Recent advances in smart hydrogels for biomedical applications: From self-assembly to functional approaches

Abstract This review discusses basic aspects used to control the architecture and functional properties of smart hydrogels. The introduction briefly outlines what has been accomplished regarding smart hydrogels and explores historical aspects and the fundamental understanding of these systems. Then, a short discussion on the chemical interactions and the main variables involved in architectural construction is exhibited. Further analysis provides the basis for optimizing biological responses through system modulation. Finally, we outline perspectives and challenges for building smart hydrogels into functionalized and modulated delivery systems.

[1]  E. Gil,et al.  Stimuli-reponsive polymers and their bioconjugates , 2004 .

[2]  Anders Carlsson,et al.  Thermal gelation of nonionic cellulose ethers and ionic surfactants in water , 1990 .

[3]  Dean-Mo Liu,et al.  Controlled pulsatile drug release from a ferrogel by a high-frequency magnetic field , 2007 .

[4]  S. Wild,et al.  Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. , 2004, Diabetes care.

[5]  Robert Langer,et al.  Incorporation of a matrix metalloproteinase-sensitive substrate into self-assembling peptides - a model for biofunctional scaffolds. , 2008, Biomaterials.

[6]  A. Gnanamani,et al.  pH and redox sensitive albumin hydrogel: A self-derived biomaterial , 2015, Scientific Reports.

[7]  San-Yuan Chen,et al.  Characterization and drug release behavior of highly responsive chip-like electrically modulated reduced graphene oxide–poly(vinyl alcohol) membranes , 2012 .

[8]  H. Berghmans,et al.  Molecular complex formation in the system poly(vinyl methyl ether)/water , 2000 .

[9]  P. Claesson,et al.  Surface grafted chitosan gels. Part II. Gel formation and characterization. , 2014, Langmuir : the ACS journal of surfaces and colloids.

[10]  D. M. Tope,et al.  Psychological techniques for controlling the adverse side effects of cancer chemotherapy: findings from a decade of research. , 1992, Journal of pain and symptom management.

[11]  Yihua Chen,et al.  A thermo-degradable hydrogel with light-tunable degradation and drug release. , 2017, Biomaterials.

[12]  Xiaofeng Chen,et al.  Multifunctional Hydrogel with Good Structure Integrity, Self-Healing, and Tissue-Adhesive Property Formed by Combining Diels-Alder Click Reaction and Acylhydrazone Bond. , 2015, ACS applied materials & interfaces.

[13]  J. Leroux,et al.  In situ-forming hydrogels--review of temperature-sensitive systems. , 2004, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[14]  Jindrich Kopecek,et al.  Smart and genetically engineered biomaterials and drug delivery systems. , 2003, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[15]  K. Raymond,et al.  Supramolecular assembly dynamics , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[16]  Y. Bae,et al.  Cancer nanomedicines targeting tumor extracellular pH. , 2012, Colloids and surfaces. B, Biointerfaces.

[17]  M. Pishko,et al.  Release of protein from highly cross-linked hydrogels of poly(ethylene glycol) diacrylate fabricated by UV polymerization. , 2001, Biomaterials.

[18]  Jung Hyun Kim,et al.  Preparation of thermally denatured albumin gel and its pH-sensitive swelling , 1998 .

[19]  Zero-Order Release Profiles from A Multistimuli Responsive Electro-Conductive Hydrogel , 2012 .

[20]  H. Krebs,et al.  Isolation and identification of morphine N‐oxide α and β‐dihydromorphines, β‐ or γ‐isomorphine, and hydroxylated morphine as morphine metabolites in several mammalian species , 1979 .

[21]  A. Mitra,et al.  Novel delivery approaches for cancer therapeutics. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[22]  Joung-Woo Choi,et al.  pH-sensitive oncolytic adenovirus hybrid targeting acidic tumor microenvironment and angiogenesis. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[23]  S. Harding,et al.  Various non-injectable delivery systems for the treatment of diabetes mellitus. , 2009, Endocrine, metabolic & immune disorders drug targets.

