Robert Langer

Idenix Pharmaceuticals, Inc., Cambridge, Massachusetts, United States

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Publications (949)7217.8 Total impact

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    ABSTRACT: Dynamically restructuring pH-responsive hydrogels are synthesized, employing dynamic covalent chemistry between phenylboronic acid and cis-diol modified poly(ethylene glycol) macromonomers. These gels display shear-thinning behavior, followed by a rapid structural recovery (self-healing). Size-dependent in vitro controlled and glucose-responsive release of proteins from the hydrogel network, as well as the biocompatibility of the gels, are evaluated both in vitro and in vivo.
    Advanced Materials 11/2015; DOI:10.1002/adma.201502902 · 17.49 Impact Factor
  • Dong-Kwon Lim · Ryan G. Wylie · Robert Langer · Daniel S. Kohane ·
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    ABSTRACT: Vascular endothelial growth factor 165 (VEGF165) is an important extracellular protein involved in pathological angiogenesis in diseases such as cancer, wet age-related macular degeneration (wet-AMD) and retinitis pigmentosa. VEGF165 exists in two different isoforms: the angiogenic VEGF165a, and the anti-angiogenic VEGF165b. In some angiogenic diseases the proportion of VEGF165b may be equal to or higher than that of VEGF165a. Therefore, developing therapeutics that inhibit VEGF165a and not VEGF165b may result in greater anti-angiogenic activity and therapeutic benefit. To this end, we report the selective binding properties of sulfated hyaluronic acid (s-HA). Selective biopolymers offer several advantages over antibodies or aptamers including cost effective and simple synthesis, and the ability to make nanoparticles or hydrogels for drug delivery applications or VEGF165a sequestration. Limiting sulfation to the C-6 hydroxyl (C-6 OH) in the N-acetyl-glucosamine repeat unit of hyaluronic acid (HA) resulted in a polymer with strong affinity for VEGF165a but not VEGF165b. Increased sulfation beyond the C-6 OH (i.e. greater than 1 sulfate group per HA repeat unit) resulted in s-HA polymers that bound both VEGF165a and VEGF165b. The C-6 OH sulfated HA (Mw 150 kDa) showed strong binding properties to VEGF165a with a fast association rate constant (Ka; 2.8 × 10(6) M(-1) s(-1)), slow dissociation rate constant (Kd; 2.8 × 10(-3) s(-1)) and strong equilibrium binding constant (KD; ∼1.0 nM)), which is comparable to the non-selective VEGF165 binding properties of the commercialized therapeutic anti-VEGF antibody (Avastin(®)). The C-6 OH sulfated HA also inhibited human umbilical vein endothelial cell (HUVEC) survival and proliferation and human dermal microvascular endothelial cell (HMVEC) tube formation. These results demonstrate that the semi-synthetic natural polymer, C-6 OH sulfated HA, may be a promising biomaterial for the treatment of angiogenesis-related disease.
    Biomaterials 10/2015; 77. DOI:10.1016/j.biomaterials.2015.10.074 · 8.56 Impact Factor
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    ABSTRACT: In vivo implantation of sterile materials and devices results in a foreign body immune response leading to fibrosis of implanted material. Neutrophils, one of the first immune cells to be recruited to implantation sites, have been suggested to contribute to the establishment of the inflammatory microenvironment that initiates the fibrotic response. However, the precise numbers and roles of neutrophils in response to implanted devices remains unclear. Using a mouse model of peritoneal microcapsule implantation, we show 30-500 fold increased neutrophil presence in the peritoneal exudates in response to implants. We demonstrate that these neutrophils secrete increased amounts of a variety of inflammatory cytokines and chemokines. Further, we observe that they participate in the foreign body response through the formation of neutrophil extracellular traps (NETs) on implant surfaces. Our results provide new insight into neutrophil function during a foreign body response to peritoneal implants which has implications for the development of biologically compatible medical devices.
