Publications by authors named "Robert S Langer"

51 Publications

Controlled delivery of gold nanoparticle-coupled miRNA therapeutics an injectable self-healing hydrogel.

Nanoscale 2021 Nov 24. Epub 2021 Nov 24.

David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge 02142, MA, USA.

Differential expression of microRNAs (miRNAs) plays a role in many diseases, including cancer and cardiovascular diseases. Potentially, miRNAs could be targeted with miRNA-therapeutics. Sustained delivery of these therapeutics remains challenging. This study couples miR-mimics to PEG-peptide gold nanoparticles (AuNP) and loads these AuNP-miRNAs in an injectable, shear thinning, self-assembling polymer nanoparticle (PNP) hydrogel drug delivery platform to improve delivery. Spherical AuNPs coated with fluorescently labelled miR-214 are loaded into an HPMC-PEG-b-PLA PNP hydrogel. Release of AuNP/miRNAs is quantified, AuNP-miR-214 functionality is shown in HEK293 cells, and AuNP-miRNAs are tracked in a 3D bioprinted human model of calcific aortic valve disease (CAVD). Lastly, biodistribution of PNP-AuNP-miR-67 is assessed after subcutaneous injection in C57BL/6 mice. AuNP-miRNA release from the PNP hydrogel demonstrates a linear pattern over 5 days up to 20%. AuNP-miR-214 transfection in HEK293 results in 33% decrease of Luciferase reporter activity. In the CAVD model, AuNP-miR-214 are tracked into the cytoplasm of human aortic valve interstitial cells. Lastly, 11 days after subcutaneous injection, AuNP-miR-67 predominantly clears the liver and kidneys, and fluorescence levels are again comparable to control animals. Thus, the PNP-AuNP-miRNA drug delivery platform provides linear release of functional miRNAs and has potential for applications.
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http://dx.doi.org/10.1039/d1nr04973aDOI Listing
November 2021

A New Approach for Microfabrication of Printed Circuit Boards with Ultrafine Traces.

ACS Appl Mater Interfaces 2019 Sep 13;11(38):35376-35381. Epub 2019 Sep 13.

Langer Lab , Massachusetts Institute of Technology , Cambridge , Massachusetts 02139 , United States.

The advances in micro/nanofabrication techniques have enabled miniaturization of printed circuit boards (PCBs) for various applications such as portable devices, smart sensors, and IoTs, to name a few. PCBs provide electrical connectivity between the components as well as mechanical support. Down-scaling of PCBs is crucial for miniaturization of large systems and devices. Currently, microtraces down to 25 μm can be microfabricated with the current microfabrication processes at an industrial scale. In the present work, we report a new approach for microfabrication of PCBs with trace widths down to 3 μm on commercially available PCB substrates. We used electroplating/electroetching, sputtering, and photolithography to achieve these fine trace sizes. The proposed fabrication technique can be used in microelectronics, system on chip, MEMS, and miniaturized circuits and systems in general.
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http://dx.doi.org/10.1021/acsami.9b08761DOI Listing
September 2019

Nanofibrillar Patches of Commensal Skin Bacteria.

Biomacromolecules 2019 01 19;20(1):102-108. Epub 2018 Jul 19.

Institute of Condensed Matter and Nanosciences , Université Catholique de Louvain , Croix du Sud 1/L7.04.02 , Louvain-la-Neuve , 1348 , Belgium.

We demonstrate entrapment of the commensal skin bacteria Staphylococcus epidermidis in mats composed of soft nanotubes made by membrane-templated layer-by-layer (LbL) assembly. When cultured in broth, the resulting nanofibrillar patches efficiently delay the escape of bacteria and their planktonic growth, while displaying high steady-state metabolic activity. Additionally, the material properties and metabolic activity can be further tuned by postprocessing the patches with additional polysaccharide LbL layers. These patches offer a promising methodology for the fabrication of bacterial skin dressings for the treatment of skin dysbiosis while preventing adverse effects due to bacterial proliferation.
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http://dx.doi.org/10.1021/acs.biomac.8b00735DOI Listing
January 2019

Controlling the Growth of Staphylococcus epidermidis by Layer-By-Layer Encapsulation.

ACS Appl Mater Interfaces 2018 May 3;10(19):16250-16259. Epub 2018 May 3.

