Donald E Ingber

Harvard University, Cambridge, Massachusetts, United States

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Publications (336)2240.54 Total impact

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    ABSTRACT: Thrombosis and biofouling of extracorporeal circuits and indwelling medical devices cause significant morbidity and mortality worldwide. We apply a bioinspired, omniphobic coating to tubing and catheters and show that it completely repels blood and suppresses biofilm formation. The coating is a covalently tethered, flexible molecular layer of perfluorocarbon, which holds a thin liquid film of medical-grade perfluorocarbon on the surface. This coating prevents fibrin attachment, reduces platelet adhesion and activation, suppresses biofilm formation and is stable under blood flow in vitro. Surface-coated medical-grade tubing and catheters, assembled into arteriovenous shunts and implanted in pigs, remain patent for at least 8 h without anticoagulation. This surface-coating technology could reduce the use of anticoagulants in patients and help to prevent thrombotic occlusion and biofouling of medical devices.
    Nature Biotechnology 10/2014; · 32.44 Impact Factor
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    ABSTRACT: Here we describe a blood-cleansing device for sepsis therapy inspired by the spleen, which can continuously remove pathogens and toxins from blood without first identifying the infectious agent. Blood flowing from an infected individual is mixed with magnetic nanobeads coated with an engineered human opsonin-mannose-binding lectin (MBL)-that captures a broad range of pathogens and toxins without activating complement factors or coagulation. Magnets pull the opsonin-bound pathogens and toxins from the blood; the cleansed blood is then returned back to the individual. The biospleen efficiently removes multiple Gram-negative and Gram-positive bacteria, fungi and endotoxins from whole human blood flowing through a single biospleen unit at up to 1.25 liters per h in vitro. In rats infected with Staphylococcus aureus or Escherichia coli, the biospleen cleared >90% of bacteria from blood, reduced pathogen and immune cell infiltration in multiple organs and decreased inflammatory cytokine levels. In a model of endotoxemic shock, the biospleen increased survival rates after a 5-h treatment.
    Nature medicine. 09/2014;
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  • Javier G. Fernandez, Donald E. Ingber
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    ABSTRACT: Despite the urgent need for sustainable materials for mass‐produced commercial products, and the incredible diversity of naturally biodegradable materials with desired structural properties, the use of regenerated biomaterials in modern engineering remains extremely limited. Chitin is a prime example: although it is responsible for some of the most remarkable mechanical properties exhibited by natural materials, including nacre, insect cuticle, and crustacean shells, and it is the most abundant organic compound on earth after cellulose, it has not been utilized in manufacturing strategies for commercial applications. Here we describe how analysis of differences in the molecular arrangement and mechanical properties of chitosan polymer that result from different processing methods led to development of a scalable manufacturing strategy for production of large three‐dimensional (3D) objects of chitosan. This chitosan fabrication method offers a new pathway for large‐scale production of fully compostable engineered components with complex forms, and establishes chitosan as a viable bioplastic that could potentially be used in place of existing non‐degradable plastics for commercial manufacturing. Large‐scale functional components made of chitosan are fabricated. The mechanical properties of chitosan depend on the processing method, and their study result in new manufacturing methods to produce large objects of chitosan with mechanical properties similar to common synthetic polymers. These chitosan materials are completely recyclable, compostable, and their breakdown products support plant growth.
    Macromolecular Materials and Engineering 08/2014; 299(8). · 2.34 Impact Factor
  • Javier G. Fernandez, Donald E. Ingber
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    ABSTRACT: Cover: A chess piece made of a chitosan‐based composite (queen) behind a commercial chess piece (king). The study on the correlation between molecular arrangement and mechanical characteristics of chitinous materials leads to use of the second most abundant biopolymer on earth for manufacture of several large‐scale 3D objects and composites. Further details can be found in the article by J. G. Fernandez and D. E. Ingber* on page 932.
    Macromolecular Materials and Engineering 08/2014; 299(8). · 2.34 Impact Factor
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    ABSTRACT: Microfluidic water-in-oil droplets that serve as separate, chemically isolated compartments can be applied for single-cell analysis; however, to investigate encapsulated cells effectively over prolonged time periods, an array of droplets must remain stationary on a versatile substrate for optimal cell compatibility. We present here a platform of unique geometry and substrate versatility that generates a stationary nanodroplet array by using wells branching off a main microfluidic channel. These droplets are confined by multiple sides of a nanowell and are in direct contact with a biocompatible substrate of choice. The device is operated by a unique and reversed loading procedure that eliminates the need for fine pressure control or external tubing. Fluorocarbon oil isolates the droplets and provides soluble oxygen for the cells. By using this approach, the metabolic activity of single adherent cells was monitored continuously over time, and the concentration of viable pathogens in blood-derived samples was determined directly by measuring the number of colony-formed droplets. The method is simple to operate, requires a few microliters of reagent volume, is portable, is reusable, and allows for cell retrieval. This technology may be particularly useful for multiplexed assays for which prolonged and simultaneous visual inspection of many isolated single adherent or nonadherent cells is required.
