Person:
Langer, Robert

Profile Picture

Email Address

AA Acceptance Date

Birth Date

Research Projects

Organizational Units

Job Title

Last Name

Langer

First Name

Robert

Name

Langer, Robert
Author's Publications: search.filters.isAuthorOfPublication.0e50e5ec-7b2c-4559-a0c5-a1bdbf0e35a7

Search Results

Now showing 1 - 10 of 57
  • No Thumbnail Available
    Publication
    Robotically handled whole-tissue culture system for the screening of oral drug formulations
    (Springer Science and Business Media LLC, 2020-04-27) von Erlach, Thomas; Saxton, Sarah; Shi, Yunhua; Reker, Daniel; Minahan, Daniel; Javid, Farhad; Lee, Young-Ah Lucy; Schoellhammer, Carl; Esfandiary, Tina; Cleveland, Cody; Booth, Lucas; Lin, Jiaqi; Levy, Hannah; Blackburn, Sophie; Hayward, Alison; Langer, Robert; Traverso, Giovanni
    For nearly four decades cancer-derived cell line monolayers have served as the recognized standard for the modeling of gastrointestinal (GI) absorption and have been widely used as a tool for oral drug development. However, they show limited in vivo predictability. We have developed approaches to cultivate porcine GI tissue and enable it to function ex vivo for prolonged periods. We then created an interface design that can achieve fully automated high-throughput interrogation of whole segments of the GI tract. This GI Tract-Tissue Robotic Interface System (GI-TRIS) demonstrated high predictive capacity of human oral drug absorption (Spearman correlation coefficient of 0.906 vs 0.302 for Caco-2 cell based systems) while allowing a sample throughput of several thousand samples per day in a fully automated robotic facility. To examine the capacity of the GI-TRIS, we analyzed the intestinal absorption of 2930 formulations with the peptide drug oxytocin resulting in the discovery of a novel enhancer that resulted in an 11.3-fold increase in oral bioavailability of oxytocin in vivo in a large animal model while no disruption of the intestinal tissue was observed. In sum, the GI-TRIS system has the potential to transform oral drug formulation development and introduces the ORIS concept as a pre-clinical strategy for a wide range of applications.
  • No Thumbnail Available
    Publication
    Long-Term Implant Fibrosis Prevention in Rodents and Non-Human Primates Using Localized Deliverable Crystals
    (Nature Publishing Group, 2019-06-24) Farah, Shady; Doloff, Joshua; Han, Hye Jung; Olafson, Katy; McAvoy, Malia; Graham, Adam; Langer, Robert; Anderson, Daniel; Sadraei, Atieh; Vyas, Keval; Tam, Hok Hei; Holliser-Locke, Jennifer; Kowalski, Piotr; Griffin, Marissa; Ashley, Meng; McGarrigle, James; Oberholzer, Jose; Weir, Gordon; Greiner, Dale
    Implantable medical devices have revolutionized modern medicine. However, immune-mediated foreign body response (FBR) to the materials of these devices can limit their function or even induce failure. Here we describe long-term controlled release formulations for local anti-inflammatory release through the development of compact, solvent-free crystals. The compact lattice structure of these crystals allows for very slow, surface dissolution and high drug density. These formulations suppress FBR in both rodents and non-human primates for at least 1.3 years and 6 months, respectively. Formulations inhibited fibrosis across multiple implant sites—subcutaneous, intraperitoneal and intramuscular. In particular incorporation of GW2580, a Colony Stimulating Factor 1 Receptor (CSF1R) inhibitor, into a range of devices including human islet microencapsulation systems, electrode-based continuous glucose-sensing monitors and muscle-stimulating devices, inhibits fibrosis, thereby allowing for extended function. We believe that local, long-term controlled release with the crystal formulations described here enhances and extends function in a range of medical devices and provides a generalized solution to the local immune response to implanted biomaterials.
  • No Thumbnail Available
    Publication
    A Luminal Unfolding Microneedle Injector for Oral Delivery of Macromolecules
    (Springer Science and Business Media LLC, 2019-10) Abramson, Alex; Caffarel-Salvador, Ester; Soares, Vance; Minahan, Daniel; Tian, Ryan Yu; Lu, Xiaoya; Dellal, David; Gao, Yuan; Kim, Soyoung; Wainer, Jacob; Collins, Joy; Tamang, Siddartha; Hayward, Alison; Yoshitake, Tadayuki; Lee, Hsiang-Chieh; Fujimoto, James; Fels, Johannes; Frederiksen, Morten Revsgaard; Rahbek, Ulrik; Roxhed, Niclas; Langer, Robert; Traverso, Giovanni
