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Controlling the movement of molecules

Published online by Cambridge University Press:  14 May 2019

Robert Langer*
Affiliation:
Massachusetts Institute of Technology, Cambridge, MA, USA
*
Author for correspondence: Robert Langer, E-mail: rlanger@mit.edu

Abstract

The ability to control the movement of molecules is both fascinating scientifically as well as being critically important to the well-being of our planet and its people. In particular, the sustained release of molecules over prolonged periods at controlled rates has had and will continue to have enormous implications for the delivery of substances in medicine, agriculture, the environment, nutrition, aquaculture, household consumer products, and numerous other areas. This field is advancing at a rapidly accelerating pace. In this article, I largely discuss our own work, starting 45 years ago, in enabling the controlled release of macromolecules from biocompatible polymers. I also discuss the synthesis of novel materials to affect molecular movement and I then examine external approaches for controlling the movement of molecules through materials, using forces such as electric, acoustic, and magnetic fields. I further discuss approaches for controlling molecular movement through physiologic barriers, such as the skin, lung, and intestine. Finally, I outline several future areas of this field, including how it can affect the developing world, the ability to control the movement of molecules into mammalian cells, and the design of intelligent approaches to control molecular delivery.

Type
Review
Copyright
Copyright © Cambridge University Press 2019 

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References

Abramson, A, Caffarel-Salvador, E, Khang, M, Dellal, D, Silverstein, D, Gao, Y, Frederiksen, M, Vegge, A, Hubálek, F, Water, J, Friderichsen, A, Fels, J, Kirk, R, Cleveland, C, Collins, J, Tamang, S, Hayward, A, Landh, T, Buckley, S, Roxhed, N, Rahbek, U, Langer, R and Traverso, G (2019) An ingestible self-orienting system for oral delivery of macromolecules. Science 363, 611615.Google Scholar
Akinc, A, Zumbuehl, A, Goldberg, M, Leshchiner, E, Busini, V, Hossain, N, Bacallado, S, Nguyen, D, Fuller, J, Alvarez, R, Borodovsky, A, Borland, T, Constein, R, de Fougerolles, A, Dorkin, J, Jayaprakash, K, Jayaraman, M, John, M, Kotelianski, V, Manoharan, M, Nechev, L, Qin, J, Racie, T, Raitcheva, D, Rajeev, K, Sah, D, Soutschek, J, Toudjarska, I, Vornlocher, HP, Zimmermann, T, Langer, R and Anderson, D (2008) A combinatorial library of lipid-like materials for delivery of RNAi therapeutics. Nature Biotechnology 26, 561569, PMID: 18438401, PMCID: N/A – NIH not acknowledged on this paper.Google Scholar
Anselmo, A, Xu, X, Buerkli, S, Zeng, Y, Tang, W, McHugh, K, Behrens, A, Rosenberg, E, Duan, A, Sugarman, J, Zhuang, J, Collins, J, Lu, X, Graf, T, Tzeng, S, Rose, S, Nguyen, T, Le, X, Guerra, A, Freed, L, Weinstock, S, Sears, C, Nikolic, B, Wood, L, Oxley, J, Moretti, D, Zimmermann, M, Langer, R and Jaklenec, A (2019) Development of a heat-stable microparticle platform for oral micronutrient delivery: from conception to human trials. Submitted.Google Scholar
Balazs, A, Calef, D, Deutch, J, Siegel, R and Langer, R (1985) The role of polymer matrix structure & interparticle interactions in diffusion limited drug release. Biophysical Journal 47, 97104.Google Scholar
Ball, P (1999) Made to Measure: New Materials for the 21st Century. Princeton, NJ: Princeton University Press, p. 241.Google Scholar
Batycky, R, Hanes, J, Langer, R and Edwards, D (1997) Theoretical model of erosion and macromolecular drug release from biodegrading microspheres. Journal of Pharmaceutical Science 86, 14641477.Google Scholar