    Proceedings of the National Academy of Sciences of the United States of America. 07/2014;
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    ABSTRACT: Certain lower organisms achieve organ regeneration by reverting differentiated cells into tissue-specific progenitors that re-enter embryonic programs. During muscle regeneration in the urodele amphibian, post-mitotic multinucleated skeletal myofibers transform into mononucleated proliferating cells upon injury, and a transcription factor-msx1 plays a role in their reprograming. Whether this powerful regeneration strategy can be leveraged in mammals remains unknown, as it has not been demonstrated that the dedifferentiated progenitor cells arising from muscle cells overexpressing Msx1 are lineage-specific and possess the same potent regenerative capability as their amphibian counterparts. Here we show that ectopic expression of Msx1 reprograms post-mitotic, multinucleated, primary mouse myotubes to become proliferating mononuclear cells. These dedifferentiated cells reactivate genes expressed by embryonic muscle progenitor cells and generate only muscle tissue in vivo both in an ectopic location and inside existing muscle. More importantly, distinct from adult muscle satellite cells, these cells appear both to fuse with existing fibers and to regenerate myofibers in a robust and time-dependent manner. Upon transplantation into a degenerating muscle, these dedifferentiated cells generated a large number of myofibers that increased over time and replenished almost half of the cross-sectional area of the muscle in only 12 weeks. Our study demonstrates that mammals can harness a muscle regeneration strategy used by lower organisms when the same molecular pathway is activated. Stem Cells 2014.
    Stem Cells 06/2014; · 7.70 Impact Factor
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    ABSTRACT: Nanoparticle-based therapeutics are poised to become a leading delivery strategy for cancer treatment because they potentially offer higher selectivity, reduced toxicity, longer clearance times, and increased efficacy compared to conventional systemic therapeutic approaches. This article reviews existing nanoparticle technologies and methods that are used to target drugs to treat cancer by altering signal transduction or modulating the tumor microenvironment. We also consider the implications of recent advances in the nanotherapeutics field for the future of cancer therapy.
    Advanced drug delivery reviews 05/2014; · 11.96 Impact Factor
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    ABSTRACT: Current in vitro hematopoiesis models fail to demonstrate the cellular diversity and complex functions of living bone marrow; hence, most translational studies relevant to the hematologic system are conducted in live animals. Here we describe a method for fabricating 'bone marrow-on-a-chip' that permits culture of living marrow with a functional hematopoietic niche in vitro by first engineering new bone in vivo, removing it whole and perfusing it with culture medium in a microfluidic device. The engineered bone marrow (eBM) retains hematopoietic stem and progenitor cells in normal in vivo-like proportions for at least 1 week in culture. eBM models organ-level marrow toxicity responses and protective effects of radiation countermeasure drugs, whereas conventional bone marrow culture methods do not. This biomimetic microdevice offers a new approach for analysis of drug responses and toxicities in bone marrow as well as for study of hematopoiesis and hematologic diseases in vitro.
    Nature Methods 05/2014; · 23.57 Impact Factor
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    Donald E. Ingber, Ning Wang, Dimitrije Stamenovic
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    ABSTRACT: The recent convergence between physics and biology has led many physicists to enter the fields of cell and developmental biology. One of the most exciting areas of interest has been the emerging field of mechanobiology that centers on how cells control their mechanical properties, and how physical forces regulate cellular biochemical responses, a process that is known as mechanotransduction. In this article, we review the central role that tensegrity (tensional integrity) architecture, which depends on tensile prestress for its mechanical stability, plays in biology. We describe how tensional prestress is a critical governor of cell mechanics and function, and how use of tensegrity by cells contributes to mechanotransduction. Theoretical tensegrity models are also described that predict both quantitative and qualitative behaviors of living cells, and these theoretical descriptions are placed in context of other physical models of the cell. In addition, we describe how tensegrity is used at multiple size scales in the hierarchy of life—from individual molecules to whole living organisms—to both stabilize three-dimensional form and to channel forces from the macroscale to the nanoscale, thereby facilitating mechanochemical conversion at the molecular level.
    Reports on Progress in Physics 04/2014; 77:046603. · 13.23 Impact Factor
  • Donald E Ingber, Ning Wang, Dimitrije Stamenović
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    ABSTRACT: The recent convergence between physics and biology has led many physicists to enter the fields of cell and developmental biology. One of the most exciting areas of interest has been the emerging field of mechanobiology that centers on how cells control their mechanical properties, and how physical forces regulate cellular biochemical responses, a process that is known as mechanotransduction. In this article, we review the central role that tensegrity (tensional integrity) architecture, which depends on tensile prestress for its mechanical stability, plays in biology. We describe how tensional prestress is a critical governor of cell mechanics and function, and how use of tensegrity by cells contributes to mechanotransduction. Theoretical tensegrity models are also described that predict both quantitative and qualitative behaviors of living cells, and these theoretical descriptions are placed in context of other physical models of the cell. In addition, we describe how tensegrity is used at multiple size scales in the hierarchy of life-from individual molecules to whole living organisms-to both stabilize three-dimensional form and to channel forces from the macroscale to the nanoscale, thereby facilitating mechanochemical conversion at the molecular level.
