Lessons from nature: stimuli-responsive polymers and their biomedical applications.

Response to stimulus is a basic process of living systems. Based on the lessons from nature, scientists have been designing useful materials that respond to external stimuli such as temperature, pH, light, electric field, chemicals and ionic strength. These responses are manifested as dramatic changes in one of the following: shape, surface characteristics, solubility, formation of an intricate molecular self-assembly or a sol-to-gel transition. Applications of stimuli-responsive, or 'smart', polymers in delivery of therapeutics, tissue engineering, bioseparations, sensors or actuators have been studied extensively and numerous papers and patents are evidence of rapid progress in this area. Understanding the structure-property relationship is essential for the further development and rational design of new functional smart materials. For example, kinetic and thermodynamic control of the coil-to-globule transition could be achieved through changes in polymer composition and topology.

[1]  C. Booth,et al.  Association of Diblock and Triblock Copolymers of Ethylene Oxide and Butylene Oxide in Aqueous Solution , 1996 .

[2]  Ron Dagani MOLECULAR MAGIC WITH MICROWAVES: Scientists are discovering new ways to use microwaves in organic synthesis, materials processing, waste remediation , 1997 .

[3]  Haeshin Lee,et al.  Conjugation of Trypsin by Temperature‐Sensitive Polymers Containing a Carbohydrate Moiety: Thermal Modulation of Enzyme Activity , 1998, Biotechnology progress.

[4]  Françoise M. Winnik,et al.  Volumetric studies of aqueous polymer solutions using pressure perturbation calorimetry: A new look at the temperature-induced phase transition of poly(N-isopropylacrylamide) in water and D2O , 2001 .

[5]  Y. Bae,et al.  Drug release from biodegradable injectable thermosensitive hydrogel of PEG-PLGA-PEG triblock copolymers. , 2000, Journal of controlled release : official journal of the Controlled Release Society.

[6]  Paul F. Barbara,et al.  Discrete Intensity Jumps and Intramolecular Electronic Energy Transfer in the Spectroscopy of Single Conjugated Polymer Molecules , 1997 .

[7]  Sandalphon,et al.  Infrared photorefractive polymers and their applications for imaging. , 1998, Science.

[8]  A. Hoffman,et al.  Hemolytic activity of pH-responsive polymer-streptavidin bioconjugates. , 1999, Bioconjugate chemistry.

[9]  T. Park,et al.  Synthesis and Characterization of Thermally Reversible Bioconjugates Composed of α-chymotrypsin and poly(N-isopropylacrylamide-co-acrylamido-2-deoxy -D-glucose) , 1999 .

[10]  M. Torres-Lugo,et al.  Molecular design and in vitro studies of novel pH-sensitive hydrogels for the oral delivery of calcitonin , 1999 .

[11]  Sang Beom Lee,et al.  A New Class of Biodegradable Thermosensitive Polymers. I. Synthesis and Characterization of Poly(organophosphazenes) with Methoxy-Poly(ethylene glycol) and Amino Acid Esters as Side Groups , 1999 .

[12]  D. Wirtz,et al.  Reversible hydrogels from self-assembling artificial proteins. , 1998, Science.

[13]  Y. Bae,et al.  Insulin release from islets of Langerhans entrapped in a poly(N-isopropylacrylamide-co-acrylic acid) polymer gel. , 1999, Journal of biomaterials science. Polymer edition.

[14]  N. Brandon,et al.  GABAA-receptor-associated protein links GABAA receptors and the cytoskeleton , 1999, Nature.

[15]  Kell Mortensen,et al.  Structural study on the micelle formation of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock copolymer in aqueous solution , 1993 .

[16]  T. Okano,et al.  Comb-type grafted hydrogels with rapid deswelling response to temperature changes , 1995, Nature.

[17]  J. Cummings,et al.  High-performance liquid chromatographic technique for the simultaneous determination of lactone and hydroxy acid forms of camptothecin and SN-38 in tissue culture media and cancer cells. , 2001, Analytical biochemistry.

[18]  Kiyotaka Sakai,et al.  Rapid Deswelling Response of Poly(N-isopropylacrylamide) Hydrogels by the Formation of Water Release Channels Using Poly(ethylene oxide) Graft Chains , 1998 .