David H. Koch Institute for Integrative Cancer Research , Massachusetts Institute of Technology , 500 Main Street , Cambridge , Massachusetts 02139 , United States.

Commensal skin bacteria such as Staphylococcus epidermidis are currently being considered as possible components in skin-care and skin-health products. However, considering the potentially adverse effects of commensal skin bacteria if left free to proliferate, it is crucial to develop methodologies that are capable of maintaining bacteria viability while controlling their proliferation. Here, we encapsulate S. epidermidis in shells of increasing thickness using layer-by-layer assembly, with either a pair of synthetic polyelectrolytes or a pair of oppositely charged polysaccharides. We study the viability of the cells and their delay of growth depending on the composition of the shell, its thickness, the charge of the last deposited layer, and the degree of aggregation of the bacteria which is varied using different coating procedures-among which is a new scalable process that easily leads to large amounts of nonaggregated bacteria. We demonstrate that the growth of bacteria is not controlled by the mechanical properties of the shell but by the bacteriostatic effect of the polyelectrolyte complex, which depends on the shell thickness and charge of its outmost layer, and involves the diffusion of unpaired amine sites through the shell. The lag times of growth are sufficient to prevent proliferation for daily topical applications.
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http://dx.doi.org/10.1021/acsami.8b01988DOI Listing
May 2018

Towards a defined ECM and small molecule based monolayer culture system for the expansion of mouse and human intestinal stem cells.

Biomaterials 2018 Feb 26;154:60-73. Epub 2017 Oct 26.

Division of BioEngineering in Medicine, Department of Medicine, Center for Regenerative Therapeutics, Brigham and Women's Hospital, United States; Harvard Medical School, United States; Harvard Stem Cell Institute, United States; Harvard - Massachusetts Institute of Technology (MIT) Division of Health Sciences and Technology, United States. Electronic address:

Current ISC culture systems face significant challenges such as animal-derived or undefined matrix compositions, batch-to-batch variability (e.g. Matrigel-based organoid culture), and complexity of assaying cell aggregates such as organoids which renders the research and clinical translation of ISCs challenging. Here, through screening for suitable ECM components, we report a defined, collagen based monolayer culture system that supports the growth of mouse and human intestinal epithelial cells (IECs) enriched for an Lgr5 population comparable or higher to the levels found in a standard Matrigel-based organoid culture. The system, referred to as the Bolstering Lgr5 Transformational (BLT) Sandwich culture, comprises a collagen IV-coated porous substrate and a collagen I gel overlay which sandwich an IEC monolayer in between. The distinct collagen cues synergistically regulate IEC attachment, proliferation, and Lgr5 expression through maximizing the engagement of distinct cell surface adhesion receptors (i.e. integrin α2β1, integrin β4) and cell polarity. Further, we apply our BLT Sandwich system to identify that the addition of a bone morphogenetic protein (BMP) receptor inhibitor (LDN-193189) improves the expansion of Lgr5-GFP cells from mouse small intestinal crypts by nearly 2.5-fold. Notably, the BLT Sandwich culture is capable of expanding human-derived IECs with higher LGR5 mRNA levels than conventional Matrigel culture, providing superior expansion of human LGR5 ISCs. Considering the key roles Lgr5 ISCs play in intestinal epithelial homeostasis and regeneration, we envision that our BLT Sandwich culture system holds great potential for understanding and manipulating ISC biology in vitro (e.g. for modeling ISC-mediated gut diseases) or for expanding a large number of ISCs for clinical utility (e.g. for stem cell therapy).
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http://dx.doi.org/10.1016/j.biomaterials.2017.10.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5735007PMC
February 2018

Glucose-responsive insulin by molecular and physical design.

Nat Chem 2017 09;9(10):937-943

Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

The concept of a glucose-responsive insulin (GRI) has been a recent objective of diabetes technology. The idea behind the GRI is to create a therapeutic that modulates its potency, concentration or dosing relative to a patient's dynamic glucose concentration, thereby approximating aspects of a normally functioning pancreas. From the perspective of the medicinal chemist, the GRI is also important as a generalized model of a potentially new generation of therapeutics that adjust potency in response to a critical therapeutic marker. The aim of this Perspective is to highlight emerging concepts, including mathematical modelling and the molecular engineering of insulin itself and its potency, towards a viable GRI. We briefly outline some of the most important recent progress toward this goal and also provide a forward-looking viewpoint, which asks if there are new approaches that could spur innovation in this area as well as to encourage synthetic chemists and chemical engineers to address the challenges and promises offered by this therapeutic approach.
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http://dx.doi.org/10.1038/nchem.2857DOI Listing
September 2017

High-throughput Nuclear Delivery and Rapid Expression of DNA via Mechanical and Electrical Cell-Membrane Disruption.