[24]  Seung‐Woo Cho,et al.  Synthesis of electroconductive hydrogel films by an electro-controlled click reaction and their application to drug delivery systems , 2015 .

[25]  F. Topuz,et al.  Hydrogels in sensing applications , 2012 .

[26]  Buddy D. Ratner,et al.  Glucose sensitive membranes for controlled delivery of insulin: Insulin transport studies , 1985 .

[27]  L. Sorokin The impact of the extracellular matrix on inflammation , 2010, Nature Reviews Immunology.

[28]  John-Christopher Boyer,et al.  Near infrared light triggered release of biomacromolecules from hydrogels loaded with upconversion nanoparticles. , 2012, Journal of the American Chemical Society.

[29]  A. Azmi,et al.  A multi-targeted approach to suppress tumor-promoting inflammation. , 2015, Seminars in cancer biology.

[30]  T. Miyata Biomolecule-Responsive Hydrogels , 2010 .

[31]  Matthias P Lutolf,et al.  Bovine primary chondrocyte culture in synthetic matrix metalloproteinase-sensitive poly(ethylene glycol)-based hydrogels as a scaffold for cartilage repair. , 2004, Tissue engineering.

[32]  Patrick Couvreur,et al.  Stimuli-responsive nanocarriers for drug delivery. , 2013, Nature materials.

[33]  John O. Edwards,et al.  Polyol Complexes and Structure of the Benzeneboronate Ion , 1959 .

[34]  B. Mattiasson,et al.  Smart polymers: Physical forms and bioengineering applications , 2007 .

[35]  F. Andreopoulos,et al.  Delivery of basic fibroblast growth factor (bFGF) from photoresponsive hydrogel scaffolds. , 2006, Biomaterials.

[36]  D. Mooney,et al.  Hydrogels for tissue engineering: scaffold design variables and applications. , 2003, Biomaterials.

[37]  Z. Šklubalová,et al.  Stimuli-sensitive hydrogels in controlled and sustained drug delivery. , 2003, Medicina.

[38]  P. Bernfeld,et al.  Antigens and Enzymes Made Insoluble by Entrapping Them into Lattices of Synthetic Polymers , 1963, Science.

[39]  T. Miyata,et al.  Biologically Stimuli‐Responsive Hydrogels , 2013 .

[40]  Qiang Zhang,et al.  Novel thermo-sensitive hydrogel system with paclitaxel nanocrystals: High drug-loading, sustained drug release and extended local retention guaranteeing better efficacy and lower toxicity. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

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

[42]  I. Donati,et al.  Polysaccharide-based networks from homogeneous chitosan-tripolyphosphate hydrogels: synthesis and characterization. , 2014, Biomacromolecules.

[43]  Irina Popescu,et al.  Poly(N-isopropylacrylamide-co-methacrylic acid) pH/thermo-responsive porous hydrogels as self-regulated drug delivery system. , 2014, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[44]  Juan Fan,et al.  Thermosensitive hydrogel used in dual drug delivery system with paclitaxel-loaded micelles for in situ treatment of lung cancer. , 2014, Colloids and surfaces. B, Biointerfaces.

[45]  Lei Xing,et al.  Coordination bonding based pH-responsive drug delivery systems , 2013 .

[46]  Mark D. Losego,et al.  Hydrogel-Based Glucose Sensors: Effects of Phenylboronic Acid Chemical Structure on Response , 2013 .

[47]  C. Satish,et al.  Hydrogels as controlled drug delivery systems: Synthesis, crosslinking, water and drug transport mechanism , 2006 .

[48]  Leonardo M. B. Ferreira,et al.  Alginate hydrogel improves anti‐angiogenic bevacizumab activity in cancer therapy , 2017, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[49]  R. Leblanc,et al.  A Novel Photoscissile Poly(ethylene glycol)-Based Hydrogel , 2001 .

[50]  T. Giri Alginate Containing Nanoarchitectonics for Improved Cancer Therapy , 2016 .

[51]  Carsten Werner,et al.  Bio-responsive polymer hydrogels homeostatically regulate blood coagulation , 2013, Nature Communications.

