plastic parts for defects during process optimization, ii) monitor the degradation of plastics after exposure to harsh environmental conditions, and iii) detect counterfeit polymers by density is demonstrated. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    Advanced Materials 01/2015; · 15.41 Impact Factor
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    ABSTRACT: This paper investigates the influence of the interface between a gold or silver metal electrode and an n-alkyl SAM (supported on that electrode) on the rate of charge transport across junctions with structure Met(Au or Ag)TS/A(CH2)nH//Ga2O3 by comparing measurements of current density, J(V), for Met/AR = Au/thiolate (Au/SR), Ag/thiolate (Ag/SR), Ag/carboxylate (Ag/O2C), and Au/acetylene (Au/C≡CR), where R is an n-alkyl group. Values of J0 and β (from the Simmons equation) were indistinguishable for these four interfaces. Since the anchoring groups, A, have large differences in their physical and electronic properties, the observation that they are indistinguishable in their influence on the injection current, J0 (V = 0.5) indicates that these four Met/A interfaces do not contribute to the shape of the tunneling barrier in a way that influences J(V).
    ACS Nano 01/2015; · 12.03 Impact Factor
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    ABSTRACT: Although simple and low-cost interventions for sickle cell disease (SCD) exist in many developing countries, child mortality associated with SCD remains high, in part, because of the lack of access to diagnostic tests for SCD. A density-based test using aqueous multiphase systems (SCD-AMPS) is a candidate for a low-cost, point-of-care diagnostic for SCD. In this paper, the field evaluation of SCD-AMPS in a large (n = 505) case-control study in Zambia is described. Of the two variations of the SCD-AMPS used, the best system (SCD-AMPS-2) demonstrated a sensitivity of 86% (82-90%) and a specificity of 60% (53-67%). Subsequent analysis identified potential sources of false positives that include clotting, variation between batches of SCD-AMPS, and shipping conditions. Importantly, SCD-AMPS-2 was 84% (62-94%) sensitive in detecting SCD in children between 6 months and 1 year old. In addition to an evaluation of performance, an assessment of end-user operability was done with health workers in rural clinics in Zambia. These health workers rated the SCD-AMPS tests to be as simple to use as lateral flow tests for malaria and HIV.
    PLoS ONE 12/2014; 9(12):e114540. · 3.53 Impact Factor
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    ABSTRACT: This paper reports the development of Metal-amplified Density Assays, or MADAs - a method of conducting quantitative or multiplexed assays, including immunoassays, by using Magnetic Levitation (MagLev) to measure metal-amplified changes in the density of beads labeled with biomolecules. The binding of target analytes (i.e. proteins, antibodies, antigens) to complementary ligands immobilized on the surface of the beads, followed by a chemical amplification of the binding in a form that results in a change in the density of the beads (achieved by using gold nanoparticle-labeled biomolecules, and electroless deposition of gold or silver), translates analyte binding events into changes in density measureable using MagLev. A minimal model based on diffusion-limited growth of hemispherical nuclei on a surface reproduces the dynamics of the assay. A MADA - when performed with antigens and antibodies - is called a Density-Linked Immunosorbent Assay, or DeLISA. Two immunoassays provided a proof of principle: a competitive quantification of the concentration of neomycin in whole milk, and a multiplexed detection of antibodies against Hepatitis C virus NS3 protein and syphilis T. pallidum p47 protein in serum. MADAs, including DeLISAs, require, besides the requisite biomolecules and amplification reagents, minimal specialized equipment (two permanent magnets, a ruler or a capillary with calibrated length markings) and no electrical power to obtain a quantitative readout of analyte concentration. With further development, the method may be useful in resource-limited or point-of-care settings.