[19]  Sung Wan Kim,et al.  Biodegradable block copolymers as injectable drug-delivery systems , 1997, Nature.

[20]  C. Booth,et al.  block-Copoly(oxyethylene/oxybutylene/oxyethylene), E40B15E40, in aqueous solution: micellisation, gelation and drug release , 1993 .

[21]  S. W. Kim,et al.  pH-sensitive cationic polymer gene delivery vehicle: N-Ac-poly(L-histidine)-graft-poly(L-lysine) comb shaped polymer. , 2000, Bioconjugate chemistry.

[22]  Sung Wan Kim,et al.  Biodegradable thermosensitive micelles of PEG-PLGA-PEG triblock copolymers , 1999 .

[23]  A. Hoffman,et al.  Site-specific polymer-streptavidin bioconjugate for pH-controlled binding and triggered release of biotin. , 2000, Bioconjugate chemistry.

[24]  T. Hashimoto,et al.  Direct Observation of Internal Structures in Poly(N-isopropylacrylamide) Chemical Gels , 1999 .

[25]  Y. Bae,et al.  New biodegradable polymers for injectable drug delivery systems. , 1999, Journal of controlled release : official journal of the Controlled Release Society.

[26]  T. Park,et al.  Founder's Award, Society for Biomaterials. Sixth World Biomaterials Congress 2000, Kamuela, HI,May 15-20, 2000. Really smart bioconjugates of smart polymers and receptor proteins. , 2000, Journal of Biomedical Materials Research.

[27]  R Langer,et al.  Stimulation of neurite outgrowth using an electrically conducting polymer. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[28]  Steven H. Goods,et al.  Direct Measurement of Extension and Force in Conductive Polymer Gel Actuators , 2001 .

[29]  Jan Feijen,et al.  Thermosensitive Micelle-Forming Block Copolymers of Poly(ethylene glycol) and Poly(N-isopropylacrylamide) , 1997 .

[30]  M. Malmsten,et al.  Water self-diffusion in aqueous block copolymer solutions , 1992 .

[31]  T. Okano,et al.  Novel bifunctional polymer with reactivity and temperature sensitivity , 2000, Journal of biomaterials science. Polymer edition.

[32]  D. Tirrell,et al.  Tuning the response of a pH-sensitive membrane switch , 1995 .

[33]  Y. Lim,et al.  A self-destroying polycationic polymer: Biodegradable poly(4-hydroxy-L- proline ester) , 1999 .

[34]  L. Bromberg Polyether-Modified Poly(acrylic acid): Synthesis and Applications , 1998 .

[35]  J. Cappello,et al.  In-situ self-assembling protein polymer gel systems for administration, delivery, and release of drugs. , 1998, Journal of controlled release : official journal of the Controlled Release Society.

[36]  Guohua Chen,et al.  Temperature sensitivity of a hydrogel network containing different LCST oligomers grafted to the hydrogel backbone , 1998 .

[37]  Y. Bae,et al.  In situ gelation of PEG-PLGA-PEG triblock copolymer aqueous solutions and degradation thereof. , 2000, Journal of biomedical materials research.

[38]  R. Bhardwaj,et al.  Controlled‐release delivery system for the α‐MSH analog Melanotan‐I using poloxamer 407 , 1996 .

[39]  Karin Schillén,et al.  Characterization of a Poly(ethylene oxide)-Poly(propylene oxide) Triblock Copolymer (EO27-PO39-EO27) in Aqueous Solution , 1994 .

[40]  S. W. Kim,et al.  Biodegradable Polyester, Poly[α-(4-Aminobutyl)-l-Glycolic Acid], as a Non-Toxic Gene Carrier , 2004, Pharmaceutical Research.

[41]  A. Hoffman,et al.  The design and synthesis of polymers for eukaryotic membrane disruption. , 1999, Journal of controlled release : official journal of the Controlled Release Society.

[42]  C. Booth,et al.  Effect of Block Structure on the Micellization and Gelation of Aqueous Solutions of Copolymers of Ethylene Oxide and Butylene Oxide , 1994 .

[43]  F. Szoka,et al.  In vitro gene delivery by degraded polyamidoamine dendrimers. , 1996, Bioconjugate chemistry.

[44]  Y. Bae,et al.  Novel pH-sensitive polymers containing sulfonamide groups , 1999 .