[52]  Sytze J Buwalda,et al.  Hydrogels in a historical perspective: from simple networks to smart materials. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[53]  N. Peppas,et al.  Design of pH-Responsive Biomaterials to Enable the Oral Route of Hematological Factor IX , 2016, Annals of Biomedical Engineering.

[54]  San-Yuan Chen,et al.  Preparation and characterization of smart magnetic hydrogels and its use for drug release , 2006 .

[55]  Sang Jun Park,et al.  Swelling behavior of interpenetrating polymer network hydrogels composed of poly(vinyl alcohol) and chitosan , 2003 .

[56]  F. I. Boni,et al.  Gellan gum microspheres crosslinked with trivalent ion: effect of polymer and crosslinker concentrations on drug release and mucoadhesive properties , 2016, Drug development and industrial pharmacy.

[57]  V. Pillay,et al.  A Polyvinyl Alcohol-Polyaniline Based Electro-Conductive Hydrogel for Controlled Stimuli-Actuable Release of Indomethacin , 2011 .

[58]  R. Holt Diagnosis, epidemiology and pathogenesis of diabetes mellitus: An update for psychiatrists , 2004, British Journal of Psychiatry.

[59]  Atsushi Harada,et al.  Design of environment-sensitive supramolecular assemblies for intracellular drug delivery: polymeric micelles that are responsive to intracellular pH change. , 2003, Angewandte Chemie.

[60]  R. DeFronzo,et al.  Skeletal Muscle Insulin Resistance Is the Primary Defect in Type 2 Diabetes , 2009, Diabetes Care.

[61]  Jingxin Guo,et al.  Dissolution kinetics of pH responsive alginate-pectin hydrogel particles. , 2016, Food research international.

[62]  M. Repka,et al.  Matrix metalloproteinase-sensitive thermogelling polymer for bioresponsive local drug delivery. , 2011, Acta biomaterialia.

[63]  R. Medzhitov Inflammation 2010: New Adventures of an Old Flame , 2010, Cell.

[64]  E. Doelker,et al.  Intra-articular drug delivery systems for the treatment of rheumatic diseases: a review of the factors influencing their performance. , 2009, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[65]  Xin Chen,et al.  A pH-Responsive Hydrogel Based on a Tumor-Targeting Mesoporous Silica Nanocomposite for Sustained Cancer Labeling and Therapy. , 2016, Macromolecular rapid communications.

[66]  D. Schmaljohann Thermo- and pH-responsive polymers in drug delivery. , 2006, Advanced drug delivery reviews.

[67]  Liang Ge,et al.  Development of a thermally responsive nanogel based on chitosan-poly(N-isopropylacrylamide-co-acrylamide) for paclitaxel delivery. , 2014, Journal of pharmaceutical sciences.

[68]  Kinam Park,et al.  Environment-sensitive hydrogels for drug delivery , 2001 .

[69]  O. Warburg [Origin of cancer cells]. , 1956, Oncologia.

[70]  R. Leblanc,et al.  Nitrocinnamate-functionalized gelatin: synthesis and "smart"hydrogel formation via photo-cross-linking. , 2005, Biomacromolecules.

[71]  Tianwei Tan,et al.  Superabsorbent hydrogels from poly(aspartic acid) with salt-, temperature- and pH-responsiveness properties , 2005 .

[72]  Tingyun Yang,et al.  Glucose-responsive hydrogels based on dynamic covalent chemistry and inclusion complexation. , 2014, Soft matter.

[73]  Seema Agarwal,et al.  Polymers with upper critical solution temperature in aqueous solution. , 2012, Macromolecular rapid communications.

[74]  J. Hilborn,et al.  Smart Design of Stable Extracellular Matrix Mimetic Hydrogel: Synthesis, Characterization, and In Vitro and In Vivo Evaluation for Tissue Engineering , 2013 .

[75]  Electrically controlled release of macromolecules from cross-linked hyaluronic acid hydrogels , 1995 .

[76]  Daisy P. Cross,et al.  Facile synthesis and characterization of disulfide-cross-linked hyaluronic acid hydrogels for protein delivery and cell encapsulation. , 2011, Biomacromolecules.