    Reports on Progress in Physics 04/2014; 77(4):046603. · 13.23 Impact Factor
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    ABSTRACT: A biologically inspired thermoresponsive polymer has been developed that mechanically induces tooth differentiation in vitro and in vivo by promoting mesenchymal cell compaction as seen in each pore of the scaffold. This normally occurs during the physiological mesenchymal condensation response that triggers tooth formation in the embryo.
    Advanced Materials 02/2014; · 14.83 Impact Factor
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    ABSTRACT: Solid tumors are characterized by high interstitial fluid pressure, which drives fluid efflux from the tumor core. Tumor-associated interstitial flow (IF) at a rate of ∼3 µm/s has been shown to induce cell migration in the upstream direction (rheotaxis). However, the molecular biophysical mechanism that underlies upstream cell polarization and rheotaxis remains unclear. We developed a microfluidic platform to investigate the effects of IF fluid stresses imparted on cells embedded within a collagen type I hydrogel, and we demonstrate that IF stresses result in a transcellular gradient in β1-integrin activation with vinculin, focal adhesion kinase (FAK), FAK(PY397), F actin, and paxillin-dependent protrusion formation localizing to the upstream side of the cell, where matrix adhesions are under maximum tension. This previously unknown mechanism is the result of a force balance between fluid drag on the cell and matrix adhesion tension and is therefore a fundamental, but previously unknown, stimulus for directing cell movement within porous extracellular matrix.
    Proceedings of the National Academy of Sciences 02/2014; 111(7):2447-52. · 9.81 Impact Factor
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    ABSTRACT: Although a number of growth factors and receptors are known to control tumor angiogenesis, relatively little is known about the mechanism by which these factors influence directional endothelial cell migration required for cancer microvessel formation. Recently, the focal adhesion protein, paxillin, was shown to be required for directional migration of fibroblasts in vitro. Here we show that paxillin knockdown enhances endothelial cell migration in vitro and stimulates angiogenesis during normal development and in response to tumor angiogenic factors in vivo. Paxillin produces these effects by decreasing expression of neuropilin 2 (NRP2). Moreover, soluble factors secreted by tumors that stimulate vascular ingrowth, including VEGF, also decrease endothelial cell expression of paxillin and NRP2, and over-expression of NRP2 reverses these effects. These results suggest that the VEGF-paxillin-NRP2 pathway could represent a new therapeutic target for cancer and other angiogenesis-related diseases.
    Journal of Cell Science 02/2014; · 5.88 Impact Factor
  • Adam Lucio, Donald Ingber, Otger Campas
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    ABSTRACT: Here we describe a detailed protocol to produce biocompatible droplets that permit the measurement of mechanical stresses at cell and tissue scales. The droplets can be used as force transducers in vivo, ex vivo and in vitro, to measure mechanical stresses in situ, in 3D and time. Versatile and modular droplet coatings using biotinylated molecules, such as ligands for specific adhesion receptors, enable the targeting of specific tissues or cells. Droplet sizes can be varied to measure forces at different scales (tissue and cell scales) and the range of measurable mechanical stresses ranges within approximately 0.3-100 kPa. The protocol described in this article is divided in three sections. First, we describe the generation and stabilization of biocompatible droplets. Next, we explain the steps necessary to functionalize the droplet surface. Finally, we describe how to characterize the mechanical properties of the droplets, so that they can be used as calibrated mechanical probes. The procedure to generate, stabilize and functionalize the droplets is straightforward and can be completed in about three hours with basic laboratory resources. The calibration of the droplet's mechanical properties to perform quantitative stress measurements is also straightforward, but requires the proper equipment to measure interfacial tension (such as a tensiometer). Calibrated droplets can be used to quantify cell-generated mechanical stresses by analyzing the tri-dimensional shape of the droplet.
    01/2014;
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    ABSTRACT: Development of three dimensional (3D) microenvironments that direct stem cell differentiation into functional cell types remains a major challenge in the field of regenerative medicine. Here, we describe a new platform to address this challenge by utilizing a robotic microarray spotter for testing stem cell fates inside various miniaturized cell-laden gels in a systematic manner. To demonstrate the feasibility of our platform, we evaluated the osteogenic differentiation of human mesenchymal stem cells (hMSCs) within combinatorial 3D niches. We were able to identify specific combinations, that enhanced the expression of osteogenic markers. Notably, these 'hit' combinations directed hMSCs to form mineralized tissue when conditions were translated to 3D macroscale hydrogels, indicating that the miniaturization of the experimental system did not alter stem cell fate. Overall, our findings confirmed that the 3D cell-laden gel microarray can be used for screening of different conditions in a rapid, cost-effective, and multiplexed manner for a broad range of tissue engineering applications.
    Scientific Reports 01/2014; 4:3896. · 5.08 Impact Factor