Nat Biomed Eng 2017 9;1. Epub 2017 Mar 9.

Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Nuclear transfection of DNA into mammalian cells is challenging yet critical for many biological and medical studies. Here, by combining cell squeezing and electric-field-driven transport in a device that integrates microfluidic channels with constrictions and microelectrodes, we demonstrate nuclear delivery of plasmid DNA within 1 hour after treatment, the most rapid DNA expression in a high-throughput setting (up to millions of cells per minute per device). Passing cells at high speed through microfluidic constrictions smaller than the cell diameter mechanically disrupts the cell membrane, allowing a subsequent electric field to further disrupt the nuclear envelope and drive DNA molecules into the cytoplasm and nucleus. By tracking the localization of the ESCRT-III (endosomal sorting complexes required for transport) protein CHMP4B, we show that the integrity of the nuclear envelope is recovered within 15 minutes of treatment. We also provide insight into subcellular delivery by comparing the performance of the disruption-and-field-enhanced method with those of conventional chemical, electroporation, and manual-injection systems.
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http://dx.doi.org/10.1038/s41551-017-0039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5602535PMC
March 2017

Cytosolic delivery of siRNA by ultra-high affinity dsRNA binding proteins.

Nucleic Acids Res 2017 Jul;45(13):7602-7614

Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

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.
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http://dx.doi.org/10.1093/nar/gkx546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5570165PMC
July 2017

Synergistic interactions with PI3K inhibition that induce apoptosis.

Elife 2017 05 31;6. Epub 2017 May 31.

Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, United States.

Activating mutations involving the PI3K pathway occur frequently in human cancers. However, PI3K inhibitors primarily induce cell cycle arrest, leaving a significant reservoir of tumor cells that may acquire or exhibit resistance. We searched for genes that are required for the survival of PI3K mutant cancer cells in the presence of PI3K inhibition by conducting a genome scale shRNA-based apoptosis screen in a mutant human breast cancer cell. We identified 5 genes () whose suppression induced cell death upon PI3K inhibition. We showed that small molecule inhibitors of the PIM2 and ZAK kinases synergize with PI3K inhibition. In addition, using a microscale implementable device to deliver either siRNAs or small molecule inhibitors in vivo, we showed that suppressing these 5 genes with PI3K inhibition induced tumor regression. These observations identify targets whose inhibition synergizes with PI3K inhibitors and nominate potential combination therapies involving PI3K inhibition.
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http://dx.doi.org/10.7554/eLife.24523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5479695PMC
May 2017

Integrated genetic and pharmacologic interrogation of rare cancers.

Nat Commun 2016 06 22;7:11987. Epub 2016 Jun 22.

Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.

Identifying therapeutic targets in rare cancers remains challenging due to the paucity of established models to perform preclinical studies. As a proof-of-concept, we developed a patient-derived cancer cell line, CLF-PED-015-T, from a paediatric patient with a rare undifferentiated sarcoma. Here, we confirm that this cell line recapitulates the histology and harbours the majority of the somatic genetic alterations found in a metastatic lesion isolated at first relapse. We then perform pooled CRISPR-Cas9 and RNAi loss-of-function screens and a small-molecule screen focused on druggable cancer targets. Integrating these three complementary and orthogonal methods, we identify CDK4 and XPO1 as potential therapeutic targets in this cancer, which has no known alterations in these genes. These observations establish an approach that integrates new patient-derived models, functional genomics and chemical screens to facilitate the discovery of targets in rare cancers.
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http://dx.doi.org/10.1038/ncomms11987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4917959PMC
June 2016

Bioinspired Nanoparticulate Medical Glues for Minimally Invasive Tissue Repair.

Adv Healthc Mater 2015 Nov 27;4(16):2587-96. Epub 2015 Jul 27.

Department of Medicine, Center for Regenerative Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Harvard Stem Cell Institute, Harvard-MIT Division of Health Science and Technology, 65 Landsdowne Street, Cambridge, MA, 02139, USA.