    Lab on a Chip 12/2014; · 5.70 Impact Factor
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    ABSTRACT: Spectrally encoded confocal microscopy (SECM) is a reflectance confocal microscopy technology that can rapidly image large areas of luminal organs at microscopic resolution. One of the main challenges for large-area SECM imaging in vivo is maintaining the same imaging depth within the tissue when patient motion and tissue surface irregularity are present. In this paper, we report the development of a miniature vari-focal objective lens that can be used in an SECM endoscopic probe to conduct adaptive focusing and to maintain the same imaging depth during in vivo imaging. The vari-focal objective lens is composed of an aspheric singlet with an NA of 0.5, a miniature water chamber, and a thin elastic membrane. The water volume within the chamber was changed to control curvature of the elastic membrane, which subsequently altered the position of the SECM focus. The vari-focal objective lens has a diameter of 5 mm and thickness of 4 mm. A vari-focal range of 240 μm was achieved while maintaining lateral resolution better than 2.6 μm and axial resolution better than 26 μm. Volumetric SECM images of swine esophageal tissues were obtained over the vari-focal range of 260 μm. SECM images clearly visualized cellular features of the swine esophagus at all focal depths, including basal cell nuclei, papillae, and lamina propria.
    Biomedical Optics Express 12/2014; 5(12). · 3.50 Impact Factor
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    ABSTRACT: The hydrophobic effect—the tendency of nonpolar solutes to aggregate in aqueous solution, and the driving force of many biomolecular recognition events—arises from the energetically favorable rearrangement of molecules of water. A detailed understanding of the mechanism by which these rearrangements alter the thermodynamics of ligand-protein interactions is essential for (i) predicting the thermodynamic influence of conditions that alter solvation structure (e.g. the presence of other solutes, structural changes in interacting species) and for (ii) exploiting the hydrophobic effect in the rational design of tight-binding ligands. In this work, we studied the thermodynamic repercussions of incremental perturbations to solvation structure by examining the influence of Hofmeister anions on the thermodynamics of hydrophobic interactions between Human Carbonic Anhydrase II (HCA, EC 4.2.11) and arylsulfonamide ligands. Using a combination of calorimetry, x-ray crystallography, and molecular dynamics simulations, we show that chaotropes displace the zinc-bound water inside the active site of HCAII, triggering rearrangements in networks of water that give rise to large and nearly compensating changes in the enthalpy and entropy of binding. These changes scale with the surface tension increment of these ions and, eventually, give rise to an entropically dominated hydrophobic effect that differs dramatically from the enthalpically dominated effect that governs HCAII-arylsulfonamide association in the absence of Hofmeister anions. We will discuss the implications of these results for existing theories of hydrophobic ligand-protein interactions.
    14 AIChE Annual Meeting; 11/2014
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    ABSTRACT: Diagnostic tests in resource-limited settings require technologies that are affordable and easy to use with minimal infrastructure. Colorimetric detection methods that produce results that are readable by eye, without reliance on specialized and expensive equipment, have great utility in these settings. We report a colorimetric method that integrates a paper-based immunoassay with a rapid, visible-light-induced polymerization to provide high visual contrast between a positive and a negative result. Using Plasmodium falciparum histidine-rich protein 2 as an example, we demonstrate that this method allows visual detection of proteins in complex matrices such as human serum and provides quantitative information regarding analyte levels when combined with cellphone-based imaging. It also allows the user to decouple the capture of analyte from signal amplification and visualization steps.
    Lab on a Chip 11/2014; · 5.70 Impact Factor
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    ABSTRACT: Molecular rectification is a particularly attractive phenomenon to examine in studying structure-property relationships in charge transport across molecular junctions, since the tunneling currents across the same molecular junction are measured, at opposite biases, with the same electrodes, molecule(s), and contacts. This type of experiment minimizes the complexities arising from measurements of current densities at one polarity using replicate junctions. This paper describes a new organic molecular rectifier: a junction having the structure AgTS/S(CH2)11-4-methyl-2,2'-bipyridyl//Ga2O3/EGaIn (AgTS: template-stripped silver substrate; EGaIn: eutectic gallium-indium alloy) which shows reproducible rectification with mean r+ = |J(+1.0V)|/|J(-1.0V)| ~85 ± 2. This system is important because rectification occurs at polarity opposite to that of the analogous but much more extensively studied systems based on ferrocene. It establishes that rectification is due to the SAM, and not to redox reactions involving the Ga2O3 film. Comparisons among SAM-based junctions incorporating the Ga2O3/EGaIn top-electrode and a variety of heterocyclic terminal groups indicate that the metal-free bipyridyl group, not other features of the junction, is responsible for the rectification. The paper also describes a structural concept that unifies values of rectification taken from a variety of literature sources.