Bawa, R, Siegel, R, Marasca, B, Karel, M and Langer, R (1985) An explanation for the sustained release of macromolecules from polymers. Journal of Controlled Release l, 259267.Google Scholar
Bellinger, A, Jafari, M, Grant, T, Zhang, S, Slater, H, Wenger, E, Mo, S, Lee, Y, Mazdiyasni, H, Kogan, L, Barman, R, Cleveland, C, Booth, L, Bensel, T, Minahan, D, Hurowitz, H, Tai, T, Daily, J, Nikolic, B, Wood, L, Eckhoff, P, Langer, R and Traverso, G (2016) Oral, ultra-long-lasting drug delivery: application toward malaria elimination goals. Science Translational Medicine 4, 365ra157, PMCID: PMC5264553.Google Scholar
Brem, H and Langer, R (1996) Polymer-based drug delivery to the brain. Scientific American: Science and Medicine 3, 5261.Google Scholar
Carmeliet, P (2005) Angiogenesis in life, disease, and medicine. Nature 438, 932936.Google Scholar
Chowdhary, S, Ryken, T and Newton, H (2015) Survival outcomes and safety of carmustine wafers in the treatment of high-grade gliomas: a meta-analysis. Journal of Neurooncology 122, 367382. PMID: 25630625.Google Scholar
Cline, H, Debski, E and Constantine-Paton, M (1987) N-methyl-D-aspartate receptor antagonist desegregates eye specific stripes. PNAS 84, 43424345.Google Scholar
Cohen, J, Siegel, R and Langer, R (1984) Sintering technique for preparation of polymer matrices for the sustained release of macromolecules. Journal of Pharmaceutical Sciences 73, 10341037.Google Scholar
Cohen, S, Yoshioka, T, Lucarelli, M, Hwang, L and Langer, R (1991) Controlled delivery systems for proteins based on poly(lactic/glycolic acid) Microspheres. Pharmaceutical Research 8, 713720.Google Scholar
Connolly, D, Heuvelman, D, Nelson, R, Olander, J, Eppley, B, Delfino, J, Siegel, N, Leimgruber, R and Feder, J (1989) Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis. Journal of Clinical Investigation 84, 14701478.Google Scholar
Cooke, R (2001) Dr. Folkmans War: Angiogenesis and the Struggle to Defeat Cancer. New York, NY: Random House, p. 179.Google Scholar
Cramer, D (1998) Applied vascular biology: can angiogenesis inhibitors help control malignant growth. Annals of Internal Medicine 129, 841843.Google Scholar
Dahlman, J, Barnes, C, Khan, O, Thiriot, A, Jhunjunwala, S, Shaw, T, Xing, Y, Sage, H, Sahay, G, Speciner, L, Bader, A, Bogorad, R, Yin, H, Racie, T, Dong, Y, Jiang, S, Seedorf, D, Dave, A, Sandu, K, Webber, M, Novobrantseva, T, Ruda, V, Lytton-Jean, A, Levins, C, Kalish, B, Mudge, D, Perez, M, Abezgauz, L, Dutta, P, Smith, L, Charisse, K, Kieran, M, Fitzgerald, K, Nahrendorf, M, Danino, D, Tuder, R, von Andrian, U, Akinc, A, Schroeder, A, Panigrahy, D, Kotelianski, V, Langer, R and Anderson, D (2014) In vivo endothelial siRNA delivery using polymeric nanoparticles with low molecular weight. Nature Nanotechnology 9, 648655, PMCID: PMC4207430.Google Scholar
DiTommaso, T, Cole, J, Cassereau, L, Buggé, J, Hanson, J, Bridgen, D, Stokes, B, Loughhead, S, Beutel, B, Gilbert, J, Nussbaum, K, Sorrentino, A, Toggweiler, J, Schmidt, T, Gyuelveszi, G, Bernstein, H and Sharei, A (2018) Cell engineering with microfluidic squeezing preserves functionality of primary immune cells in vivo. PNAS 115, E10907E10914.Google Scholar
Domb, A and Langer, R (1987) Polyanhydrides: I. preparation of high molecular weight polyanhydrides. Journal of Polymer Science 25, 33733386.Google Scholar
Domb, A, Cravalho, EG and Langer, R (1988 a) The synthesis of poly(hydroxamic) from poly(acrylamide). Journal of Polymer Science 26, 26232630.Google Scholar
Domb, A, Ron, E and Langer, R (1988 b) Polyanhydrides II. One step polymerization using phosgene or diphosgene as coupling agents. Macromolecules 21, 19251929.Google Scholar