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.
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http://dx.doi.org/10.1002/adhm.201500419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4715574PMC
November 2015

Klaus Mosbach tribute.

Biotechnol Bioeng 2015 Apr 20;112(4):645-7. Epub 2015 Jan 20.

Editor-in-Chief, Gilbert Newton Lewis Professor, Dean of College of Chemistry, University of California, Berkeley, CA, USA.

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http://dx.doi.org/10.1002/bit.25507DOI Listing
April 2015

The art of entrepreneurship.

Science 2014 Nov;346(6213):1146

Trisha Gura is a freelance writer who lives in Boston. For more on life and careers visit www.sciencecareers.org.

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http://dx.doi.org/10.1126/science.346.6213.1146DOI Listing
November 2014

High throughput screening for biomaterials discovery.

J Control Release 2014 Sep 30;190:115-26. Epub 2014 Jun 30.

Laboratory of Biophysics and Surface Analysis, School of Pharmacy, The University of Nottingham, Nottingham, NG7 2RD, UK.

Using microarray technologies thousands of biomedical materials can be screened in a rapid, parallel and cost effective fashion to identify the optimum candidate that fulfils a specific biomedical application. High throughput surface characterization (HTSC) of printed microarrays has played a key role in the discovery and development of biomedical materials. This review focuses on the production and HTSC of microarrays, their application in specific biomedical fields and a future perspective on the development of this technology.
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http://dx.doi.org/10.1016/j.jconrel.2014.06.045DOI Listing
September 2014

Photothermally targeted thermosensitive polymer-masked nanoparticles.

Nano Lett 2014 Jul 9;14(7):3697-701. Epub 2014 Jun 9.

Laboratory for Biomaterials and Drug Delivery, §Department of Anesthesiology, Division of Critical Care Medicine, Children's Hospital Boston, Harvard Medical School , 300 Longwood Avenue, Boston, Massachusetts 02115, United States.

The targeted delivery of therapeutic cargos using noninvasive stimuli has the potential to improve efficacy and reduce off-target effects (toxicity). Here, we demonstrate a targeting mechanism that uses a thermoresponsive copolymer to mask a peptide ligand that binds a widely distributed receptor (integrin β1) on the surface of silica core-gold shell nanoparticles. The nanoparticles convert NIR light into heat, which causes the copolymer to collapse, exposing the ligand peptide, allowing cell binding. The use of NIR light could allow targeting of plasmonic nanoparticles deep within tissues. This approach could be extended to a variety of applications including photothermal therapy and drug delivery.
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http://dx.doi.org/10.1021/nl403733zDOI Listing
July 2014

Single compartment drug delivery.

J Control Release 2014 Sep 4;190:157-71. Epub 2014 May 4.

The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Drug design is built on the concept that key molecular targets of disease are isolated in the diseased tissue. Systemic drug administration would be sufficient for targeting in such a case. It is, however, common for enzymes or receptors that are integral to disease to be structurally similar or identical to those that play important biological roles in normal tissues of the body. Additionally, systemic administration may not lead to local drug concentrations high enough to yield disease modification because of rapid systemic metabolism or lack of sufficient partitioning into the diseased tissue compartment. This review focuses on drug delivery methods that physically target drugs to individual compartments of the body. Compartments such as the bladder, peritoneum, brain, eye and skin are often sites of disease and can sometimes be viewed as "privileged," since they intrinsically hinder partitioning of systemically administered agents. These compartments have become the focus of a wide array of procedures and devices for direct administration of drugs. We discuss the rationale behind single compartment drug delivery for each of these compartments, and give an overview of examples at different development stages, from the lab bench to phase III clinical trials to clinical practice. We approach single compartment drug delivery from both a translational and a technological perspective.
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http://dx.doi.org/10.1016/j.jconrel.2014.04.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4179298PMC
September 2014

Adjuvant-carrying synthetic vaccine particles augment the immune response to encapsulated antigen and exhibit strong local immune activation without inducing systemic cytokine release.

Vaccine 2014 May 1;32(24):2882-95. Epub 2014 Mar 1.

Selecta Biosciences, Watertown, MA 02472, USA.