[77]  P. Dubruel,et al.  Smart polymer hydrogels: properties, synthesis and applications , 2014 .

[78]  Zhenzhong Zhang,et al.  Functionalized graphene oxide-based thermosensitive hydrogel for near-infrared chemo-photothermal therapy on tumor , 2016, Journal of biomaterials applications.

[79]  A. Froelich,et al.  Application of gellan gum in pharmacy and medicine. , 2014, International journal of pharmaceutics.

[80]  Eun Seong Lee,et al.  Self-organized nanogels responding to tumor extracellular pH: pH-dependent drug release and in vitro cytotoxicity against MCF-7 cells. , 2007, Bioconjugate chemistry.

[81]  J. Kopeček Hydrogel biomaterials: a smart future? , 2007, Biomaterials.

[82]  Rein V Ulijn,et al.  Enzyme-triggered self-assembly of peptide hydrogels via reversed hydrolysis. , 2006, Journal of the American Chemical Society.

[83]  Antonios G Mikos,et al.  Thermoresponsive hydrogels in biomedical applications. , 2008, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[84]  L. Chu,et al.  Smart Hydrogel Functional Materials , 2013 .

[85]  Jean-Marie Lehn,et al.  Toward complex matter: Supramolecular chemistry and self-organization , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[86]  Alexander Kros,et al.  Light controlled protein release from a supramolecular hydrogel. , 2010, Chemical communications.

[87]  B. Sumerlin,et al.  Future perspectives and recent advances in stimuli-responsive materials , 2010 .

[88]  Robert Langer,et al.  Injectable and Glucose-Responsive Hydrogels Based on Boronic Acid-Glucose Complexation. , 2016, Langmuir : the ACS journal of surfaces and colloids.

[89]  Seema Agarwal,et al.  Polymers with Upper Critical Solution Temperature in Aqueous Solution: Unexpected Properties from Known Building Blocks. , 2013, ACS macro letters.

[90]  R. Hoogenboom,et al.  Solution polymeric optical temperature sensors with long-term memory function powered by supramolecular chemistry. , 2015, Chemistry.

[91]  K. Arndt,et al.  Stimuli-Responsive Polymer Systems , 2012 .

[92]  Li Zhou,et al.  Facile one-pot synthesis of iron oxide nanoparticles cross-linked magnetic poly(vinyl alcohol) gel beads for drug delivery. , 2012, ACS applied materials & interfaces.

[93]  Daniel Scherman,et al.  Growth factor delivery approaches in hydrogels. , 2009, Biomacromolecules.

[94]  K. Sawahata,et al.  Electrically controlled drug delivery system using polyelectrolyte gels , 1990 .

[95]  Kinam Park,et al.  Hydrogels for delivery of bioactive agents: a historical perspective. , 2013, Advanced drug delivery reviews.

[96]  N. Sarkar Thermal gelation properties of methyl and hydroxypropyl methylcellulose , 1979 .

[97]  Zheng Wang,et al.  pH-sensitive interpenetrating network hydrogels based on chitosan derivatives and alginate for oral drug delivery. , 2013, Carbohydrate polymers.

[98]  L. Punzi,et al.  Arthrocentesis and Synovial Fluid Analysis in Clinical Practice , 2009, Annals of the New York Academy of Sciences.

[99]  Kinam Park,et al.  Synthesis of superporous hydrogels: hydrogels with fast swelling and superabsorbent properties. , 1999, Journal of biomedical materials research.

[100]  R. C. Evangelista,et al.  Development and characterization of cross-linked gellan gum and retrograded starch blend hydrogels for drug delivery applications. , 2017, Journal of the mechanical behavior of biomedical materials.

[101]  A. Mikos,et al.  Review: Hydrogels for cell immobilization , 2000, Biotechnology and bioengineering.

[102]  Kinam Park,et al.  Biomedical Applications of Hydrogels Handbook , 2010 .

[103]  Eric P. Holowka,et al.  Drug Delivery: Materials Design and Clinical Perspective , 2014 .