Domb, A, Gallardo, C and Langer, R (1989) Poly(anhydrides) 3. Poly(anhydrides) based on aliphaticaromatic diacids. Macromolecules 22, 32003204.Google Scholar
Edelman, E, Kost, J, Bobeck, H and Langer, R (1985) Regulation of drug release from porous polymer matrices by oscillating magnetic fields. Journal of Biomedical Materials Research 19, 6783.Google Scholar
Edwards, D and Langer, R (1994) A linear theory of transdermal transport phenomena. Journal of Pharmaceutical Sciences 83, 13151334.Google Scholar
Edwards, D, Hanes, J, Caponetti, G, Hrkach, J, Ben-Jebria, A, Eskew, M, Mintzes, J, Deaver, D, Lotan, N and Langer, R (1997) Large porous aerosols for pulmonary drug delivery. Science 276, 18681871.Google Scholar
Farra, R, Sheppard, N, McCabe, L, Neer, R, Anderson, J, Santini, J, Cima, M and Langer, R (2012) First in-human testing of a wirelessly controlled drug delivery microchip. Science Translational Medicine 4, 122ra21.Google Scholar
Fischel-Ghodsian, F, Brown, L, Mathiowitz, E, Brandenburg, D and Langer, R (1988) Enzymatically controlled drug delivery. Proceedings of the National Academy of Sciences 85, 24032406.Google Scholar
Fukaya, M, Ueda, H, Sato, A, Kaeriyama, M, Ando, H, Zohar, Y, Urano, A and Yamauchi, K (1998) Acceleration of gonadal maturation in anadromous maturing sockeye salmon by gonadotropin-releasing hormone analog implantation. Fisheries Science 64, 948951.Google Scholar
Fung, LK, Shin, M, Tyler, B, Brem, H and Saltzman, WM (1996) Chemotherapeutic drugs released from polymers: distribution of 1,3-bis(2-chloroethyl)-1-nitrosourea in the rat brain. Pharmaceutical Research 13, 671682. PMID 8860421.Google Scholar
Fung, LK, Ewend, MG, Sills, A, Sipos, EP, Thompson, R, Watts, M, Colvin, OM, Brem, H and Saltzman, WM (1998) Pharmacokinetics of interstitial delivery of carmustine, 4-hydroperoxycyclophosphamide, and paclitaxel from a biodegradable polymer implant in the monkey brain. Cancer Research 58, 672684, PMID 9485020.Google Scholar
Gospodarowicz, D, Bialecki, H and Thakral, T (1979) Angiogenic activity of the fibroblast and epidermal growth factor. Experimental Eye Research 28, 501514.Google Scholar
Gref, R, Minamitake, Y, Peracchia, M, Trubetskoy, V, Torchillin, V and Langer, R (1994) Biodegradable long-circulating polymeric nanospheres. Science 263, 16001603.Google Scholar
Haller, MF and Saltzman, WM (1998) Localized delivery of proteins in the brain: can transport be customized? Pharmaceutical Research 15, 377385. PMID 9563066.Google Scholar
Holland, MCH, Hassin, S and Zohar, Y (2003) The effects of long-term testosterone, gonadotropin-releasing hormone agonist and pimozide treatments on testicular development and luteinizing hormone levels in juvenile and early maturing striped bass, Morone saxatilis. General and Comparative Endocrinology 129, 178187 (featured on the journal cover).Google Scholar
Hsieh, D, Langer, R and Folkman, J (1981) Magnetic modulation of release of macromolecules from Polymers. Proceedings of the National Academy of Sciences 78, 18631867.Google Scholar
Hsieh, D, Rhine, W and Langer, R (1983) Zero-order controlled release polymer matrices for micromolecules and macromolecules. Journal of Pharmaceutical Sciences 72, 1722.Google Scholar
Hsu, T and Langer, R (1985) Polymers for the controlled release of macromolecules: effect of molecular weight of ethylene-vinyl acetate copolymer. Journal of Biomedical Materials Research 19, 445460.Google Scholar
Johnson, M, Berk, D, Blankschtein, D, Golan, D, Jain, R and Langer, R (1996) Lateral diffusion of small compounds in human stratum corneum and model lipid bilayer systems. Biophysics Journal 71, 26562668.Google Scholar
