Robert Langer

Massachusetts Institute of Technology, Cambridge, Massachusetts, United States

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Publications (932)6894.26 Total impact

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    ABSTRACT: Depth resolved and en face OCT visualization in vivo may have important clinical applications in endoscopy. We demonstrate a high speed, two-dimensional (2D) distal scanning capsule with a micromotor for fast rotary scanning and a pneumatic actuator for precision longitudinal scanning. Longitudinal position measurement and image registration were performed by optical tracking of the pneumatic scanner. The 2D scanning device enables high resolution imaging over a small field of view and is suitable for OCT as well as other scanning microscopies. Large field of view imaging for screening or surveillance applications can also be achieved by proximally pulling back or advancing the capsule while scanning the distal high-speed micromotor. Circumferential en face OCT was demonstrated in living swine at 250 Hz frame rate and 1 MHz A-scan rate using a MEMS tunable VCSEL light source at 1300 nm. Cross-sectional and en face OCT views of the upper and lower gastrointestinal tract were generated with precision distal pneumatic longitudinal actuation as well as proximal manual longitudinal actuation. These devices could enable clinical studies either as an adjunct to endoscopy, attached to an endoscope, or as a swallowed tethered capsule for non-endoscopic imaging without sedation. The combination of ultrahigh speed imaging and distal scanning capsule technology could enable both screening and surveillance applications.
    Biomedical Optics Express 04/2015; 6(4). DOI:10.1364/BOE.6.001146 · 3.50 Impact Factor
  • Giovanni Traverso, Robert Langer
    Nature 03/2015; 519(7544):S19. DOI:10.1038/519S19a · 42.35 Impact Factor
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    ABSTRACT: Targeted RNA delivery to lung endothelial cells has potential for treatment for conditions that involve inflammation, such as chronic asthma, and obstructive pulmonary disease. To this end, chemically-modified dendrimer nanomaterials were synthesized and optimized for targeted small interfering RNA (siRNA) delivery to lung vasculature. Using a combinatorial approach, the free amines on multigenerational poly(amido amine) and poly(propylenimine) dendrimers were substituted with alkyl chains of increasing length. The top performing materials from in vivo screens were found to primarily target tie2-expressing lung endothelial cells. At high doses, the dendrimer-lipid derivatives did not cause chronic increases in proinflammatory cytokines. We believe these materials have potential as agents for the pulmonary delivery of RNA therapeutics.
    Nano Letters 03/2015; DOI:10.1021/nl5048972 · 13.03 Impact Factor
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    ABSTRACT: Cellular microarrays have become extremely useful in expediting the investigation of large libraries of (bio)materials for both in vitro and in vivo biomedical applications. An exceedingly simple strategy is developed for the fabrication of non-cell-adhesive substrates supporting the immobilization of diverse (bio)material features, including both monomeric and polymeric adhesion molecules (e.g., RGD and polylysine), hydrogels, and polymers. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    Advanced Healthcare Materials 03/2015; 4(4). DOI:10.1002/adhm.201400594
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    ABSTRACT: Mouldable hydrogels that flow on applied stress and rapidly self-heal are increasingly utilized as they afford minimally invasive delivery and conformal application. Here we report a new paradigm for the fabrication of self-assembled hydrogels with shear-thinning and self-healing properties employing rationally engineered polymer-nanoparticle (NP) interactions. Biopolymer derivatives are linked together by selective adsorption to NPs. The transient and reversible interactions between biopolymers and NPs enable flow under applied shear stress, followed by rapid self-healing when the stress is relaxed. We develop a physical description of polymer-NP gel formation that is utilized to design biocompatible gels for drug delivery. Owing to the hierarchical structure of the gel, both hydrophilic and hydrophobic drugs can be entrapped and delivered with differential release profiles, both in vitro and in vivo. The work introduces a facile and generalizable class of mouldable hydrogels amenable to a range of biomedical and industrial applications.