    Journal of the American Chemical Society 11/2014; · 11.44 Impact Factor
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    ABSTRACT: This paper compares rates of charge transport across self-assembled monolayers (SAMs) of n-alkanethiolates having odd and even numbers of carbon atoms (nodd and neven) using junctions with the structure MTS/SAM//Ga2O3/EGaIn (M = Au or Ag). Measurements of current density, J(V), across SAMs of n-alkanethiolates on AuTS and AgTS demonstrated a statistically significant odd-even effect on AuTS, but not on AgTS, that could be detected using this technique. Statistical analysis showed the values of tunneling current density across SAMs of n-alkanethiolates on AuTS with nodd and neven belong to two separate sets, and while there is a significant difference between the values of injection current density, J0, for these two series (log|J0Au,even| = 4.0±0.3 and log|J0Au,odd| = 4.5±0.3), the values of tunneling decay constant, β, for nodd and neven alkyl chains are indistinguishable (βAu,even = 0.73±0.02 Å-1, and βAu,odd= 0.74±0.02 Å-1). A comparison of electrical characteristics across junctions of n-alkanethiolate SAMs on gold and silver electrodes yields indistinguishable values of β and J0, and indicates that a change that substantially alters the tilt angle of the alkyl chain (and, therefore, the thickness of the SAM) has no influence on the injection current density across SAMs of n-alkanethiolates.
    Journal of the American Chemical Society 11/2014; · 11.44 Impact Factor
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    ABSTRACT: doi: 10.1021/ac5020782
    Analytical Chemistry 11/2014; · 5.83 Impact Factor
  • Article: Ionic skin
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    ABSTRACT: Electronic skins (i.e., stretchable sheets of distributed sensors) report signals using electrons, whereas natural skins report signals using ions. Here, ionic conductors are used to create a new type of sensory sheet, called "ionic skin". Ionic skins are highly stretchable, transparent, and biocompatible. They readily measure strains from 1% to 500%, and pressure as low as 1 kPa.
    Advanced Materials 10/2014; · 15.41 Impact Factor
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    ABSTRACT: This paper describes the design and fabrication of ion-sensing Electrochemical Paper-based Analytical Devices (EPADs) in which a miniaturized paper reference electrode is integrated with a small ion-selective paper electrode (ISPE) for potentiometric measurements. Ion-sensing EPADs use printed wax barriers to define electrochemical sample and reference zones. Single-layer EPADs for sensing of chloride ions include wax-defined sample and reference zones that each incorporates a Ag/AgCl electrode. In EPADs developed for other electrolytes (potassium, sodium, and calcium ions), a PVC-based ion-selective membrane is added to separate the sample zone from a paper indicator electrode. After the addition of a small volume (less than 10 L) of sample and reference solutions to different zones, ion-sensing EPADs exhibit a linear response, over three orders of magnitude, in ranges of electrolyte concentrations that are relevant to a variety of applications, with a slope close to the theoretical value (59.2/z mV). Ion-selective EPADs provide a portable, inexpensive, and disposable way of measuring concentrations of electrolyte ions in aqueous solutions.