[45]  L. Bromberg Properties of Aqueous Solutions and Gels of Poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide)-g-poly(acrylic acid) , 1998 .

[46]  H. Hoffmann,et al.  Concentrated Aqueous Micellar Solutions of Diblock Copoly(oxyethylene/oxybutylene) E41B8: A Study of Phase Behavior , 1997 .

[47]  Anna Gutowska,et al.  Biodegradable thermoreversible gelling PLGA-g-PEG copolymers , 2001 .

[48]  M S Feld,et al.  Reversible molecular adsorption based on multiple-point interaction by shrinkable gels. , 1999, Science.

[49]  Y. Gan,et al.  Poly(N-acryloyl-N'-propylpiperazine) : A new stimuli-responsive polymer , 2000 .

[50]  A. Izumi,et al.  Design and Synthesis of Stimuli-Responsive Conjugated Polymers Having Azobenzene Units in the Main Chain , 2001 .

[51]  A. Mikos,et al.  Poly(ethylenimine) and its role in gene delivery. , 1999, Journal of controlled release : official journal of the Controlled Release Society.

[52]  T. Okano,et al.  Two-dimensional manipulation of cardiac myocyte sheets utilizing temperature-responsive culture dishes augments the pulsatile amplitude. , 2001, Tissue engineering.

[53]  H. G. Schild Poly(N-isopropylacrylamide): experiment, theory and application , 1992 .

[54]  F. Liu,et al.  Characterization of a targeted gene carrier, lactose-polyethylene glycol-grafted poly-L-lysine and its complex with plasmid DNA. , 1999, Human gene therapy.

[55]  L. Bromberg Novel Family of Thermogelling Materials via C−C Bonding between Poly(acrylic acid) and Poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) , 1998 .

[56]  Karin Schillén,et al.  Triblock Copolymers in Aqueous Solution Studied by Static and Dynamic Light Scattering and Oscillatory Shear Measurements. The Influence of Relative Block Sizes , 1992 .

[57]  B Mattiasson,et al.  'Smart' polymers and what they could do in biotechnology and medicine. , 1999, Trends in biotechnology.

[58]  Karin Schillén,et al.  Effects of salts on the micellization and gelation of a triblock copolymer studied by rheology and light scattering , 1997 .

[59]  A. Hoffman,et al.  Investigation of a stimuli-responsive copolymer by atomic force microscopy , 2000 .

[60]  A. Mikos,et al.  Recent progress in gene delivery using non-viral transfer complexes. , 2001, Journal of controlled release : official journal of the Controlled Release Society.

[61]  Anna Gutowska,et al.  Thermogelling Biodegradable Polymers with Hydrophilic Backbones: PEG-g-PLGA , 2000 .

[62]  Sung Wan Kim,et al.  Thermoreversible Gelation of PEG−PLGA−PEG Triblock Copolymer Aqueous Solutions , 1999 .

[63]  Russell J. Stewart,et al.  Hybrid hydrogels assembled from synthetic polymers and coiled-coil protein domains , 1999, Nature.

[64]  M. Malmsten,et al.  Self-assembly in aqueous block copolymer solutions , 1992 .

[65]  F. Szoka,et al.  Gene Delivery and Expression in Human Retinal Pigment Epithelial Cells: Effects of Synthetic Carriers, Serum, Extracellular Matrix and Viral Promoters , 2000, Journal of drug targeting.

[66]  J. Leroux,et al.  Novel injectable neutral solutions of chitosan form biodegradable gels in situ. , 2000, Biomaterials.

[67]  W. Foye,et al.  Principles of medicinal chemistry , 1974 .

[68]  Sang Beom Lee,et al.  A New Class of Biodegradable Thermosensitive Polymers. 2. Hydrolytic Properties and Salt Effect on the Lower Critical Solution Temperature of Poly(organophosphazenes) with Methoxypoly(ethylene glycol) and Amino Acid Esters as Side Groups , 1999 .

[69]  K. Kataoka,et al.  Stimuli-sensitive polymer gels that stiffen upon swelling , 2000 .

[70]  Alexei R. Khokhlov,et al.  pH-Responsive Gels of Hydrophobically Modified Poly(acrylic acid) , 1997 .