[104]  Valéria Maria de Oliveira Cardoso,et al.  A novel pH-responsive hydrogel-based on calcium alginate engineered by the previous formation of polyelectrolyte complexes (PECs) intended to vaginal administration , 2017, Drug development and industrial pharmacy.

[105]  Haifeng Gao,et al.  Thermosensitive poly(N-isopropylacrylamide) nanocapsules with controlled permeability , 2005 .

[106]  J. West,et al.  Hydrogel-nanoparticle composites for optically modulated cancer therapeutic delivery. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[107]  J. Sousa,et al.  Aggregation and gelation in hydroxypropylmethyl cellulose aqueous solutions. , 2008, Journal of colloid and interface science.

[108]  Jean-Marie Lehn,et al.  Dynamers: dynamic molecular and supramolecular polymers , 2005 .

[109]  Wei Wang,et al.  Nano-structured smart hydrogels with rapid response and high elasticity , 2013, Nature Communications.

[110]  H. Brøndsted,et al.  Dextran hydrogels for colon-specific drug delivery , 1995 .

[111]  Mrityunjoy Kar,et al.  Smart hydrogels as functional biomimetic systems. , 2014, Biomaterials science.

[112]  Takashi Miyata,et al.  A reversibly antigen-responsive hydrogel , 1999, Nature.

[113]  Jindřich Kopeček,et al.  Antigen Responsive Hydrogels Based on Polymerizable Antibody Fab′ Fragment , 2003 .

[114]  W. Kuhn,et al.  Reversible Dilation and Contraction by Changing the State of Ionization of High-Polymer Acid Networks , 1950, Nature.

[115]  F. Prezotti,et al.  Preparation and characterization of free films of high amylose/pectin mixtures cross-linked with sodium trimetaphosphate , 2012, Drug development and industrial pharmacy.

[116]  Baolin Guo,et al.  Preparation and properties of a pH/temperature-responsive carboxymethyl chitosan/poly(N-isopropylacrylamide)semi-IPN hydrogel for oral delivery of drugs. , 2007, Carbohydrate research.

[117]  P. Stayton,et al.  pH and Salt Effects on Surface Activity and Self-Assembly of Copolymers Containing a Weak Polybase. , 2016, Langmuir : the ACS journal of surfaces and colloids.

[118]  Kytai Truong Nguyen,et al.  Photopolymerizable hydrogels for tissue engineering applications. , 2002, Biomaterials.

[119]  T. Segura,et al.  Imine Hydrogels with Tunable Degradability for Tissue Engineering. , 2015, Biomacromolecules.

[120]  Bing Xu,et al.  Design and Synthesis of Nanofibers of Self-assembled de novo Glycoconjugates towards Mucosal Lining Restoration and Anti-Inflammatory Drug Delivery. , 2016, Tetrahedron.

[121]  Robert Langer,et al.  An inflammation-targeting hydrogel for local drug delivery in inflammatory bowel disease , 2015, Science Translational Medicine.

[122]  F. Auzel Upconversion and anti-Stokes processes with f and d ions in solids. , 2004, Chemical reviews.

[123]  M. Grinstaff,et al.  Photo-crosslinking of a self-assembled coumarin-dipeptide hydrogel , 2015 .

[124]  J. Mano,et al.  Stimuli-responsive hydrogels based on polysaccharides incorporated with thermo-responsive polymers as novel biomaterials. , 2006, Macromolecular bioscience.

[125]  Rongjun Chen,et al.  pH-responsive, lysine-based hydrogels for the oral delivery of a wide size range of molecules. , 2015, International journal of pharmaceutics.

[126]  Wahid Khan,et al.  Poly(lactic acid) based hydrogels. , 2016, Advanced drug delivery reviews.

[127]  T. Miyata,et al.  Biomolecule-sensitive hydrogels. , 2002, Advanced drug delivery reviews.

[128]  T. Park,et al.  Sodium chloride-induced phase transition in nonionic poly(N-isopropylacrylamide) gel , 1993 .

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

[130]  A. Richter Hydrogel-based μTAS , 2006 .

[131]  Robert Pelton,et al.  Poly(N-isopropylacrylamide) (PNIPAM) is never hydrophobic. , 2010, Journal of colloid and interface science.