    Insulin and other injectable biologic drugs transformed the treatment of patients suffering from diabetes1,2, yet patients and healthcare providers often prefer to use and prescribe less effective orally dosed medications3–5. Compared to subcutaneously administered drugs, oral formulations create less patient discomfort4, demonstrate greater chemical stability at high temperatures6, and don’t generate biohazardous needle waste7. An oral dosage form for biologic medications is ideal; however, macromolecule drugs are not readily absorbed into the bloodstream through the gastrointestinal tract8. We developed an ingestible capsule, termed the Luminal Unfolding Microneedle Injector (LUMI), which allows for the oral delivery of biologic drugs by rapidly propelling dissolvable drug-loaded microneedles into intestinal tissue using a set of unfolding arms. During ex vivo human and in vivo swine studies the device consistently delivered the microneedles to the tissue without causing complete thickness perforations. Using insulin as a model drug we showed that, when actuated, the LUMI provided a faster pharmacokinetic uptake profile and a systemic uptake greater than 10% compared to a subcutaneous injection over a 4 hour sampling period. With the ability to load a multitude of microneedle formulations, the device can serve as a platform to orally deliver therapeutic doses of macromolecule drugs.
  • Thumbnail Image
    Publication
    Macroporous Nanowire Nanoelectronic Scaffolds for Synthetic Tissues
    (Nature Publishing Group, 2012) Tian, Bozhi; Liu, Jia; Dvir, Tal; Jin, Lihua; Tsui, Jonathan H.; Qing, Quan; Suo, Zhigang; Langer, Robert; Kohane, Daniel; Lieber, Charles
    The development of three-dimensional (3D) synthetic biomaterials as structural and bioactive scaffolds is central to fields ranging from cellular biophysics to regenerative medicine. As of yet, these scaffolds cannot electrically probe the physicochemical and biological microenvironments throughout their 3D and macroporous interior, although this capability could have a marked impact in both electronics and biomaterials. Here, we address this challenge using macroporous, flexible and free-standing nanowire nanoelectronic scaffolds (nanoES), and their hybrids with synthetic or natural biomaterials. 3D macroporous nanoES mimic the structure of natural tissue scaffolds, and they were formed by self-organization of coplanar reticular networks with built-in strain and by manipulation of 2D mesh matrices. NanoES exhibited robust electronic properties and have been used alone or combined with other biomaterials as biocompatible extracellular scaffolds for 3D culture of neurons, cardiomyocytes and smooth muscle cells. Furthermore, we show the integrated sensory capability of the nanoES by real-time monitoring of the local electrical activity within 3D nanoES/cardiomyocyte constructs, the response of 3D-nanoES-based neural and cardiac tissue models to drugs, and distinct pH changes inside and outside tubular vascular smooth muscle constructs.
  • Thumbnail Image
    Publication
    Genetic and hypoxic alterations of the microRNA-210-ISCU1/2 axis promote iron–sulfur deficiency and pulmonary hypertension
    (BlackWell Publishing Ltd, 2015) White, Kevin; Lu, Yu; Annis, Sofia; Hale, Andrew E; Chau, B Nelson; Dahlman, James E; Hemann, Craig; Opotowsky, Alexander; Vargas, Sara; Rosas, Ivan; Perrella, Mark; Osorio, Juan C; Haley, Kathleen; Graham, Brian B; Kumar, Rahul; Saggar, Rajan; Saggar, Rajeev; Wallace, W Dean; Ross, David J; Khan, Omar F; Bader, Andrew; Gochuico, Bernadette R; Matar, Majed; Polach, Kevin; Johannessen, Nicolai M; Prosser, Haydn M; Anderson, Daniel; Langer, Robert; Zweier, Jay L; Bindoff, Laurence A; Systrom, David; Waxman, Aaron; Jin, Richard C; Chan, Stephen Y
    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.
  • Thumbnail Image
    Publication
    Cytosolic delivery of siRNA by ultra-high affinity dsRNA binding proteins
    (Oxford University Press, 2017) Yang, Nicole J.; Kauke, Monique J.; Sun, Fangdi; Yang, Lucy F.; Maass, Katie F.; Traxlmayr, Michael W.; Yu, Yao; Xu, Yingda; Langer, Robert; Anderson, Daniel; Wittrup, K. Dane