    Nature Communications 02/2015; 6:6295. DOI:10.1038/ncomms7295 · 10.74 Impact Factor
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    ABSTRACT: Since its discovery and isolation, exogenous insulin has dramatically changed the outlook for patients with diabetes. However, even when patients strictly follow an insulin regimen, serious complications can result as patients experience both hyperglycemic and hypoglycemic states. Several chemically or genetically modified insulins have been developed that tune the pharmacokinetics of insulin activity for personalized therapy. Here, we demonstrate a strategy for the chemical modification of insulin intended to promote both long-lasting and glucose-responsive activity through the incorporation of an aliphatic domain to facilitate hydrophobic interactions, as well as a phenylboronic acid for glucose sensing. These synthetic insulin derivatives enable rapid reversal of blood glucose in a diabetic mouse model following glucose challenge, with some derivatives responding to repeated glucose challenges over a 13-h period. The best-performing insulin derivative provides glucose control that is superior to native insulin, with responsiveness to glucose challenge improved over a clinically used long-acting insulin derivative. Moreover, continuous glucose monitoring reveals responsiveness matching that of a healthy pancreas. This synthetic approach to insulin modification could afford both long-term and glucose-mediated insulin activity, thereby reducing the number of administrations and improving the fidelity of glycemic control for insulin therapy. The described work is to our knowledge the first demonstration of a glucose-binding modified insulin molecule with glucose-responsive activity verified in vivo.
    Proceedings of the National Academy of Sciences 02/2015; DOI:10.1073/pnas.1424684112 · 9.81 Impact Factor
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    ABSTRACT: Low-frequency ultrasound presents an attractive method for transdermal drug delivery. The controlled, yet non-specific nature of enhancement broadens the range of therapeutics that can be delivered, while minimizing necessary reformulation efforts for differing compounds. Long and inconsistent treatment times, however, have partially limited the attractiveness of this method. Building on recent advances made in this area, the simultaneous use of low- and high-frequency ultrasound is explored in a physiologically relevant experimental setup to enable the translation of this treatment to testing in vivo. Dual-frequency ultrasound, utilizing 20kHz and 1MHz wavelengths simultaneously, was found to significantly enhance the size of localized transport regions (LTRs) in both in vitro and in vivo models while decreasing the necessary treatment time compared to 20kHz alone. Additionally, LTRs generated by treatment with 20kHz+1MHz were found to be more permeable than those generated with 20kHz alone. This was further corroborated with pore-size estimates utilizing hindered-transport theory, in which the pores in skin treated with 20kHz+1MHz were calculated to be significantly larger than the pores in skin treated with 20kHz alone. This demonstrates for the first time that LTRs generated with 20kHz+1MHz are also more permeable than those generated with 20kHz alone, which could broaden the range of therapeutics and doses administered transdermally. With regard to safety, treatment with 20kHz+1MHz both in vitro and in vivo appeared to result in no greater skin disruption than that observed in skin treated with 20kHz alone, an FDA-approved modality. This study demonstrates that dual-frequency ultrasound is more efficient and effective than single-frequency ultrasound and is well-tolerated in vivo. Copyright © 2015. Published by Elsevier B.V.
    Journal of Controlled Release 02/2015; 202. DOI:10.1016/j.jconrel.2015.02.002 · 7.26 Impact Factor
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    ABSTRACT: High-density lipoprotein (HDL) is a natural nanoparticle that exhibits an intrinsic affinity for atherosclerotic plaque macrophages. Its natural targeting capability as well as the option to incorporate lipophilic payloads, e.g., imaging or therapeutic components, in both the hydrophobic core and the phospholipid corona make the HDL platform an attractive nanocarrier. To realize controlled release properties, we developed a hybrid polymer/HDL nanoparticle comprised of a lipid/apolipoprotein coating that encapsulates a poly(lactic-co-glycolic acid) (PLGA) core. This novel HDL-like nanoparticle (PLGA-HDL) displayed natural HDL characteristics, including preferential uptake by macrophages and a good cholesterol efflux capacity, combined with a typical PLGA nanoparticle slow release profile. In vivo studies carried out with an ApoE knockout mouse model of atherosclerosis showed clear accumulation of PLGA-HDL nanoparticles in atherosclerotic plaques, which co-localized with plaque macrophages. This bio-mimetic platform integrates the targeting capacity of HDL bio-mimetic nanoparticles with the characteristic versatility of PLGA based nanocarriers.