Publication Stats

34k Citations
2,240.54 Total Impact Points

Institutions

  • 1993–2014
    • Harvard University
      • • Wyss Institute for Biologically Inspired Engineering
      • • Department of Chemistry and Chemical Biology
      • • School of Engineering and Applied Sciences
      • • Department of Environmental Health
      Cambridge, Massachusetts, United States
  • 1987–2014
    • Boston Children's Hospital
      • Department of Pathology
      Boston, Massachusetts, United States
  • 2013
    • Boston Medical Center
      Boston, Massachusetts, United States
    • University of Pennsylvania
      Philadelphia, Pennsylvania, United States
  • 1989–2013
    • Harvard Medical School
      • • Department of Surgery
      • • Department of Pathology
      Boston, Massachusetts, United States
  • 2011
    • The University of Calgary
      Calgary, Alberta, Canada
  • 2009
    • University of Illinois, Urbana-Champaign
      • Department of Mechanical Science and Engineering
      Urbana, IL, United States
  • 2008
    • University of Toledo
      Toledo, Ohio, United States
    • New England Complex Systems Institute
      Cambridge, Massachusetts, United States
    • University of Florida
      • Department of Chemical Engineering
      Gainesville, FL, United States
    • Zhejiang University
      • Department of Civil Engineering
      Hangzhou, Zhejiang Sheng, China
  • 1996–2007
    • Boston University
      • Department of Biomedical Engineering
      Boston, MA, United States
  • 1991–2007
    • Brigham and Women's Hospital
      • • Department of Medicine
      • • Division of Renal Medicine
      Boston, MA, United States
  • 2006
    • Alpert Medical School - Brown University
      • Department of Medicine
      Providence, RI, United States
  • 1991–2004
    • Massachusetts Institute of Technology
      • • Department of Mechanical Engineering
      • • Department of Chemical Engineering
      Cambridge, MA, United States
  • 1999–2003
    • Johns Hopkins University
      • Department of Biomedical Engineering
      Baltimore, MD, United States
    • University of Massachusetts Boston
      Boston, Massachusetts, United States
  • 2002
    • University of California, San Francisco
      San Francisco, California, United States
  • 2000
    • Carnegie Mellon University
      • Department of Materials Science and Engineering
      Pittsburgh, PA, United States
  • 1994
    • The Scripps Research Institute
      La Jolla, California, United States
  • 1990
    • Childrens Hospital of Pittsburgh
      Pittsburgh, Pennsylvania, United States
  • 1981
    • Yale-New Haven Hospital
      New Haven, Connecticut, United States