    Analytical Chemistry 09/2014; · 5.83 Impact Factor
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    ABSTRACT: Although effective low-cost interventions exist, child mortality attributable to sickle cell disease (SCD) remains high in low-resource areas due, in large part, to the lack of accessible diagnostic methods. The presence of dense (ρ > 1.120 g/cm(3)) cells is characteristic of SCD. The fluid, self-assembling step-gradients in density created by aqueous multiphase systems (AMPSs) identifies SCD by detecting dense cells. AMPSs separate different forms of red blood cells by density in a microhematocrit centrifuge and provide a visual means to distinguish individuals with SCD from those with normal hemoglobin or with nondisease, sickle-cell trait in under 12 min. Visual evaluation of a simple two-phase system identified the two main subclasses of SCD [homozygous (Hb SS) and heterozygous (Hb SC)] with a sensitivity of 90% (73-98%) and a specificity of 97% (86-100%). A three-phase system identified these two types of SCD with a sensitivity of 91% (78-98%) and a specificity of 88% (74-98%). This system could also distinguish between Hb SS and Hb SC. To the authors' knowledge, this test demonstrates the first separation of cells by density with AMPSs, and the usefulness of AMPSs in point-of-care diagnostic hematology.
    Proceedings of the National Academy of Sciences 09/2014; · 9.81 Impact Factor
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    ABSTRACT: This paper demonstrates the enrichment of reticulocytes by centrifuging whole blood through aqueous multiphase systems (AMPSs)—immiscible phases of solutions of polymers that form step-gradients in density. The interfaces of an AMPS concentrate cells; this concentration facilitates the extraction of blood enriched for reticulocytes. AMPS enrich reticulocytes from blood from both healthy and hemochromatosis donors. Varying the osmolality and density of the phases of AMPS provides different levels of enrichment and yield of reticulocytes. A maximum enrichment of reticulocytemia of 64 ± 3 % was obtained from donors with hemochromatosis. When used on peripheral blood from normal donors, AMPS can provide a higher yield of enriched reticulocytes and a higher proportion of reticulocytes expressing CD71 than differential centrifugation followed by centrifugation over Percoll. Blood enriched for reticulocytes by AMPS could be useful for research on malaria. Several species of malaria parasites show a preference to invade young erythrocytes and reticulocytes; this preference complicates in vitro cultivation of these species in human blood. Plasmodium knowlesi malaria parasites invade normal human blood enriched for reticulocytes by AMPSs at a rate 2.2 times greater (p-value < 0.01) than they invade unenriched blood. Parasite invasion in normal blood enriched by AMPS was 1.8 times greater (p-value < 0.05) than in blood enriched to a similar reticulocytemia by differential centrifugation followed by centrifugation over Percoll. The enrichment of reticulocytes that are invaded by malaria parasites demonstrates that AMPSs can provide a label-free method to enrich cells for biological research.
    American Journal of Hematology 09/2014; · 3.48 Impact Factor
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    ABSTRACT: Many processes involve the movement of a disordered collection of small particles (e.g., powders, grain, dust, and granular foods). These particles move chaotically, interact randomly among themselves, and gain electrical charge by contact electrification. Understanding the mechanisms of contact electrification of multiple interacting particles has been challenging, in part due to the complex movement and interactions of the particles. To examine the processes contributing to contact electrification at the level of single particles, a system was constructed in which an array of millimeter-sized polymeric beads of different materials were agitated on a dish. The dish was filled almost completely with beads, such that beads did not exchange positions. At the same time, during agitation, there was sufficient space for collisions with neighboring beads. The charge of the beads was measured individually after agitation. Results of systematic variations in the organization and composition of the interacting beads showed that three mechanisms determined the steady-state charge of the beads: (i) contact electrification (charging of beads of different materials), (ii) contact de-electrification (discharging of beads of the same charge polarity to the atmosphere), and (iii) a long-range influence across beads not in contact with one another (occurring, plausibly, by diffusion of charge from a bead with a higher charge to a bead with a lower charge of the same polarity).