    Bioconjugate Chemistry 02/2015; DOI:10.1021/bc500517k · 4.82 Impact Factor
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    ABSTRACT: A transesterfication reaction is used to synthesize tri-thiol-functionalized-ethoxylated polyols that are combined with polyethylene glycol diacrylates to form a biodegradable hydrogel library. Hydrogels display nonswelling equilibration and offer temporal control over material degradation and the release of biomolecules. Demonstrated in vitro biocompatibility makes this a versatile platform that can be used for local drug delivery to volume-constrained anatomical sites.
    Advanced Materials 01/2015; 27(1). DOI:10.1002/adma.201403724 · 15.41 Impact Factor
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    ABSTRACT: Current treatments to control pathological or unwanted immune responses often use broadly immunosuppressive drugs. New approaches to induce antigen-specific immunological tolerance that control both cellular and humoral immune responses are desirable. Here we describe the use of synthetic, biodegradable nanoparticles carrying either protein or peptide antigens and a tolerogenic immunomodulator, rapamycin, to induce durable and antigen-specific immune tolerance, even in the presence of potent Toll-like receptor agonists. Treatment with tolerogenic nanoparticles results in the inhibition of CD4+ and CD8+ T-cell activation, an increase in regulatory cells, durable B-cell tolerance resistant to multiple immunogenic challenges, and the inhibition of antigen-specific hypersensitivity reactions, relapsing experimental autoimmune encephalomyelitis, and antibody responses against coagulation factor VIII in hemophilia A mice, even in animals previously sensitized to antigen. Only encapsulated rapamycin, not the free form, could induce immunological tolerance. Tolerogenic nanoparticle therapy represents a potential novel approach for the treatment of allergies, autoimmune diseases, and prevention of antidrug antibodies against biologic therapies.
    Proceedings of the National Academy of Sciences 12/2014; 112(2). DOI:10.1073/pnas.1408686111 · 9.81 Impact Factor
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    ABSTRACT: Cell-based therapy is a promising modality to address many unmet medical needs. In addition to genetic engineering, material-based, biochemical, and physical science-based approaches have emerged as novel approaches to modify cells. Non-genetic engineering of cells has been applied in delivering therapeutics to tissues, homing of cells to the bone marrow or inflammatory tissues, cancer imaging, immunotherapy, and remotely controlling cellular functions. This new strategy has unique advantages in disease therapy and is complementary to existing gene-based cell engineering approaches. A better understanding of cellular systems and different engineering methods will allow us to better exploit engineered cells in biomedicine. Here, we review non-genetic cell engineering techniques and applications of engineered cells, discuss the pros and cons of different methods, and provide our perspectives on future research directions.
    Advanced Drug Delivery Reviews 12/2014; DOI:10.1016/j.addr.2014.12.003 · 12.71 Impact Factor
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    ABSTRACT: A library of dendrimers was synthesized and optimized for targeted small interfering RNA (siRNA) delivery to different cell subpopulations within the liver. Using a combinatorial approach, a library of these nanoparticle-forming materials was produced wherein the free amines on multigenerational poly(amido amine) and poly(propylenimine) dendrimers were substituted with alkyl chains of increasing length, and evaluated for their ability to deliver siRNA to liver cell subpopulations. Interestingly, two lead delivery materials could be formulated in a manner to alter their tissue tropism within the liver—with formulations from the same material capable of preferentially delivering siRNA to 1) endothelial cells, 2) endothelial cells and hepatocytes, or 3) endothelial cells, hepatocytes, and tumor cells in vivo. The ability to broaden or narrow the cellular destination of siRNA within the liver may provide a useful tool to address a range of liver diseases.