Augmentation of immunogenicity can be achieved by particulate delivery of an antigen and by its co-administration with an adjuvant. However, many adjuvants initiate strong systemic inflammatory reactions in vivo, leading to potential adverse events and safety concerns. We have developed a synthetic vaccine particle (SVP) technology that enables co-encapsulation of antigen with potent adjuvants. We demonstrate that co-delivery of an antigen with a TLR7/8 or TLR9 agonist in synthetic polymer nanoparticles results in a strong augmentation of humoral and cellular immune responses with minimal systemic production of inflammatory cytokines. In contrast, antigen encapsulated into nanoparticles and admixed with free TLR7/8 agonist leads to lower immunogenicity and rapid induction of high levels of inflammatory cytokines in the serum (e.g., TNF-a and IL-6 levels are 50- to 200-fold higher upon injection of free resiquimod (R848) than of nanoparticle-encapsulated R848). Conversely, local immune stimulation as evidenced by cellular infiltration of draining lymph nodes and by intranodal cytokine production was more pronounced and persisted longer when SVP-encapsulated TLR agonists were used. The strong local immune activation achieved using a modular self-assembling nanoparticle platform markedly enhanced immunogenicity and was equally effective whether antigen and adjuvant were co-encapsulated in a single nanoparticle formulation or co-delivered in two separate nanoparticles. Moreover, particle encapsulation enabled the utilization of CpG oligonucleotides with the natural phosphodiester backbone, which are otherwise rapidly hydrolyzed by nucleases in vivo. The use of SVP may enable clinical use of potent TLR agonists as vaccine adjuvants for indications where cellular immunity or robust humoral responses are required.
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http://dx.doi.org/10.1016/j.vaccine.2014.02.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4059049PMC
May 2014

Enhanced photothermal effect of plasmonic nanoparticles coated with reduced graphene oxide.

Nano Lett 2013 Sep 6;13(9):4075-9. Epub 2013 Aug 6.

Laboratory for Biomaterials and Drug Delivery, Department of Anesthesiology, Division of Critical Care Medicine, Children's Hospital Boston, Harvard Medical School , 300 Longwood Avenue, Boston, Massachusetts 02115, United States.

We report plasmonic gold nanoshells and nanorods coated with reduced graphene oxide that produce an enhanced photothermal effect when stimulated by near-infrared (NIR) light. Electrostatic interactions between nanosized graphene oxide and gold nanoparticles followed by in situ chemical reduction generated reduced graphene oxide-coated nanoparticles; the coating was demonstrated using Raman and HR-TEM. Reduced graphene oxide-coated gold nanoparticles showed enhanced photothermal effect compared to noncoated or nonreduced graphene oxide-coated gold nanoparticles. Reduced graphene oxide-coated gold nanoparticles killed cells more rapidly than did noncoated or nonreduced graphene oxide-coated gold nanoparticles.
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http://dx.doi.org/10.1021/nl4014315DOI Listing
September 2013

Combinatorial synthesis with high throughput discovery of protein-resistant membrane surfaces.

Biomaterials 2013 Aug 22;34(26):6133-8. Epub 2013 May 22.

Howard P. Isermann Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180-3590, USA.

Using combinatorial methods, we synthesized a series of new vinyl amide monomers and graft-polymerized them to light-sensitive poly(ether sulfone) (PES) porous films for protein resistance. To increase the discovery rate and statistical confidence, we developed high throughput surface modification methods (HTP) that allow synthesis, screening and selection of desirable monomers from a large library in a relatively short time (days). A series of amide monomers were synthesized by amidation of methacryloyl chloride with amines and grafted onto commercial poly(ether sulfone) (PES) membranes using irradiation from atmospheric pressure plasma (APP). The modified PES membrane surfaces were then tested and screened for static protein adhesion using HTP. Hydroxyl amide monomers N-(3-hydroxypropyl)methacrylamide (A3), N-(4-hydroxybutyl)methacrylamide (A4), and N-(4-hydroxybutyl)methacrylamide (A6), ethylene glycol (EG) monomer N-(3-methoxypropyl)methacrylamide (A7), and N-(2-(dimethylamino)ethyl)-N-methylmethacrylamide (A8), and N-(2-(diethylamino)ethyl)-N-methylmethacrylamide (A9) all terminated with tertiary amines and were shown to have protein resistance. The PES membranes modified with these monomers exhibited both low protein adhesion (i.e. membrane plugging or fouling) and high flux. Their performance is comparable with previously identified best performing PEG and zwitterionic monomers, i.e. the so-called gold-standard for protein resistance. Combining a Hansen solubility parameter (HSP) analysis of the amide monomers and the HTP filtration results, we conclude that monomer solubility in water correlates with protein-resistant surfaces, presumably through its effects on surface-water interactions.
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http://dx.doi.org/10.1016/j.biomaterials.2013.04.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3957435PMC
August 2013

Injectable nano-network for glucose-mediated insulin delivery.

