Donald E Ingber

Harvard University, Cambridge, Massachusetts, United States

Are you Donald E Ingber?

Claim your profile

Publications (339)2290.85 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Trans-epithelial electrical resistance (TEER) measurements are widely used as real-time, non-destructive, and label-free measurements of epithelial and endothelial barrier function. TEER measurements are ideal for characterizing tissue barrier function in organs-on-chip studies for drug testing and investigation of human disease models; however, published reports using this technique have reported highly conflicting results even with identical cell lines and experimental setups. The differences are even more dramatic when comparing measurements in conventional Transwell systems with those obtained in microfluidic systems. Our goal in this work was therefore to enhance the fidelity of TEER measurements in microfluidic organs-on-chips, specifically using direct current (DC) measurements of TEER, as this is the most widely used method reported in the literature. Here we present a mathematical model that accounts for differences measured in TEER between microfluidic chips and Transwell systems, which arise from differences in device geometry. The model is validated by comparing TEER measurements obtained in a microfluidic gut-on-a-chip device versus in a Transwell culture system. Moreover, we show that even small gaps in cell coverage (e.g., 0.4%) are sufficient to cause a significant (~80%) drop in TEER. Importantly, these findings demonstrate that TEER measurements obtained in microfluidic systems, such as organs-on-chips, require special consideration, specifically when results are to be compared with measurements obtained from Transwell systems.
    Lab on a Chip 11/2014; · 5.70 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Obstruction of normal blood flow, which occurs in a variety of diseases, including thromboembolism in stroke and atherosclerosis, is a leading cause of death and long-term adult disability in the Western world. This review focuses on a novel nanotherapeutic drug-delivery platform that is mechanically activated within blood vessels by high-fluid shear stresses to selectively target drugs to sites of vascular obstruction. In vitro and in vivo studies have shown that this approach can be used to efficiently lyse clots using a significantly lower amount of thrombolytic drug than is required when administered in a soluble formulation. This nanotherapeutic strategy can potentially improve both the efficacy and safety of thrombolytic drugs, particularly in patients who are at high risk for brain hemorrhage, and thus provide a new approach for the treatment of many life-threatening and debilitating vascular disorders.
    JAMA Neurology 11/2014; · 7.58 Impact Factor
  • [Show abstract] [Hide abstract]
    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
  • Source
  • Source
  • [Show abstract] [Hide abstract]
    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;
  • Source
  • Sangeeta N Bhatia, Donald E Ingber
    [Show abstract] [Hide abstract]
    ABSTRACT: An organ-on-a-chip is a microfluidic cell culture device created with microchip manufacturing methods that contains continuously perfused chambers inhabited by living cells arranged to simulate tissue- and organ-level physiology. By recapitulating the multicellular architectures, tissue-tissue interfaces, physicochemical microenvironments and vascular perfusion of the body, these devices produce levels of tissue and organ functionality not possible with conventional 2D or 3D culture systems. They also enable high-resolution, real-time imaging and in vitro analysis of biochemical, genetic and metabolic activities of living cells in a functional tissue and organ context. This technology has great potential to advance the study of tissue development, organ physiology and disease etiology. In the context of drug discovery and development, it should be especially valuable for the study of molecular mechanisms of action, prioritization of lead candidates, toxicity testing and biomarker identification.
    Nature Biotechnology 08/2014; · 32.44 Impact Factor
  • Javier G. Fernandez, Donald E. Ingber
    [Show abstract] [Hide abstract]
    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
    [Show abstract] [Hide abstract]
    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
  • [Show abstract] [Hide abstract]
    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;
  • Source
  • Source
  • [Show abstract] [Hide abstract]
    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
  • [Show abstract] [Hide abstract]
    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
  • [Show abstract] [Hide abstract]
    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
  • Source
    Donald E. Ingber, Ning Wang, Dimitrije Stamenovic
    [Show abstract] [Hide abstract]
    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
    [Show abstract] [Hide abstract]
    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
  • Source
    [Show abstract] [Hide abstract]
    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
  • [Show abstract] [Hide abstract]
    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

Publication Stats

35k Citations
2,290.85 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
  • 1989–2014
    • Harvard Medical School
      • • Department of Surgery
      • • Department of Pathology
      Boston, 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
  • 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
    • Zhejiang University
      • Department of Civil Engineering
      Hangzhou, Zhejiang Sheng, China
    • University of Toledo
      Toledo, Ohio, United States
    • University of Florida
      • Department of Chemical Engineering
      Gainesville, FL, United States
  • 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
  • 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
    • Wolfson Childrens Hospital
      Jacksonville, Florida, United States
  • 1981
    • Yale-New Haven Hospital
      New Haven, Connecticut, United States