    Angewandte Chemie 12/2014; 126(52). DOI:10.1002/ange.201408221
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    ABSTRACT: A library of dendrimers was synthesized and optimized for targeted small interfering RNA (siRNA) delivery to different cell subpopulations within the liver. Using a combinatorial approach, a library of these nanoparticle-forming materials was produced wherein the free amines on multigenerational poly(amido amine) and poly(propylenimine) dendrimers were substituted with alkyl chains of increasing length, and evaluated for their ability to deliver siRNA to liver cell subpopulations. Interestingly, two lead delivery materials could be formulated in a manner to alter their tissue tropism within the liver—with formulations from the same material capable of preferentially delivering siRNA to 1) endothelial cells, 2) endothelial cells and hepatocytes, or 3) endothelial cells, hepatocytes, and tumor cells in vivo. The ability to broaden or narrow the cellular destination of siRNA within the liver may provide a useful tool to address a range of liver diseases.
    Angewandte Chemie International Edition 12/2014; 53(52). DOI:10.1002/anie.201408221 · 11.34 Impact Factor
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    ABSTRACT: A new class of material resistant to bacterial attachment has been discovered that is formed from polyacrylates with hydrocarbon pendant groups. In this study, the relationship between the nature of the hydrocarbon moiety and resistance to bacteria is explored, comparing cyclic, aromatic, and linear chemical groups. A correlation is shown between bacterial attachment and a parameter derived from the partition coefficient and the number of rotatable bonds of the materials' pendant groups. This correlation is applicable to 86% of the hydrocarbon pendant moieties surveyed, quantitatively supporting the previous qualitative observation that bacteria are repelled from poly(meth)acrylates containing a hydrophilic ester group when the pendant group is both rigid and hydrophobic. This insight will help inform and predict the further development of polymers resistant to bacterial attachment.
    Advanced Healthcare Materials 12/2014; DOI:10.1002/adhm.201400648
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    ABSTRACT: Nanotechnology-based approaches hold substantial potential for improving the care of patients with diabetes. Nanoparticles are being developed as imaging contrast agents to assist in the early diagnosis of type 1 diabetes. Glucose nanosensors are being incorporated in implantable devices that enable more accurate and patient-friendly real-time tracking of blood glucose levels, and are also providing the basis for glucose-responsive nanoparticles that better mimic the body's physiological needs for insulin. Finally, nanotechnology is being used in non-invasive approaches to insulin delivery and to engineer more effective vaccine, cell and gene therapies for type 1 diabetes. Here, we analyse the current state of these approaches and discuss key issues for their translation to clinical practice.
    dressNature Reviews Drug Discovery 11/2014; 14(1). DOI:10.1038/nrd4477 · 37.23 Impact Factor
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    ABSTRACT: Abstracts: * 051214 Topical Drug Delivery in Ulcerative Colitis Using an Inflammation-targeted Hydrogel.pdf (89.4KB) - Uploading Abstracts
    14 AIChE Annual Meeting; 11/2014
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    ABSTRACT: The in vivo application of aptamers as therapeutics could be improved by enhancing target-specific accumulation while minimizing off-target uptake. We designed a light-triggered system that permits spatiotemporal regulation of aptamer activity in vitro and in vivo. Cell binding by the aptamer was prevented by hybridizing the aptamer to a photo-labile complementary oligonucleotide. Upon irradiation at the tumor site, the aptamer was liberated, leading to prolonged intratumoral retention. The relative distribution of the aptamer to the liver and kidney was also significantly decreased, compared to that of the free aptamer.