    PLoS ONE 09/2015; 10(9):e0137550. DOI:10.1371/journal.pone.0137550 · 3.23 Impact Factor
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    Shady Farah · Joshua C. Dolof · Daniel G. Anderson · Robert Langer ·
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    ABSTRACT: Chitosan is one of the most reported polysaccharides in drug delivery systems and applications due to its outstanding merits including improved biocompatibility, bioactivity and ease of modification. The main goal of this contribution is to line up the experimental procedures for chitosan nanoparticle formation techniques and chemical modifications for self-assembly of amphiphilic-modified chitosan and their recent drug delivery applications.
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    ABSTRACT: Cardiomyocytes from human stem cells have applications in regenerative medicine and can provide models for heart disease and toxicity screening. Soluble components of the culture system such as growth factors within serum and insoluble components such as the substrate on which cells adhere to are important variables controlling the biological activity of cells. Using a combinatorial materials approach we develop a synthetic, chemically defined cellular niche for the support of functional cardiomyocytes derived from human embryonic stem cells (hESC-CMs) in a serum-free fully defined culture system. Almost 700 polymers were synthesized and evaluated for their utility as growth substrates. From this group, 20 polymers were identified that supported cardiomyocyte adhesion and spreading. The most promising 3 polymers were scaled up for extended culture of hESC-CMs for 15 days and were characterized using patch clamp electrophysiology and myofibril analysis to find that functional and structural phenotype was maintained on these synthetic substrates without the need for coating with extracellular matrix protein. In addition, we found that hESC-CMs cultured on a co-polymer of isobornyl methacrylate and tert-butylamino-ethyl methacrylate exhibited significantly longer sarcomeres relative to gelatin control. The potential utility of increased structural integrity was demonstrated in an in vitro toxicity assay that found an increase in detection sensitivity of myofibril disruption by the anti-cancer drug doxorubicin at a concentration of 0.05 μM in cardiomyocytes cultured on the co-polymer compared to 0.5 μM on gelatin. The chemical moieties identified in this large-scale screen provide chemically defined conditions for the culture and manipulation of hESC-CMs, as well as a framework for the rational design of superior biomaterials. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
    Biomaterials 08/2015; 61. DOI:10.1016/j.biomaterials.2015.05.019 · 8.56 Impact Factor
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    ABSTRACT: There is a clinical need for new, more effective treatments for chronic and debilitating inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis. Targeting drugs selectively to the inflamed intestine may improve therapeutic outcomes and minimize systemic toxicity. We report the development of an inflammation-targeting hydrogel (IT-hydrogel) that acts as a drug delivery system to the inflamed colon. Hydrogel microfibers were generated from ascorbyl palmitate, an amphiphile that is generally recognized as safe (GRAS) by the U.S. Food and Drug Administration. IT-hydrogel microfibers loaded with the anti-inflammatory corticosteroid dexamethasone (Dex) were stable, released drug only upon enzymatic digestion, and demonstrated preferential adhesion to inflamed epithelial surfaces in vitro and in two mouse colitis models in vivo. Dex-loaded IT-hydrogel enemas, but not free Dex enemas, administered every other day to mice with colitis resulted in a significant reduction in inflammation and were associated with lower Dex peak serum concentrations and, thus, less systemic drug exposure. Ex vivo analysis of colon tissue samples from patients with ulcerative colitis demonstrated that IT-hydrogel microfibers adhered preferentially to mucosa from inflamed lesions compared with histologically normal sites. The IT-hydrogel drug delivery platform represents a promising approach for targeted enema-based therapies in patients with colonic IBD.