Johnson, M, Blankschtein, D and Langer, R (1997) Evaluation of solute permeation through the stratum corneum: lateral bilayer diffusion as the primary transport mechanism. Journal of Pharmaceutical Science 86, 11621172.Google Scholar
Kalb, R and Hockfield, S (1990) Induction of a neuronal proteoglycan by the NMDA receptor in the developing spinal cord. Science 250, 294296.Google Scholar
Kirtane, A, Abouzid, O, Minahan, D, Bensel, T, Hill, AL, Selinger, C, Bershteyn, A, Craig, M, Mo, SS, Mazdiyasni, H, Cleveland, C, Rogner, J, Lee, Y, Booth, L, Javid, F, Wu, S, Grant, G, Bellinger, A, Nikolic, B, Hayward, A, Wood, L, Eckhoff, PA, Nowak, M, Langer, R and Traverso, G (2018) Development of an oral once-weekly drug delivery system for HIV antiretroviral therapy. Nature Communications 9, Article 2.Google Scholar
Kost, J, Leong, K and Langer, R (1989) Ultrasound-enhanced polymer degradation and release of incorporated substances. Proceedings of the National Academy of Sciences 86, 76637666.Google Scholar
Kost, J, Mitragotri, S, Gabbay, R, Pishko, M and Langer, R (2000) Non-invasive blood glucose measurement using ultrasound. Nature Medicine 6, 347350.Google Scholar
Lahann, J, Mitragotri, S, Tran, T, Kaido, H, Sundaran, J, Hoffer, S, Somorjai, GA and Langer, R (2003) Reversible switching of surfaces. Science 299, 371374.Google Scholar
Langer, R and Folkman, J (1976) Polymers for the sustained release of proteins and other macromolecules. Nature 263, 797800.Google Scholar
Langer, R and Folkman, J (1978) Sustained release of macromolecules from polymers. Polymeric Delivery Systems, Midland Macro. Monograph 5, 175196, R. Kostelnik, ed., Gordon and Breach, New York.Google Scholar
Langer, R, Brem, H, Falterman, K, Klein, M and Folkman, J (1976) Isolation of a cartilage factor that inhibits tumor neovascularization. Science 193, 7072.Google Scholar
Langer, R, Rhine, W, Hsieh, D and Folkman, J (1980) Control of release kinetics of macromolecules from polymers. Journal of Membrane Science 7, 333350.Google Scholar
Lash, A (2014) Langer, Led Zeppelin, and Hookups: Three Days Behind the BIO Scenes. Exome.com. Available at https://xconomy.com/san-diego/2014/06/27/langer-led-zeppelin-and-hookups-three-days-behind-the-bio-scenes (Accessed 28 February 2019).Google Scholar
Laurencin, C, Domb, A, Morris, C, Brown, V, Chasin, M, McConnell, R, Lange, N and Langer, R (1990) Poly(anhydride) administration in high doses in vivo: studies of biocompatibility and toxicology. Journal of Biomedical Materials Research 24, 14631481.Google Scholar
Lendlein, A and Langer, R (2002) Biodegradable, elastic shape memory polymers for potential biomedical applications. Science 296, 16731676.Google Scholar
Lendlein, A, Jiang, H, Junger, O and Langer, R (2005) Light-induced shape-memory polymers. Nature 434, 879882.Google Scholar
Leong, K, Brott, B and Langer, R (1985) Bioerodible polyanhydrides as drug-carrier matrices: I. characterization, degradation and release characteristics. Journal of Biomedical Materials Research 19, 941955.Google Scholar
Leong, K, D'Amore, P, Marletta, M and Langer, R (1986) Bioerodible polyanhydrides as drug-carrier matrices II: biocompatibility and chemical reactivity. Journal of Biomedical Materials Research 20, 5164.Google Scholar
Levy, D, Kost, J, Meshulam, Y and Langer, R (1989) Effect of ultrasound on transdermal drug delivery to rats and guinea pigs. Journal of Clinical Investigation 83, 20742078.Google Scholar
Liang, J, Yu, J and Robertson, R (1995) Sustained inhibition of acetylcholinesterase activity does not disrupt early geniculocortical ingrowth to developing rat visual cortex. Developmental Brain Research 86, 354358.Google Scholar