    Proceedings of the National Academy of Sciences 11/2014; DOI:10.1073/pnas.1420105111 · 9.81 Impact Factor
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    ABSTRACT: Introduction: Transplantation of donor pancreatic islet cells into diabetics to restore normoglycemia has been common practice for decades. However, major hurdles still exist that drastically limit the efficacy of this treatment for patients. One major problem is the need for immunosuppressive therapies to prevent rejection of transplanted cells. To overcome this barrier efforts have been placed in developing a bioartificial pancreas, whereby islets are encapsulated within a semi-permeable immunoprotective barrier and then transplanted into diabetic patients. The long-term function of the bioartificial pancreas is dependent on its interaction with the host immune system. Immune recognition initiates a cascade of cellular processes leading to foreign body reactions, which include persistent inflammation, fibrosis (walling-off), and damage to the surrounding tissue. These unwanted effects are deleterious to the function and viability of the encapsulated islet cells. Towards the development of more biocompatible hydrogels we investigated the influence of hydrogel geometry on host recognition and fibrosis. Materials and Methods: To investigate our hypothesis we fabricated a series of Ba cross-linked SLG20 alginate microcapsules of varying geometries with precise dimensions. Using wild type C57BL/6 mice, a robust model for fibrosis we interrogated the effects of fibrosis formation on our capsules to identify a unique geometry that proved to be most efficacious at resisting fibrosis. Rat and human derived pancreatic islet cells where then encapsulated lead capsule formulations and transplanted to Streptozocin (STZ) treatment diabetes induced C57BL/6 mice and monitored ability to restore normoglycemia over time. Results and Discussion: Alginate based hydrogels of tuned geometry significantly abrogated foreign body reactions and fibrosis when compared to conventional alginate microcapsules. Tuned hydrogel capsules resisted fibrosis for at least 6 months when transplanted in the intraperitoneal space, a common site for bioartifical pancreas transplantation. Our study of probing immune cells recruited to transplanted materials implicates the limited activation of macrophages, a key driver of host recognition, as central to these truncated foreign body responses. Most significantly, diabetic mice treated with tuned format bioartificial pancreas maintained normoglycemic for over 6 months, producing a 3-fold improvement over mice treated with conventional format alginate based bioartificial pancreas. Conclusions: We have demonstrated that by simply tuning the geometry of transplanted materials we can drastically influence their host recognition and propagation of foreign body reactions. Using these findings we fabricated a tuned format alginate based bioartificial pancreas, which was demonstrated to be significantly longer lasting and more efficacious than conventional format bioartificial pancreas systems. As such, we believe tuned format capsules could lead to a much improved cell encapsulation therapy strategy for type 1 diabetes. Furthermore, we believe that our findings have significant implications on the design of in vivo-transplanted biomedical devices for a range of applications including cell transplantation, controlled drug release, implantable sensors, and prosthesis for tissue engineering.
    14 AIChE Annual Meeting; 11/2014
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    ABSTRACT: Inadvertent battery ingestion in children and the associated morbidity and mortality results in thousands of emergency room visits every year. Given the risk for serious electrochemical burns within hours of ingestion, the current standard of care for the treatment of batteries in the esophagus is emergent endoscopic removal. Safety standards now regulate locked battery compartments in toys, which have resulted in a modest reduction in inadvertent battery ingestion; specifically, 3,461 ingestions were reported in 2009, and 3,366 in 2013. Aside from legislation, minimal technological development has taken place at the level of the battery to limit injury. We have constructed a waterproof, pressure-sensitive coating, harnessing a commercially available quantum tunneling composite. Quantum tunneling composite coated (QTCC) batteries are nonconductive in the low-pressure gastrointestinal environment yet conduct within the higher pressure of standard battery housings. Importantly, this coating technology enables most battery-operated equipment to be powered without modification. If these new batteries are swallowed, they limit the external electrolytic currents responsible for tissue injury. We demonstrate in a large-animal model a significant decrease in tissue injury with QTCC batteries compared with uncoated control batteries. In summary, here we describe a facile approach to increasing the safety of batteries by minimizing the risk for electrochemical burn if the batteries are inadvertently ingested, without the need for modification of most battery-powered devices.