[132]  M. Akashi,et al.  Fabrication of Surface-Modified Hydrogels with Polyion Complex for Controlled Release , 2010 .

[133]  O. Korotych,et al.  Multipurpose smart hydrogel systems. , 2011, Advances in colloid and interface science.

[134]  Sanjay K. Jain,et al.  Perspectives of biodegradable natural polysaccharides for site-specific drug delivery to the colon. , 2007, Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques.

[135]  Ozougwu Ozougwu,et al.  The pathogenesis and pathophysiology of type 1 and type 2 diabetes mellitus , 2013 .

[136]  K. Arndt,et al.  Thermo-sensitive poly(methyl vinyl ether) micro-gel formed by high energy radiation , 2001 .

[137]  N. Peppas,et al.  Hybrid responsive hydrogel carriers for oral delivery of low molecular weight therapeutic agents. , 2015, Journal of drug delivery science and technology.

[138]  L. Schmidt‐Mende,et al.  ZnO - nanostructures, defects, and devices , 2007 .

[139]  K. Szaciłowski,et al.  Bioinorganic photochemistry: frontiers and mechanisms. , 2005, Chemical reviews.

[140]  Mengrui Liu,et al.  Internal stimuli-responsive nanocarriers for drug delivery: Design strategies and applications. , 2017, Materials science & engineering. C, Materials for biological applications.

[141]  K. Sen,et al.  Studies on thermoresponsive polymers: Phase behaviour, drug delivery and biomedical applications , 2015 .

[142]  N. Pantoustier,et al.  Synthesis and swelling behavior of pH-responsive polybase brushes. , 2007, Langmuir : the ACS journal of surfaces and colloids.

[143]  Hans P Merkle,et al.  Drug delivery's quest for polymers: Where are the frontiers? , 2015, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[144]  Masato Ikeda,et al.  Supramolecular hydrogel capsule showing prostate specific antigen-responsive function for sensing and targeting prostate cancer cells , 2010 .

[145]  Gulden Camci-Unal,et al.  Activated‐Ester‐Type Photocleavable Crosslinker for Preparation of Photodegradable Hydrogels Using a Two‐Component Mixing Reaction , 2015, Advanced healthcare materials.

[146]  A. Gallardo,et al.  Smart Polymers and Their Applications as Biomaterials , 2007 .

[147]  Toshinobu Yogo,et al.  High-frequency, magnetic-field-responsive drug release from magnetic nanoparticle/organic hybrid based on hyperthermic effect. , 2010, ACS applied materials & interfaces.

[148]  S. Nannarone,et al.  Prevention of plasticizer leaching from PVC medical devices by using organic -inorganic hybrid coatings , 2004 .

[149]  Rein V. Ulijn,et al.  Enzyme-responsive materials: a new class of smart biomaterials , 2006 .

[150]  T. Xia,et al.  Understanding biophysicochemical interactions at the nano-bio interface. , 2009, Nature materials.

[151]  Q. Dong,et al.  Injectable and Biodegradable pH-Responsive Hydrogels for Localized and Sustained Treatment of Human Fibrosarcoma. , 2015, ACS applied materials & interfaces.

[152]  K. Anoop,et al.  Smart polymers for the controlled delivery of drugs – a concise overview , 2014, Acta pharmaceutica Sinica. B.

[153]  Chaoliang He,et al.  Biodegradable pH-responsive polyacrylic acid derivative hydrogels with tunable swelling behavior for oral delivery of insulin , 2013 .

[154]  H. Otsuka,et al.  Dynamic covalent polymers: Reorganizable polymers with dynamic covalent bonds , 2009 .

[155]  C. Tribet,et al.  Light-Triggered Association of Bovine Serum Albumin and Azobenzene-Modified Poly(acrylic acid) in Dilute and Semidilute Solutions , 2006 .

[156]  Y. Cohen,et al.  Characterization of glucose-sensitive insulin release systems in simulated in vivo conditions. , 2000, Biomaterials.