    Abstract Protein-based methods of siRNA delivery are capable of uniquely specific targeting, but are limited by technical challenges such as low potency or poor biophysical properties. Here, we engineered a series of ultra-high affinity siRNA binders based on the viral protein p19 and developed them into siRNA carriers targeted to the epidermal growth factor receptor (EGFR). Combined in trans with a previously described endosome-disrupting agent composed of the pore-forming protein Perfringolysin O (PFO), potent silencing was achieved in vitro with no detectable cytotoxicity. Despite concerns that excessively strong siRNA binding could prevent the discharge of siRNA from its carrier, higher affinity continually led to stronger silencing. We found that this improvement was due to both increased uptake of siRNA into the cell and improved pharmacodynamics inside the cell. Mathematical modeling predicted the existence of an affinity optimum that maximizes silencing, after which siRNA sequestration decreases potency. Our study characterizing the affinity dependence of silencing suggests that siRNA-carrier affinity can significantly affect the intracellular fate of siRNA and may serve as a handle for improving the efficiency of delivery. The two-agent delivery system presented here possesses notable biophysical properties and potency, and provide a platform for the cytosolic delivery of nucleic acids.
  • Thumbnail Image
    Publication
    Circulating Magnetic Microbubbles for Localized Real-Time Control of Drug Delivery by Ultrasonography-Guided Magnetic Targeting and Ultrasound
    (Ivyspring International Publisher, 2018) Chertok, Beata; Langer, Robert
    Image-guided and target-selective modulation of drug delivery by external physical triggers at the site of pathology has the potential to enable tailored control of drug targeting. Magnetic microbubbles that are responsive to magnetic and acoustic modulation and visible to ultrasonography have been proposed as a means to realize this drug targeting strategy. To comply with this strategy in vivo, magnetic microbubbles must circulate systemically and evade deposition in pulmonary capillaries, while also preserving magnetic and acoustic activities in circulation over time. Unfortunately, challenges in fabricating magnetic microbubbles with such characteristics have limited progress in this field. In this report, we develop magnetic microbubbles (MagMB) that display strong magnetic and acoustic activities, while also preserving the ability to circulate systemically and evade pulmonary entrapment. Methods: We systematically evaluated the characteristics of MagMB including their pharmacokinetics, biodistribution, visibility to ultrasonography and amenability to magneto-acoustic modulation in tumor-bearing mice. We further assessed the applicability of MagMB for ultrasonography-guided control of drug targeting. Results: Following intravenous injection, MagMB exhibited a 17- to 90-fold lower pulmonary entrapment compared to previously reported magnetic microbubbles and mimicked circulation persistence of the clinically utilized Definity microbubbles (>10 min). In addition, MagMB could be accumulated in tumor vasculature by magnetic targeting, monitored by ultrasonography and collapsed by focused ultrasound on demand to activate drug deposition at the target. Furthermore, drug delivery to target tumors could be enhanced by adjusting the magneto-acoustic modulation based on ultrasonographic monitoring of MagMB in real-time. Conclusions: Circulating MagMB in conjunction with ultrasonography-guided magneto-acoustic modulation may provide a strategy for tailored minimally-invasive control over drug delivery to target tissues.
  • Thumbnail Image
    Publication
    Colony Stimulating Factor-1 Receptor is a central component of the foreign body response to biomaterial implants in rodents and non-human primates
    (2017) Doloff, Joshua C.; Veiseh, Omid; Vegas, Arturo J.; Tam, Hok Hei; Farah, Shady; Ma, Minglin; Li, Jie; Bader, Andrew; Chiu, Alan; Sadraei, Atieh; Aresta-Dasilva, Stephanie; Griffin, Marissa; Jhunjhunwala, Siddharth; Webber, Matthew; Siebert, Sean; Tang, Katherine; Chen, Michael; Langan, Erin; Dholokia, Nimit; Thakrar, Raj; Qi, Meirigeng; Oberholzer, Jose; Greiner, Dale L.; Langer, Robert; Anderson, Daniel
    Host recognition and immune-mediated foreign body response (FBR) to biomaterials can compromise the performance of implanted medical devices. To identify key cell and cytokine targets, here we perform in-depth systems analysis of innate and adaptive immune system responses to implanted biomaterials in rodents and non-human primates. While macrophages are indispensable to the fibrotic cascade, surprisingly neutrophils and complement are not. Macrophages, via CXCL13, lead to downstream B cell recruitment, which further potentiated fibrosis, as confirmed by B cell knock out and CXCL13 neutralization. Interestingly, Colony Stimulating Factor-1 Receptor (CSF1R) is significantly increased following implantation of multiple biomaterial classes: ceramic, polymer, and hydrogel. Its inhibition, like macrophage depletion, leads to complete loss of fibrosis, but spares other macrophage functions such as wound healing, ROS production, and phagocytosis. Our results indicate targeting CSF1R may allow for a more selective method of fibrosis inhibition, and improve biomaterial biocompatibility without the need for broad immunosuppression.