    Proceedings of the National Academy of Sciences 11/2014; DOI:10.1073/pnas.1418423111 · 9.81 Impact Factor
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    ABSTRACT: Biodegradable polymers with high mechanical strength, flexibility and optical transparency, optimal degradation properties and biocompatibility are critical to the success of tissue engineered devices and drug delivery systems. Most biodegradable polymers suffer from a short half life due to rapid degradation upon implantation, exceedingly high stiffness, and limited ability to functionalize the surface with chemical moieties. This work describes the fabrication of microfluidic networks from poly(ester amide), poly(1,3-diamino-2-hydroxypropane-co-polyol sebacate) (APS), a recently developed biodegradable elastomeric poly(ester amide). Microfluidic scaffolds constructed from APS exhibit a much lower Young's Modulus and a significantly longer degradation half-life than those of previously reported systems. The device is fabricated using a modified replica-molding technique, which is rapid, inexpensive, reproducible, and scalable, making the approach ideal for both rapid prototyping and manufacturing of tissue engineering scaffolds.
    Organogenesis 10/2014; 6(4):212-6. DOI:10.4161/org.6.4.12909 · 2.60 Impact Factor

Publication Stats

68k Citations
6,894.26 Total Impact Points

Institutions

  • 1976–2015
    • Massachusetts Institute of Technology
      • • Department of Chemical Engineering
      • • Division of Health Sciences and Technology
      • • Department of Biological Engineering
      Cambridge, Massachusetts, United States
  • 2010–2014
    • Johns Hopkins University
      • • Department of Neurosurgery
      • • Department of Chemical and Biomolecular Engineering
      Baltimore, Maryland, United States
    • Lankenau Institute for Medical Research
      Wynnewood, Oklahoma, United States
  • 1993–2013
    • Harvard Medical School
      • • Department of Surgery
      • • Department of Medicine
      Boston, Massachusetts, United States
  • 1999–2012
    • University of Nottingham
      • Laboratory of Biophysics and Surface Analysis
      Nottigham, England, United Kingdom
    • Massachusetts General Hospital
      • Department of Surgery
      Boston, Massachusetts, United States
  • 1983–2012
    • Boston Children's Hospital
      • • Department of Cardiac Surgery
      • • Children's Hospital Primary Care Center
      Boston, Massachusetts, United States
  • 2011
    • McMaster University
      • Department of Chemical Engineering
      Hamilton, Ontario, Canada
    • Cambridge Institute of Technology
      Ranchi, Jharkhand, India
  • 2005–2010
    • Technion - Israel Institute of Technology
      • Department of Biomedical Engineering
      H̱efa, Haifa District, Israel
  • 2009
    • Lund University
      • Department of Ophthalmology
      Lund, Skane, Sweden
  • 2007–2008
    • University of Coimbra
      • Centro de Neurociências e Biologia Celular (CNC)
      Coimbra, Distrito de Coimbra, Portugal
    • Gwangju Institute of Science and Technology
      • Department of Life Sciences
      Gwangju, Gwangju, South Korea
  • 1993–2007
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2006
    • University of Delaware
      • Department of Materials Science and Engineering
      Newark, DE, United States
    • Columbia University
      • Department of Biomedical Engineering
      New York, New York, United States
    • University of Toronto
      • Department of Chemical Engineering and Applied Chemistry
      Toronto, Ontario, Canada
  • 2004
    • Georgia Institute of Technology
      • School of Chemical & Biomolecular Engineering
      Atlanta, GA, United States
    • Università degli studi di Parma
      • Department of Pharmacy
      Parma, Emilia-Romagna, Italy
  • 2003–2004
    • Case Western Reserve University
      • • Department of Biomedical Engineering
      • • Department of Macromolecular Science and Engineering
      Cleveland, OH, United States
    • Yale University
      New Haven, Connecticut, United States
    • University of Wisconsin–Madison
      • Department of Chemical and Biological Engineering
      Madison, Wisconsin, United States
  • 2002–2004
    • University of California, San Francisco
      • Department of Surgery
      San Francisco, CA, United States
  • 1999–2001
    • Duke University
      Durham, North Carolina, United States
  • 1996
    • Wilford Hall Ambulatory Surgery Center
      Lackland Air Force Base, Texas, United States
    • William Penn University
      University Park, Florida, United States
  • 1992
    • 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