    Journal of the American Chemical Society 08/2014; · 11.44 Impact Factor
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    ABSTRACT: This paper describes several noncontact methods of orienting objects in 3D space using Magnetic Levitation (MagLev). The methods use two permanent magnets arranged coaxially with like poles facing and a container containing a paramagnetic liquid in which the objects are suspended. Absent external forcing, objects levitating in the device adopt predictable static orientations; the orientation depends on the shape and distribution of mass within the objects. The orientation of objects of uniform density in the MagLev device shows a sharp geometry-dependent transition: an analytical theory rationalizes this transition and predicts the orientation of objects in the MagLev device. Manipulation of the orientation of the levitating objects in space is achieved in two ways: (i) by rotating and/or translating the MagLev device while the objects are suspended in the paramagnetic solution between the magnets; (ii) by moving a small external magnet close to the levitating objects while keeping the device stationary. Unlike mechanical agitation or robotic selection, orienting using MagLev is possible for objects having a range of different physical characteristics (e.g., different shapes, sizes, and mechanical properties from hard polymers to gels and fluids). MagLev thus has the potential to be useful for sorting and positioning components in 3D space, orienting objects for assembly, constructing noncontact devices, and assembling objects composed of soft materials such as hydrogels, elastomers, and jammed granular media.
    Proceedings of the National Academy of Sciences 08/2014; · 9.81 Impact Factor
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    ABSTRACT: Self-assembled monolayers (SAMs), prepared by reaction of terminal n-alkynes (HC≡C(CH</sub>2)</sub>nCH</sub>3, n = 5, 7, 9, and 11) with Au(111) at 60</sup>oC were characterized using scanning tunneling microscopy (STM), infra-red reflection absorption spectroscopy (IRRAS), X-ray photoelectron spectroscopy (XPS), and contact angles of water. In contrast to previous spectroscopic studies of this type of SAMs, these combined microscopic and spectroscopic experiments confirm formation of highly-ordered SAMs having packing densities and molecular chain orientations very similar to those of alkanethiolates on Au(111). Physical properties-hydrophobicity, high surface order, and packing density-also suggest that SAMs of alkynes are similar to SAMs of alkanethiols. The formation of high-quality SAMs from alkynes requires careful preparation and manipulation of reactants in an oxygen-free environment: trace quantities of oxygen lead to oxidized contaminants and disordered surface films. The oxidation process occurs during formation of the SAM; via oxidation of the -C≡C- group (most likely catalyzed by the gold substrate in the presence of O</sub>2).
    Journal of the American Chemical Society 08/2014; · 11.44 Impact Factor

Publication Stats

61k Citations
6,419.53 Total Impact Points

Institutions

  • 1984–2015
    • Harvard University
      • Department of Chemistry and Chemical Biology
      Cambridge, Massachusetts, United States
  • 2012
    • Beth Israel Deaconess Medical Center
      • Division of Infectious Diseases
      Boston, MA, United States
    • VU University Amsterdam
      • Department of Molecular Cell Physiology
      Amsterdam, North Holland, Netherlands
  • 2011
    • National University of Singapore
      • Department of Chemistry
      Singapore, Singapore
  • 2010
    • University of Alicante
      Alicante, Valencia, Spain
    • Hebrew University of Jerusalem
      Yerushalayim, Jerusalem District, Israel
    • Washington University in St. Louis
      • Department of Energy, Environmental, and Chemical Engineering
      Saint Louis, MO, United States
    • Lawrence Livermore National Laboratory
      • Physical & Life Sciences Directorate
      Livermore, CA, United States
  • 2002–2008
    • Harvard Medical School
      Boston, Massachusetts, United States
    • Cornell University
      Итак, New York, United States
  • 2007
    • Universiteit Twente
      Enschede, Overijssel, Netherlands
    • University of Wisconsin, Madison
      • Department of Biochemistry
      Madison, MS, United States
  • 2005
    • University of Texas at Austin
      • Department of Chemistry and Biochemistry
      Austin, Texas, United States
  • 2002–2004
    • California Institute of Technology
      Pasadena, California, United States
  • 2003
    • University of Washington Seattle
      • Department of Materials Science and Engineering
      Seattle, WA, United States
    • University of Illinois, Urbana-Champaign
      • Department of Chemistry
      Urbana, IL, United States
  • 1967–2002
    • Massachusetts Institute of Technology
      Cambridge, Massachusetts, United States
  • 1999
    • University of Massachusetts Boston
      Boston, Massachusetts, United States
  • 1995
    • University of Pennsylvania
      • Department of Chemistry
      Philadelphia, PA, United States