    Science translational medicine 08/2015; 7(300):300ra128. DOI:10.1126/scitranslmed.aaa5657 · 15.84 Impact Factor
  • Omid Veiseh · Robert Langer ·

    Nature 08/2015; 524(7563):39-40. DOI:10.1038/524039a · 41.46 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):437-437. DOI:10.1158/1538-7445.AM2015-437 · 9.33 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):5538A-5538A. DOI:10.1158/1538-7445.AM2015-5538A · 9.33 Impact Factor
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    ABSTRACT: Shear-thinning injectable hydrogels exploit dynamic noncovalent cross-links to flow upon applied stress and rapidly self-heal once the stress is relaxed. These materials continue to gather interest as they afford minimally invasive deployment in the body for a variety of biomedical applications. Here, we present rationally engineered polymer–nanoparticle (PNP) interactions based on electrostatic forces for the fabrication of self-assembled hydrogels with shear-thinning and self-healing properties. The selective adsorption of negatively charged biopolymers, including hyaluronic acid (HA) and carboxymethylcellulose (CBMC), to biodegradable nanoparticles comprising poly(ethylene glycol)-b-poly(lactic acid) (PEG-b-PLA) is enhanced with a positively charged surfactant, cetyltrimethylammonium bromide (CTAB). We demonstrate that, in this manner, electrostatic interactions can be leveraged to fabricate PNP hydrogels and characterize the viscoelastic properties of the gels imparted by CBMC and HA. This work introduces PNP hydrogels that use common biopolymers without the need for chemical modification, yielding extremely facile preparation and processing, which when coupled with the tunability of their properties are distinguishing features for many important biomedical and industrial applications.
    ACS Macro Letters 07/2015; 4(8):848-852. DOI:10.1021/acsmacrolett.5b00416 · 5.76 Impact Factor
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    ABSTRACT: Devices resident in the stomach-used for a variety of clinical applications including nutritional modulation for bariatrics, ingestible electronics for diagnosis and monitoring, and gastric-retentive dosage forms for prolonged drug delivery-typically incorporate elastic polymers to compress the devices during delivery through the oesophagus and other narrow orifices in the digestive system. However, in the event of accidental device fracture or migration, the non-degradable nature of these materials risks intestinal obstruction. Here, we show that an elastic, pH-responsive supramolecular gel remains stable and elastic in the acidic environment of the stomach but can be dissolved in the neutral-pH environment of the small and large intestines. In a large animal model, prototype devices with these materials as the key component demonstrated prolonged gastric retention and safe passage. These enteric elastomers should increase the safety profile for a wide range of gastric-retentive devices.
    Nature Material 07/2015; 14(10). DOI:10.1038/nmat4355 · 36.50 Impact Factor
  • YongTae Kim · Robert Langer ·
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    ABSTRACT: Nanomedicine is the medical application of nanotechnology for the treatment and prevention of major ailments, including cancer and cardiovascular diseases. Despite the progress and potential of nanomedicines, many such materials fail to reach clinical trials due to critical challenges that include poor reproducibility in high-volume production that have led to failure in animal studies and clinical trials. Recent approaches using microfluidic technology have provided emerging platforms with great potential to accelerate the clinical translation of nanomedicine. Microfluidic technologies for nanomedicine development are reviewed in this chapter, together with a detailed discussion of microfluidic assembly, characterization and evaluation of nanomedicine, and a description of current challenges and future prospects.
    Reviews in Cell Biology and Molecular Medicine, Edited by Robert A. Meyers, 07/2015: pages 127-152;
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    ABSTRACT: Delivery of tissue glues through small-bore needles or trocars is critical for sealing holes, affixing medical devices, or attaching tissues together during minimally invasive surgeries. Inspired by the granule-packaged glue delivery system of sandcastle worms, a nanoparticulate formulation of a viscous hydrophobic light-activated adhesive based on poly(glycerol sebacate)-acrylate is developed. Negatively charged alginate is used to stabilize the nanoparticulate surface to significantly reduce its viscosity and to maximize injectability through small-bore needles. The nanoparticulate glues can be concentrated to ≈30 w/v% dispersions in water that remain localized following injection. With the trigger of a positively charged polymer (e.g., protamine), the nanoparticulate glues can quickly assemble into a viscous glue that exhibits rheological, mechanical, and adhesive properties resembling the native poly(glycerol sebacate)-acrylate based glues. This platform should be useful to enable the delivery of viscous glues to augment or replace sutures and staples during minimally invasive procedures. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    Advanced Healthcare Materials 07/2015; DOI:10.1002/adhm.201500419 · 5.80 Impact Factor
  • Rong Tong · Robert Langer ·
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    ABSTRACT: We review recent progress in cancer nanomedicine to overcome the delivery barriers in tumor microenvironment, including the understanding in the nanomedicine delivery process, stimulus-responsive delivery, and several new strategies to normalize tumor microenvironment. The application of nanomedicine in cancer immunotherapy, a renewed cancer therapy by recent breakthrough, is also highlighted.