ACS Nano 2013 May 2;7(5):4194-201. Epub 2013 May 2.

Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.

Diabetes mellitus, a disorder of glucose regulation, is a global burden affecting 366 million people across the world. An artificial "closed-loop" system able to mimic pancreas activity and release insulin in response to glucose level changes has the potential to improve patient compliance and health. Herein we develop a glucose-mediated release strategy for the self-regulated delivery of insulin using an injectable and acid-degradable polymeric network. Formed by electrostatic interaction between oppositely charged dextran nanoparticles loaded with insulin and glucose-specific enzymes, the nanocomposite-based porous architecture can be dissociated and subsequently release insulin in a hyperglycemic state through the catalytic conversion of glucose into gluconic acid. In vitro insulin release can be modulated in a pulsatile profile in response to glucose concentrations. In vivo studies validated that these formulations provided improved glucose control in type 1 diabetic mice subcutaneously administered with a degradable nano-network. A single injection of the developed nano-network facilitated stabilization of the blood glucose levels in the normoglycemic state (<200 mg/dL) for up to 10 days.
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http://dx.doi.org/10.1021/nn400630xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4107450PMC
May 2013

Therapeutic effect of orally administered microencapsulated oxaliplatin for colorectal cancer.

Biomaterials 2012 Jun 1;33(18):4752-61. Epub 2012 Apr 1.

The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.

Colorectal cancer is a significant source of morbidity and mortality in the United States and other Western countries. Oral delivery of therapeutics remains the most patient accepted form of medication. The development of an oral delivery formulation for local delivery of chemotherapeutics in the gastrointestinal tract can potentially alleviate the adverse side effects including systemic cytotoxicity, as well as focus therapy to the lesions. Here we develop an oral formulation of the chemotherapeutic drug oxaliplatin for the treatment of colorectal cancer. Oxaliplatin was encapsulated in pH sensitive, mucoadhesive chitosan-coated alginate microspheres. The microparticles were formulated to release the chemotherapeutics after passing through the acidic gastric environment thus targeting the intestinal tract. In vivo, these particles substantially reduced the tumor burden in an orthotopic mouse model of colorectal cancer, and reduced mortality.
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http://dx.doi.org/10.1016/j.biomaterials.2012.03.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3586541PMC
June 2012

Synergistic silencing: combinations of lipid-like materials for efficacious siRNA delivery.

Mol Ther 2011 Sep 12;19(9):1688-94. Epub 2011 Jul 12.

Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

Despite the promise of RNA interference (RNAi) therapeutics, progress toward the clinic has been slowed by the difficulty of delivering short interfering RNA (siRNA) into cellular targets within the body. Nearly all siRNA delivery vehicles developed to date employ a single cationic or ionizable material. In order to increase the material space available for development of siRNA delivery therapeutics, this study examined the possibility of using binary combinations of ionizable lipid-like materials to synergistically achieve gene silencing. Interestingly, it was found that ineffective single lipid-like materials could be formulated together in a single delivery vehicle to induce near-complete knockdown of firefly luciferase and factor VII in HeLa cells and in mice, respectively. Microscopy experiments suggested that synergistic action resulted when combining materials that respectively mediated cellular uptake and endosomal escape, two important steps in the delivery process. Together, the data indicate that formulating lipid-like materials in combination can significantly improve siRNA delivery outcomes while increasing the material space available for therapeutic development. It is anticipated that this binary formulation strategy could be applicable to any siRNA delivery material in any target cell population that utilizes the two-step endosomal delivery pathway.
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http://dx.doi.org/10.1038/mt.2011.141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3182356PMC
September 2011

Current trends in nanobiosensor technology.

Wiley Interdiscip Rev Nanomed Nanobiotechnol 2011 May-Jun;3(3):229-46. Epub 2011 Mar 9.

David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.