  • Thumbnail Image
    Publication
    Harnessing single-cell genomics to improve the physiological fidelity of organoid-derived cell types
    (BioMed Central, 2018) Mead, Benjamin E.; Ordovas-Montanes, Jose; Braun, Alexandra P.; Levy, Lauren E.; Bhargava, Prerna; Szucs, Matthew J.; Ammendolia, Dustin A.; MacMullan, Melanie A.; Yin, Xiaolei; Hughes, Travis; Wadsworth, Marc H.; Ahmad, Rushdy; Rakoff-Nahoum, Seth; Carr, Steven A.; Langer, Robert; Collins, James; Shalek, Alex K.; Karp, Jeffrey
    Background: Single-cell genomic methods now provide unprecedented resolution for characterizing the component cell types and states of tissues such as the epithelial subsets of the gastrointestinal tract. Nevertheless, functional studies of these subsets at scale require faithful in vitro models of identified in vivo biology. While intestinal organoids have been invaluable in providing mechanistic insights in vitro, the extent to which organoid-derived cell types recapitulate their in vivo counterparts remains formally untested, with no systematic approach for improving model fidelity. Results: Here, we present a generally applicable framework that utilizes massively parallel single-cell RNA-seq to compare cell types and states found in vivo to those of in vitro models such as organoids. Furthermore, we leverage identified discrepancies to improve model fidelity. Using the Paneth cell (PC), which supports the stem cell niche and produces the largest diversity of antimicrobials in the small intestine, as an exemplar, we uncover fundamental gene expression differences in lineage-defining genes between in vivo PCs and those of the current in vitro organoid model. With this information, we nominate a molecular intervention to rationally improve the physiological fidelity of our in vitro PCs. We then perform transcriptomic, cytometric, morphologic and proteomic characterization, and demonstrate functional (antimicrobial activity, niche support) improvements in PC physiology. Conclusions: Our systematic approach provides a simple workflow for identifying the limitations of in vitro models and enhancing their physiological fidelity. Using adult stem cell-derived PCs within intestinal organoids as a model system, we successfully benchmark organoid representation, relative to that in vivo, of a specialized cell type and use this comparison to generate a functionally improved in vitro PC population. We predict that the generation of rationally improved cellular models will facilitate mechanistic exploration of specific disease-associated genes in their respective cell types. Electronic supplementary material The online version of this article (10.1186/s12915-018-0527-2) contains supplementary material, which is available to authorized users.
  • Thumbnail Image
    Publication
    Mechanistic understanding of in vivo protein corona formation on polymeric nanoparticles and impact on pharmacokinetics
    (Nature Publishing Group UK, 2017) Bertrand, Nicolas; Grenier, Philippe; Mahmoudi, Morteza; Lima, Eliana M.; Appel, Eric A.; Dormont, Flavio; Lim, Jong-Min; Karnik, Rohit; Langer, Robert; Farokhzad, Omid
    In vitro incubation of nanomaterials with plasma offer insights on biological interactions, but cannot fully explain the in vivo fate of nanomaterials. Here, we use a library of polymer nanoparticles to show how physicochemical characteristics influence blood circulation and early distribution. For particles with different diameters, surface hydrophilicity appears to mediate early clearance. Densities above a critical value of approximately 20 poly(ethylene glycol) chains (MW 5 kDa) per 100 nm2 prolong circulation times, irrespective of size. In knockout mice, clearance mechanisms are identified for nanoparticles with low and high steric protection. Studies in animals deficient in the C3 protein showed that complement activation could not explain differences in the clearance of nanoparticles. In nanoparticles with low poly(ethylene glycol) coverage, adsorption of apolipoproteins can prolong circulation times. In parallel, the low-density-lipoprotein receptor plays a predominant role in the clearance of nanoparticles, irrespective of poly(ethylene glycol) density. These results further our understanding of nanopharmacology.