    The Cancer Journal 07/2015; 21(4):314-21. DOI:10.1097/PPO.0000000000000123 · 4.24 Impact Factor
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    ABSTRACT: Iron–sulfur (Fe‐S) clusters are essential for mitochondrial metabolism, but their regulation in pulmonary hypertension (PH) remains enigmatic. We demonstrate that alterations of the miR‐210‐ISCU1/2 axis cause Fe‐S deficiencies in vivo and promote PH. In pulmonary vascular cells and particularly endothelium, hypoxic induction of miR‐210 and repression of the miR‐210 targets ISCU1/2 down‐regulated Fe‐S levels. In mouse and human vascular and endothelial tissue affected by PH, miR‐210 was elevated accompanied by decreased ISCU1/2 and Fe‐S integrity. In mice, miR‐210 repressed ISCU1/2 and promoted PH. Mice deficient in miR‐210, via genetic/pharmacologic means or via an endothelial‐specific manner, displayed increased ISCU1/2 and were resistant to Fe‐S‐dependent pathophenotypes and PH. Similar to hypoxia or miR‐210 overexpression, ISCU1/2 knockdown also promoted PH. Finally, cardiopulmonary exercise testing of a woman with homozygous ISCU mutations revealed exercise‐induced pulmonary vascular dysfunction. Thus, driven by acquired (hypoxia) or genetic causes, the miR‐210‐ISCU1/2 regulatory axis is a pathogenic lynchpin causing Fe‐S deficiency and PH. These findings carry broad translational implications for defining the metabolic origins of PH and potentially other metabolic diseases sharing similar underpinnings.
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    ABSTRACT: Genital Chlamydia trachomatis (Ct) infection induces protective immunity that depends on interferon-γ–producing CD4 T cells. By contrast, we report that mucosal exposure to ultraviolet light (UV)–inactivated Ct (UV-Ct) generated regulatory T cells that exacerbated subsequent Ct infection. We show that mucosal immunization with UV-Ct complexed with charge-switching synthetic adjuvant particles (cSAPs) elicited long-lived protection in conventional and humanized mice. UV-Ct–cSAP targeted immunogenic uterine CD11b+CD103– dendritic cells (DCs), whereas UV-Ct accumulated in tolerogenic CD11b–CD103+ DCs. Regardless of vaccination route, UV-Ct–cSAP induced systemic memory T cells, but only mucosal vaccination induced effector T cells that rapidly seeded uterine mucosa with resident memory T cells (TRM cells). Optimal Ct clearance required both TRM seeding and subsequent infection-induced recruitment of circulating memory T cells. Thus, UV-Ct–cSAP vaccination generated two synergistic memory T cell subsets with distinct migratory properties.