The development of tools and processes used to fabricate, measure, and image nanoscale objects has lead to a wide range of work devoted to producing sensors that interact with extremely small numbers (or an extremely small concentration) of analyte molecules. These advances are particularly exciting in the context of biosensing, where the demands for low concentration detection and high specificity are great. Nanoscale biosensors, or nanobiosensors, provide researchers with an unprecedented level of sensitivity, often to the single molecule level. The use of biomolecule-functionalized surfaces can dramatically boost the specificity of the detection system, but can also yield reproducibility problems and increased complexity. Several nanobiosensor architectures based on mechanical devices, optical resonators, functionalized nanoparticles, nanowires, nanotubes, and nanofibers have been demonstrated in the lab. As nanobiosensor technology becomes more refined and reliable, it is likely it will eventually make its way from the lab to the clinic, where future lab-on-a-chip devices incorporating an array of nanobiosensors could be used for rapid screening of a wide variety of analytes at low cost using small samples of patient material.
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http://dx.doi.org/10.1002/wnan.136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126610PMC
September 2011

A "Self-Pinning" Adhesive Based on Responsive Surface Wrinkles.

J Polym Sci B Polym Phys 2011 Jan;49(1):40-44

Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.

Surface wrinkles are interesting since they form spontaneously into well-defined patterns. The mechanism of formation is well-studied and is associated with the development of a critical compressive stress that induces the elastic instability. In this work, we demonstrate surface wrinkles that dynamically change in response to a stimulus can improve interfacial adhesion with a hydrogel surface through the dynamic evolution of the wrinkle morphology. We observe that this control is related to the local pinning of the crack separation pathway facilitated by the surface wrinkles during debonding, which is dependent on the contact time with the hydrogel.
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http://dx.doi.org/10.1002/polb.22165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3031119PMC
January 2011

Biodegradable microfluidic scaffolds for tissue engineering from amino alcohol-based poly(ester amide) elastomers.

Organogenesis 2010 Oct-Dec;6(4):212-6

Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.

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.
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http://dx.doi.org/10.4161/org.6.4.12909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3055646PMC
June 2011

Intracranial microcapsule drug delivery device for the treatment of an experimental gliosarcoma model.

Biomaterials 2011 Apr 8;32(10):2532-9. Epub 2011 Jan 8.

Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, United States.

Controlled-release drug delivery systems are capable of treating debilitating diseases, including cancer. Brain cancer, in particular glioblastoma multiforme (GBM), is an extremely invasive cancer with a dismal prognosis. The use of drugs capable of crossing the blood-brain barrier has shown modest prolongation in patient survival, but not without unsatisfactory systemic, dose-limiting toxicity. Among the reasons for this improvement include a better understanding of the challenges of delivery of effective agents directly to the brain tumor site. The combination of carmustine delivered by biodegradable polyanhydride wafers (Gliadel(®)), with the systemic alkylating agent, temozolomide, allows much higher effective doses of the drug while minimizing the systemic toxicity. We have previously shown that locally delivering these two drugs leads to further improvement in survival in experimental models. We postulated that microcapsule devices capable of releasing temozolomide would increase the therapeutic capability of this approach. A biocompatible drug delivery microcapsule device for the intracranial delivery of temozolomide is described. Drug release profiles from these microcapsules can be modulated based on the physical chemistry of the drug and the dimensions of the release orifices in these devices. The drug released from the microcapsules in these experiments was the clinically utilized chemotherapeutic agent, temozolomide. In vitro studies were performed in order to test the function, reliability, and drug release kinetics of the devices. The efficacy of the temozolomide-filled microcapsules was tested in an intracranial experimental rodent gliosarcoma model. Immunohistochemical analysis of tissue for evidence of DNA strand breaks via terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was performed. The experimental release curves showed mass flow rates of 36 μg/h for single-orifice devices and an 88 μg/h mass flow rate for multiple-orifice devices loaded with temozolomide. In vivo efficacy results showed that localized intracranial delivery of temozolomide from microcapsule devices was capable of prolonging animal survival and may offer a novel form of treatment for brain tumors.
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http://dx.doi.org/10.1016/j.biomaterials.2010.12.020DOI Listing
April 2011

Silencing or stimulation? siRNA delivery and the immune system.

Annu Rev Chem Biomol Eng 2011 ;2:77-96

The David H. Koch Institute for Integrated Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.