Linnehan, R (2018) ‘FDA approves Inveltys for treatment of inflammation, pain after ocular surgery,’ healio.com, 8/23/2018. Available at https://www.healio.com/ophthalmology/cataract-surgery/news/online/%7Bef827c6d-648b-4a9f-8a93-7fab69b73622%7D/fda-approves-inveltys-for-treatment-of-inflammation-pain-after-ocular-surgery (Accessed 19 February 2019).Google Scholar
Lynn, D and Langer, R (2000) Degradable poly(b-amino esters): synthesis, characterization, and self-assembly with plasmid DNA. Journal of the American Chemical Society 122, 1076110768.Google Scholar
Marino, G, Panini, E, Longobardi, A, Mandich, A, Fionia, MG, Zohar, Y and Mylonas, CC (2003) Induction of ovulation in captive-reared dusky grouper, Epinephelus marginatus (Lowe, 1834), with a sustained release GnRHa implant. Aquaculture 326, 118.Google Scholar
Mathiowitz, E, Saltzman, M, Domb, A, Dor, P and Langer, R (1988) Polyanhydride microspheres as drug carriers. II: microencapsulation by solvent removal. Journal of Applied Polymer Science 35, 755774.Google Scholar
Mathiowitz, E, Dor, P, Amato, C and Langer, R (1990) Polyanhydride microspheres as drug carriers III morphology and release characterization of microspheres made by solvent removal. Polymer 31, 547556.Google Scholar
McAuslan, BR and Gole, GA (1980) Cellular and molecular mechanisms in angiogenesis. Transactions of the Ophthalmological Societies of the UK 100, 354358.Google Scholar
McHugh, K, Nguyen, T, Linehan, A, Yang, D, Behrens, A, Rose, S, Tochka, Z, Tzeng, S, Norman, J, Anselmo, A, Xu, X, Tomasic, S, Taylor, M, Lu, J, Guarecuco, R, Langer, R and Jaklenec, A (2017) Fabrication of fillable microparticles and other complex 3D microstructures. Science 357, 11381142.Google Scholar
Mitragotri, S (2013) Engineering approaches to transdermal drug delivery: a tribute to contributions of Prof. Robert Langer. Skin Pharmacology of Physiology 26, 263276. https://doi.org/10.1159/000351947.Google Scholar
Mitragotri, S, Blankschtein, D and Langer, R (1995) Ultrasound-mediated transdermal protein delivery. Science 269, 850853.Google Scholar
Mylonas, CC and Zohar, Y (1998) New techniques for the control of gamete maturation in marine fishes as tools in broodstock management. Cah. Opt. Med. 34, 193213.Google Scholar
Mylonas, CC, Richardson, BM, Minkinnen, SP and Zohar, Y (1995) Induced spawning of American shad (Alosa sapidissima) using sustained administration of gonadotropin-releasing hormone analog (GnRHa). Journal of the World Aquaculture Society 26, 3950.Google Scholar
Mylonas, CC, Gissis, A, Magnus, Y and Zohar, Y (1997) Hormonal changes in male white bass (Morone chrysops) and evaluation of milt quality after treatment with a sustained-release GnRHa delivery system. Aquaculture 153, 301313.Google Scholar
Mylonas, CC, Bridges, CR, Gordin, H, Belmonte Ríos, A, García, A, De la Gándara, F, Fauvel, C, Suquet, M, Medina, A, Papadaki, M, Heinisch, G, De Metrio, G, Corriero, A, Vassallo-Agius, R, Guzmán, JM, Mañanos, E and Zohar, Y (2007) Preparation and administration of gonadotropin-releasing hormone agonist (GnRHa) implants for the artificial control of reproductive maturation in captive-reared Atlantic bluefin tuna (Thunnus thynnus). Reviews in Fisheries Science 15, 183210.Google Scholar
National Academy of Sciences (1999) ‘Polymers and People,’ Beyond Discovery. National Academy of Sciences. Nov. 1999. Available at http://www.nasonline.org/publications/beyond-discovery.Google Scholar
Park, C and Hollenberg, M (1993) Growth factor-induced retinal regeneration in vivo. International Review of Cytology 146, 49.Google Scholar
Pearson, H (2009) Profile: being Bob Langer. Nature 458, 2224.Google Scholar