    Science 06/2015; 348(6241):1331. DOI:10.1126/science.aaa8205 · 33.61 Impact Factor
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    ABSTRACT: Hydrogels with covalently incorporated trehalose are synthesized using thiol-ene Michael addition. Trehalose hydrogels afford prolonged stabilization and -controlled release of model enzymes in vitro and in vivo as well as preservation of protein stability under heat and -lyophilization stressors. Strong and -ordered hydrogen bonding interactions within covalently incorporated trehalose hydrogels represent a possible mechanism for protein stabilization. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    Advanced Healthcare Materials 06/2015; 4(12). DOI:10.1002/adhm.201500334 · 5.80 Impact Factor
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    ABSTRACT: A scalable and cost-effective synthetic polymer substrate that supports robust expansion and subsequent multilineage differentiation of human pluripotent stem cells (hPSCs) with defined commercial media is presented. This substrate can be applied to common cultureware and used off-the-shelf after long-term storage. Expansion and differentiation of hPSCs are performed entirely on the polymeric surface, enabling the clinical potential of hPSC-derived cells to be realized. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    Advanced Materials 06/2015; 27(27). DOI:10.1002/adma.201501351 · 17.49 Impact Factor
  • Giovanni Traverso · Robert Langer ·

    Science translational medicine 05/2015; 7(289):289ed6-289ed6. DOI:10.1126/scitranslmed.aab1943 · 15.84 Impact Factor
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    ABSTRACT: The efficacy of implanted biomedical devices is often compromised by host recognition and subsequent foreign body responses. Here, we demonstrate the role of the geometry of implanted materials on their biocompatibility in vivo. In rodent and non-human primate animal models, implanted spheres 1.5 mm and above in diameter across a broad spectrum of materials, including hydrogels, ceramics, metals and plastics, significantly abrogated foreign body reactions and fibrosis when compared with smaller spheres. We also show that for encapsulated rat pancreatic islet cells transplanted into streptozotocin-treated diabetic C57BL/6 mice, islets prepared in 1.5-mm alginate capsules were able to restore blood-glucose control for up to 180 days, a period more than five times longer than for transplanted grafts encapsulated within conventionally sized 0.5-mm alginate capsules. Our findings suggest that the in vivo biocompatibility of biomedical devices can be significantly improved simply by tuning their spherical dimensions.
    Nature Material 05/2015; 14(6). DOI:10.1038/nmat4290 · 36.50 Impact Factor

Publication Stats

75k Citations
7,217.80 Total Impact Points


  • 2015
    • Idenix Pharmaceuticals, Inc.
      Cambridge, Massachusetts, United States
  • 1976-2015
    • Massachusetts Institute of Technology
      • • Department of Chemical Engineering
      • • Division of Health Sciences and Technology
      • • Department of Biological Engineering
      • • Department of Chemistry
      Cambridge, Massachusetts, United States
  • 2014
    • David H. Murdock Research Institute
      North Carolina, United States
  • 1989-2014
    • Johns Hopkins University
      • • Department of Neurosurgery
      • • Department of Chemical and Biomolecular Engineering
      Baltimore, Maryland, United States
  • 2010-2013
    • Harvard Medical School
      Boston, Massachusetts, United States
    • Hebrew University of Jerusalem
      • School of Pharmacy
      Jerusalem, Jerusalem District, Israel
  • 2011
    • Cambridge Institute of Technology
      Ranchi, Jharkhand, India
  • 1993-2011
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2007
    • University of Coimbra
      Coímbra, Coimbra, Portugal
    • Gwangju Institute of Science and Technology
      • Department of Life Sciences
      Gwangju, Gwangju, South Korea
  • 2006
    • Columbia University
      • Department of Biomedical Engineering
      New York, New York, United States
  • 2004
    • University of Michigan
      • College of Pharmacy
      Ann Arbor, MI, United States
    • Wellesley College
      • Department of Chemistry
      Уэлсли, Massachusetts, United States
  • 2003-2004
    • Case Western Reserve University
      • • Department of Biomedical Engineering
      • • Department of Macromolecular Science and Engineering
      Cleveland, OH, United States
    • University of Wisconsin–Madison
      • Department of Chemical and Biological Engineering
      Madison, Wisconsin, United States
  • 2002
    • University of California, San Francisco
      • Department of Surgery
      San Francisco, California, United States
  • 1999
    • Massachusetts General Hospital
      • Department of Surgery
      Boston, Massachusetts, United States
    • University of Nottingham
      Nottigham, England, United Kingdom
  • 1983-1997
    • Boston Children's Hospital
      • Children's Hospital Primary Care Center
      Boston, Massachusetts, United States
  • 1995
    • Friedrich-Alexander-University of Erlangen-Nürnberg
      • Division of Pharmaceutical Biology
      Erlangen, Bavaria, Germany
  • 1992-1994
    • Ben-Gurion University of the Negev
      • Department of Chemical Engineering
      Be'er Sheva`, Southern District, Israel
  • 1988
    • University of Massachusetts Boston
      Boston, Massachusetts, United States