Since its inception more than a decade ago, the field of short interfering RNA (siRNA) therapeutics has demonstrated potential in the treatment of a wide variety of diseases. The power behind RNA interference (RNAi) therapy lies in its ability to specifically silence target genes of interest. As more biological data have become available, it has become evident that, in addition to mediating RNAi, siRNA molecules have the potential to potently induce the innate immune system. One of the significant challenges facing the field today is the differentiation between therapeutic effects caused by target-specific, RNAi-mediated gene silencing and those caused by nonspecific stimulation of the innate immune system. Unless appropriate experimental measures are taken to control for RNA-induced immunostimulation, genetic manipulation can be confused with immune activation. This review attempts to provide an accessible background in siRNA-relevant immunology and to highlight the ways in which siRNA can be engineered to avoid or provoke an innate immune response.
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http://dx.doi.org/10.1146/annurev-chembioeng-061010-114133DOI Listing
May 2012

Retinal transplantation using surface modified poly(glycerol-co-sebacic acid) membranes.

Biomaterials 2010 Nov 24;31(31):7978-84. Epub 2010 Jul 24.

Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

In retinal transplantation experiments it is hypothesized that remaining diseased photoreceptor cells in the host retina and inner retinal cells in transplants physically obstruct the development of graft-host neuronal contacts which are required for vision. Recently, we developed methods for the isolation of donor photoreceptor layers in vitro, and the selective removal of host photoreceptors in vivo using biodegradable elastomeric membranes composed of poly(glycerol-co-sebacic acid) (PGS). We also coated PGS membranes with electrospun nanofibers, composed of laminin and poly(epsilon-caprolactone) (PCL), to promote attachment of embryonic retinal explants, allowing the resulting composites to be handled surgically as a single entity. Here, we report subretinal transplantation of these composites into adult porcine eyes. In hematoxylin and eosin stained sections of composite explants after 5-7 days in vitro, excellent fusion of retinas and biomaterial membranes was noted, with the immature retinal components showing laminated as well as folded and rosetted areas. The composite grafts could be transplanted in all cases and, 3 months after surgery, eyes displayed clear media, attached retinas and the grafts located subretinally. Histological examination revealed that the biomaterial membrane had degraded without any signs of inflammation. Transplanted retinas displayed areas of rosettes as well as normal lamination. In most cases inner retinal layers were present in the grafts. Laminated areas displayed well-developed photoreceptors adjacent to an intact host retinal pigment epithelium and degeneration of the host outer nuclear layer (ONL) was often observed together with occasional fusion of graft and host inner layers.
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http://dx.doi.org/10.1016/j.biomaterials.2010.07.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4059040PMC
November 2010

Establishing a model spinal cord injury in the African green monkey for the preclinical evaluation of biodegradable polymer scaffolds seeded with human neural stem cells.

J Neurosci Methods 2010 May 26;188(2):258-69. Epub 2010 Feb 26.

Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.

Given the involvement of post-mitotic neurons, long axonal tracts and incompletely elucidated injury and repair pathways, spinal cord injury (SCI) presents a particular challenge for the creation of preclinical models to robustly evaluate longitudinal changes in neuromotor function in the setting in the presence and absence of intervention. While rodent models exhibit high degrees of spontaneous recovery from SCI injury, animal care concerns preclude complete cord transections in non-human primates and other larger vertebrate models. To overcome such limitations a segmental thoracic (T9-T10) spinal cord hemisection was created and characterized in the African green monkey. Physiological tolerance of the model permitted behavioral analyses for a prolonged period post-injury, extending to predefined study termination points at which histological and immunohistochemical analyses were performed. Four monkeys were evaluated (one receiving no implant at the lesion site, one receiving a poly(lactide-co-glycolide) (PLGA) scaffold, and two receiving PLGA scaffolds seeded with human neural stem cells (hNSC)). All subjects exhibited Brown-Séquard syndrome 2 days post-injury consisting of ipsilateral hindlimb paralysis and contralateral hindlimb hypesthesia with preservation of bowel and bladder function. A 20-point observational behavioral scoring system allowed quantitative characterization of the levels of functional recovery. Histological endpoints including silver degenerative staining and Iba1 immunohistochemistry, for microglial and macrophage activation, were determined to reliably define lesion extent and correlate with neurobehavioral data, and justify invasive telemetered electromyographic and kinematic studies to more definitively address efficacy and mechanism.
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http://dx.doi.org/10.1016/j.jneumeth.2010.02.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157751PMC
May 2010
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