[157]  W. Kuhn,et al.  Reversible Dehnung und Kontraktion bei Änderung der Ionisation eines Netzwerks polyvalenter Fadenmolekülionen , 1949, Experientia.

[158]  Xiabin Jing,et al.  Thermo- and pH-responsive HPC-g-AA/AA hydrogels for controlled drug delivery applications , 2011 .

[159]  F M Andreopoulos,et al.  Light-induced tailoring of PEG-hydrogel properties. , 1998, Biomaterials.

[160]  S. Vaghani,et al.  Synthesis and characterization of carboxymethyl chitosan hydrogel: application as pH-sensitive delivery for nateglinide. , 2012, Current drug delivery.

[161]  Allan S Hoffman,et al.  Hydrogels for biomedical applications. , 2002, Advanced drug delivery reviews.

[162]  Manisha Pandey,et al.  Recent advances in the role of supramolecular hydrogels in drug delivery , 2015, Expert opinion on drug delivery.

[163]  K. Gillespie Type 1 diabetes: pathogenesis and prevention , 2006, Canadian Medical Association Journal.

[164]  E. Dragan,et al.  Design and applications of interpenetrating polymer network hydrogels. A review , 2014 .

[165]  Saswati Roy,et al.  Amino acid containing cross-linked co-polymer gels: pH, thermo and salt responsiveness , 2016 .

[166]  K. Anseth,et al.  Poly(ethylene glycol) hydrogels formed by thiol-ene photopolymerization for enzyme-responsive protein delivery. , 2009, Biomaterials.

[167]  D. Rosenzweig,et al.  Photocleavable Hydrogel-Coated Upconverting Nanoparticles: A Multifunctional Theranostic Platform for NIR Imaging and On-Demand Macromolecular Delivery. , 2016, Journal of the American Chemical Society.

[168]  Abul Kalam Azad,et al.  Chitosan membrane as a wound-healing dressing: characterization and clinical application. , 2004, Journal of biomedical materials research. Part B, Applied biomaterials.

[169]  A. Katchalsky Rapid swelling and deswelling of reversible gels of polymeric acids by ionization , 1949, Experientia.

[170]  V. Deretic Links between Autophagy, Innate Immunity, Inflammation and Crohn’s Disease , 2009, Digestive Diseases.

[171]  Jason A Burdick,et al.  Moving from static to dynamic complexity in hydrogel design , 2012, Nature Communications.

[172]  J. Rubin,et al.  Thermosensitive injectable hyaluronic acid hydrogel for adipose tissue engineering. , 2009, Biomaterials.

[173]  J. Kristl,et al.  Thermoresponsive polymers: insights into decisive hydrogel characteristics, mechanisms of gelation, and promising biomedical applications. , 2014, International journal of pharmaceutics.

[174]  San-Yuan Chen,et al.  Nano-ferrosponges for controlled drug release. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[175]  R. Bertorelle,et al.  VEGF-targeted therapy stably modulates the glycolytic phenotype of tumor cells. , 2015, Cancer research.

[176]  Ann-Christine Albertsson,et al.  Novel pH-sensitive chitosan hydrogels: swelling behavior and states of water , 2000 .

[177]  Daniel G. Anderson,et al.  Smart approaches to glucose-responsive drug delivery , 2015, Journal of drug targeting.

[178]  R. Eisenthal,et al.  A smart membrane based on an antigen‐responsive hydrogel , 2007, Biotechnology and bioengineering.

[179]  Z. Shao,et al.  Synergistic interactions during thermosensitive chitosan-β-glycerophosphate hydrogel formation , 2011 .

[180]  A. Metters,et al.  Synthetic matrix metalloproteinase-sensitive hydrogels for the conduction of tissue regeneration: Engineering cell-invasion characteristics , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[181]  S. Nair,et al.  Smart stimuli sensitive nanogels in cancer drug delivery and imaging: a review. , 2013, Current pharmaceutical design.

[182]  Kinam Park,et al.  Smart Polymeric Gels: Redefining the Limits of Biomedical Devices. , 2007, Progress in polymer science.

[183]  Laura Cipolla,et al.  Bioresponsive Hydrogels: Chemical Strategies and Perspectives in Tissue Engineering , 2016, Gels.