Peppas, N and Langer, R (1994) New challenges in biomaterials. Science 263, 17151720.Google Scholar
Pliskin, M, Ginsberg, S and Carp, N (1980) Induction of neovascularization by mitogen activated spleen cells and their supernatants. Transplantation 29, 225258.Google Scholar
Polat, B, Deen, W, Langer, R and Blankschtein, D (2012) A physical mechanism to explain the delivery of chemical penetration enhancers into skin during transdermal sonophoresis: insight into the observed synergism. Journal of Controlled Release 158, 250260, PMCID: PMC3294085.Google Scholar
Polverini, P, Cotran, R, Gimbrone, M and Unanue, E (1977) Activated macro-phages induces vascular proliferation. Nature 269, 804805.Google Scholar
Prausnitz, M, Langer, R and Weaver, J (1993 a) Electroporation of mammalian skin: a new mechanism to enhance transdermal drug delivery. Proceedings of the National Academy of Sciences 90, 1050410508.Google Scholar
Prausnitz, M, Seddick, D, Kon, A, Bose, V, Frankenburg, S, Klaus, S, Langer, R and Weaver, J (1993 b) Methods for in vivo tissue electroporation using surface electrodes. Drug Delivery 1, 125131.Google Scholar
Prausnitz, M, Pliquett, U, Langer, R and Weaver, J (1994) Rapid temporal control of transdermal drug delivery by electroporation. Pharmaceutical Research 11, 18341837.Google Scholar
Prausnitz, M, Corbett, J, Gimm, J, Golan, D, Langer, R and Weaver, J (1995) Millisecond measurement of transport during and after an electroporation pulse. Biophysical Journal 68, 18641870.Google Scholar
Prausnitz, M, Gimm, J, Weaver, J, Guy, R, Langer, R and Cullander, C (1996 a) Imaging regions of transport across human stratum corneum during high-voltage and low-voltage exposures. Journal of Pharmaceutical Sciences 85, 13631370.Google Scholar
Prausnitz, M, Lee, C, Liu, C, Pang, J, Singh, T, Weaver, J and Langer, R (1996 b) Transdermal transport efficiency during skin electroporation and iontophoresis. Journal of Controlled Release 38, 205217.Google Scholar
Preis, I and Langer, R (1979) A single-step immunization by sustained antigen release. Journal of Immunology. Methamphetamine 28, 193197.Google Scholar
Queen Elizabeth Prize for Engineering Foundation (2015) ‘Robert S. Langer, Winner Infographic,’ Queen Elizabeth Prize for Engineering Foundation. Feb. 2015, Available at http://qeprize.org/wp-content/uploads/2015/02/Winner_infographic.pdf.Google Scholar
Reh, T and Constantine-Paton, M (1985) Eye-specific segregation requires neural activity in three-eyed Rana pipiens. Journal of Neuroscience 5, 11321143.Google Scholar
Rhine, W, Hsieh, D and Langer, R (1980) Polymers for sustained macromolecule release: procedures to fabricate reproducible delivery systems and control release kinetics. Journal of Pharmaceutical Sciences 69, 265270.Google Scholar
Rosen, H, Chang, J, Wnek, G, Linhardt, R and Langer, R (1983) Bioerodible polyanhydrides for controlled drug delivery. Biomaterials 4, 131133.Google Scholar
Saltzman, W and Langer, R (1989) Transport rates of proteins in porous materials with known microgeometry. Biophysical Journal 55, 163171.Google Scholar
Santini, J, Cima, M and Langer, R (1999) A controlled-release microchip. Nature 397, 335338.Google Scholar
Schor, AM, Schor, SL and Kumar, S (1979) Importance of a collagen substratum for stimulation of capillary endothelial cell proliferation by tumor angiogenesis factor. International Journal of Cancer 24, 225234.Google Scholar
Science History Institute (2015) ‘Scientists You Must Know: Robert Langer,’ Science History Institute (formerly Chemical Heritage Foundation). 2015. Available at https://vimeo.com/104137880.Google Scholar
Sefton, M, Brown, L and Langer, R (1984) Ethylene-vinyl acetate microspheres for controlled release of macromolecules. Journal of Pharmaceutical Sciences 73, 18591861.Google Scholar
Sharei, A, Zoldan, J, Adamo, A, Sim, W-Y, Cho, N, Jackson, E, Mao, S, Schneider, S, Han, M-J, Lytton-Jean, A, Basto, PA, Jhunjhunwala, S, Lee, J, Heller, DA, Kang, JW, Hartoularos, GC, Kim, K-S, Anderson, DG, Langer, R and Jensen, KF (2013) A vector-free microfluidic platform for intracellular delivery. Proceedings of the National Academy of Sciences 110, 20822087, PMCID: PMC3568376.Google Scholar
Shing, Y, Folkman, J, Sullivan, R, Butterfield, C, Murray, J and Klags-brun, M (1984) Heparin affinity: purification of a tumor-derived capillary endothelial cell growth factor. Science 23, 12961299.Google Scholar
Silberstein, G and Daniel, C (1982) Elvax 40P implants: sustained, local release of bioactive molecules influencing mammary ductal development. Developmental Biology 93, 272278.Google Scholar
Simone, D, Prusky, G, O'Leary, D and Constantine-Paton, M (1992) N-methyl-D-aspartate receptor antagonists disrupt the formation of mammalian neural map. PNAS 89, 1059310597.Google Scholar
Sorbera, LA, Mylonas, CC, Zanuy, S, Carrillo, M and Zohar, Y (1996) Sustained administration of GnRHa increases sperm volume without altering sperm counts in the seabass (Dicentrarchus labrax). Journal of Experimental Zoology 276, 361368.Google Scholar
Stannett, V, Koros, W, Paul, D, Lonsdale, H and Baker, R (1979) Recent advances in membrane and science technology. Advances in Polymer Science 32, 69121.Google Scholar
Tamada, J and Langer, R (1993) Erosion kinetics of hydrolytically degradable polymers. Proceedings of the National Academy of Sciences 90, 552556.Google Scholar
Tang, H, Mitragotri, S, Blankschtein, D and Langer, R (2001) Theoretical description of transdermal transport of hydrophilic permeants: application to low-frequency sonophoresis. Journal of Pharmaceutical Sciences 90, 545568.Google Scholar
Tang, H, Blankschtein, D and Langer, R (2002) Effects of low-frequency ultrasound on the transdermal permeation of mannitol: comparative studies with in vivo and in vitro skin. Journal of Pharmaceutical Sciences 91, 17761794.Google Scholar
Taranger, GL, Vikingstad, E, Klenke, U, Mayer, I, Stefansson, SO, Norberg, B, Hansen, T, Zohar, Y and Andersson, E (2004) Effects of photoperiod, temperature and GnRHa treatment on the reproductive physiology of Atlantic salmon (Salmo salar L.) broodstock. Fish Physiology and Biochemistry 28, 403406.Google Scholar
Valtonen, S, Timonen, U, Toivanen, P, Kalimo, H, Kivipelto, L, Heiskanen, O, Unsgaard, G and Kuurne, T (1997) Interstitial chemotherapy with carmustine-loaded polymers for high-grade gliomas: a randomized double-blind study. Neurosurgery 41, 4449.Google Scholar
Viswanathan, M, Golin, CE, Jones, CD, Ashok, M, Blalock, SJ, Wines, RC, Coker-Schwimmer, EJ, Rosen, DL, Sista, P and Lohr, KN (2012) Interventions to improve adherence to self-administered medications for chronic diseases in the United States: a systematic review. Annals of Internal Medicine 157, 785795.Google Scholar
Zelikin, A, Shastri, V, Lynn, D, Farhadi, J, Martin, I and Langer, R (2002) Erodible conducting polymers for potential biomedical applications. Angewandte Chemie 41, 141144.Google Scholar
Zhang, S, Bellinger, A, Glettig, D, Barman, R, Lee, Y-A, Zhu, J, Cleveland, C, Montgomery, V, Gu, L, Nash, L, Maitland, D, Langer, R and Traverso, G (2015) A pH-responsive supramolecular polymer gel as an enteric elastomer for use in gastric devices. Nature Materials 10, 10651071, PMID: 26213897; PMCID: 4772966.Google Scholar
Zohar, Y and Mylonas, CC (2001) Endocrine manipulations of spawning in farmed fish: from hormones to genes. Aquaculture 197, 99136.Google Scholar