[184]  Y. Barenholz,et al.  Transferrin as a luminal target for negatively charged liposomes in the inflamed colonic mucosa. , 2009, Molecular pharmaceutics.

[185]  Stephanie D. Steichen,et al.  Stimulus-responsive hydrogels: Theory, modern advances, and applications. , 2015, Materials science & engineering. R, Reports : a review journal.

[186]  April M. Kloxin,et al.  Design of Thiol- and Light-sensitive Degradable Hydrogels using Michael-type Addition Reactions. , 2015, Polymer chemistry.

[187]  A. Russell,et al.  Photoimmobilization of organophosphorus hydrolase within a PEG-based hydrogel. , 1999, Biotechnology and bioengineering.

[188]  O. Pillai,et al.  Transdermal delivery of insulin from poloxamer gel: ex vivo and in vivo skin permeation studies in rat using iontophoresis and chemical enhancers. , 2003, Journal of controlled release : official journal of the Controlled Release Society.

[189]  M. Honavar,et al.  Monocarboxylate transporters (MCTs) in gliomas: expression and exploitation as therapeutic targets. , 2013, Neuro-oncology.

[190]  Dean-Mo Liu,et al.  Magnetic-sensitive behavior of intelligent ferrogels for controlled release of drug. , 2006, Langmuir : the ACS journal of surfaces and colloids.

[191]  Koen Raemdonck,et al.  Advanced nanogel engineering for drug delivery , 2009 .

[192]  Nicholas A Peppas,et al.  Responsive theranostic systems: integration of diagnostic imaging agents and responsive controlled release drug delivery carriers. , 2011, Accounts of chemical research.

[193]  J. Lehn Constitutional dynamic chemistry: bridge from supramolecular chemistry to adaptive chemistry. , 2012, Topics in current chemistry.

[194]  T. Okano,et al.  Drug release from electric current sensitive polymers , 1991 .

[195]  I. Tannock,et al.  Acid pH in tumors and its potential for therapeutic exploitation. , 1989, Cancer research.

[196]  Hamidreza Ghandehari,et al.  In vivo evaluation of matrix metalloproteinase responsive silk-elastinlike protein polymers for cancer gene therapy. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[197]  L. Nakopoulou,et al.  MMP-2 Protein in Invasive Breast Cancer and the Impact of MMP-2/TIMP-2 Phenotype on Overall Survival , 2004, Breast Cancer Research and Treatment.

[198]  V. Rajendra,et al.  HYDROGELS AS A DRUG DELIVERY SYSTEM AND APPLICATIONS: A REVIEW Review Article , 2012 .

[199]  Andreas Walther,et al.  Materials learning from life: concepts for active, adaptive and autonomous molecular systems. , 2017, Chemical Society reviews.

[200]  N. Peppas,et al.  Hydrogels in Pharmaceutical Formulations , 1999 .

[201]  B. Cury,et al.  Mucoadhesive beads of gellan gum/pectin intended to controlled delivery of drugs. , 2014, Carbohydrate polymers.

[202]  R. Misra,et al.  Core-shell magnetite nanoparticles surface encapsulated with smart stimuli-responsive polymer: synthesis, characterization, and LCST of viable drug-targeting delivery system. , 2007, Langmuir : the ACS journal of surfaces and colloids.

[203]  Kristi S Anseth,et al.  Hydrogels in Healthcare: From Static to Dynamic Material Microenvironments. , 2013, Acta materialia.

[204]  R. Neufeld,et al.  Modeling the controllable pH-responsive swelling and pore size of networked alginate based biomaterials. , 2009, Biomaterials.

[205]  P. Basser,et al.  Osmotic swelling of polyacrylate hydrogels in physiological salt solutions. , 2000, Biomacromolecules.

[206]  Qiang Zhang,et al.  Near infrared light-responsive and injectable supramolecular hydrogels for on-demand drug delivery. , 2016, Chemical communications.

[207]  M. Casal,et al.  Role of monocarboxylate transporters in human cancers: state of the art , 2012, Journal of Bioenergetics and Biomembranes.