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Development of dual-sensitive smart polymers by grafting chitosan with poly (N-isopropylacrylamide): an overview

Abstract

A great deal of research on polymers over the past two decades has been focused on the development of stimuli-responsive polymers to obtain materials able to respond to specific surroundings. In this paper, an overview is presented of the concepts, behavior and applicability of these “smart polymers”. Polymers that are temperature- or pH-sensitive are discussed in detail, including the response mechanisms and types of macromolecules, because they are easy to handle and have a wide range of applications. Finally, the combination of pH and temperature responsive properties by means of graft copolymerization of chitosan with poly (N-isopropylacrylamide) (PNIPAM) was chosen to represent some synthetic routes and properties of dual-sensitive polymeric systems developed currently.

Keywords:
smart polymer; thermosensitive; pH-responsive; N-isopropylacrylamide; chitosan

1 Introduction

Recently, scientists all over the world have been attempting to synthesize polymers capable of mimic the stimuli-responsive property present in common biopolymers of living organisms, in order to reach scientific and industrial applications. Frequently named as smart polymers, those materials are able to undergo fast, abrupt and reversibly alteration in their structure/properties as a response to small changes in the environment[1Galaev, I. Y., & Mattiasson, B. (1999). ‘Smart’ polymers and what they could do in biotechnology and medicine. Trends in Biotechnology, 17(8), 335-340. http://dx.doi.org/10.1016/S0167-7799(99)01345-1. PMid:10407406.
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These materials have been designed in many forms, depending on the desired application. They can be polymers chains dissolved in solutions, chemically crosslinked hydrogels, physical gels, micelles and even chains immobilized or grafted onto solid surfaces[2Gil, E. S., & Hudson, S. M. (2004). Stimuli-reponsive polymers and their bioconjugates. Progress in Polymer Science, 29(12), 1173-1222. http://dx.doi.org/10.1016/j.progpolymsci.2004.08.003.
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]. Furthermore, regardless the physical form, the smart polymers can be conjugated with biomolecules or synthetic substances, and the activity of the conjugates is going to depend on the polymer-conjugate interactions and the response of the polymer to the stimulus applied[2Gil, E. S., & Hudson, S. M. (2004). Stimuli-reponsive polymers and their bioconjugates. Progress in Polymer Science, 29(12), 1173-1222. http://dx.doi.org/10.1016/j.progpolymsci.2004.08.003.
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].

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], since they are typical variables parameters in biological and chemical systems, and they can also be easily controlled in vitro and in vivo conditions[5656 Medeiros, S. F., Santos, A. M., Fessi, H., & Elaissari, A. (2011). Stimuli-responsive magnetic particles for biomedical applications. International Journal of Pharmaceutics, 403(1-2), 139-161. http://dx.doi.org/10.1016/j.ijpharm.2010.10.011. PMid:20951779.
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http://dx.doi.org/10.1016/j.progpolymsci...
].

The aim of this paper is to present the methods of obtainment and properties of smart polymers in a compact form. It is not intended to be a complete review and therefore the selection of cited literature is of some extent personal. Our presentation is focused mainly on copolymers of chitosan with poly (N-isopropylacrylamide) (PNIPAM), due to the large number of studies found in the literature on these copolymers, but many properties are universal and can also be applied to other pH and temperature sensitive polymers.

2 Thermosensitive Polymers

Temperature is one of the most interesting properties investigated in responsive polymer systems[2Gil, E. S., & Hudson, S. M. (2004). Stimuli-reponsive polymers and their bioconjugates. Progress in Polymer Science, 29(12), 1173-1222. http://dx.doi.org/10.1016/j.progpolymsci.2004.08.003.
http://dx.doi.org/10.1016/j.progpolymsci...
,2424 Brun-Graeppi, A. K. A. S., Richard, C., Bessodes, M., Scherman, D., & Merten, O. W. (2010). Thermoresponsive surfaces for cell culture and enzyme-free cell detachment. Progress in Polymer Science, 35(11), 1311-1324. http://dx.doi.org/10.1016/j.progpolymsci.2010.07.007.
http://dx.doi.org/10.1016/j.progpolymsci...
,5959 Dimitrov, I., Trzebicka, B., Müller, A. H. E., Dworak, A., & Tsvetanov, C. B. (2007). Thermosensitive water-soluble copolymers with doubly responsive reversibly interacting entities. Progress in Polymer Science, 32(11), 1275-1343. http://dx.doi.org/10.1016/j.progpolymsci.2007.07.001.
http://dx.doi.org/10.1016/j.progpolymsci...

60 Wei, H., Cheng, S.-X., Zhang, X.-Z., & Zhuo, R.-X. (2009). Thermo-sensitive polymeric micelles based on poly(. N-isopropylacrylamide) as drug carriersProgress in Polymer Science, 34(9), 893-910. http://dx.doi.org/10.1016/j.progpolymsci.2009.05.002.
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61 Bajpai, A. K., Shukla, S. K., Bhanu, S., & Kankane, S. (2008). Responsive polymers in controlled drug delivery. Progress in Polymer Science, 33(11), 1088-1118. http://dx.doi.org/10.1016/j.progpolymsci.2008.07.005.
http://dx.doi.org/10.1016/j.progpolymsci...

62 Bajpai, A., Shukla, S., Saini, R. & Tiwari, A. (2010). Stimule responsive drug delivery systems: from introduction to application. Shawbury: iSmithers.

63 Chaterji, S., Kwon, I. K., & Park, K. (2007). Smart polymeric gels: Redefining the limits of biomedical devices. Progress in Polymer Science, 32(8-9), 1083-1122. http://dx.doi.org/10.1016/j.progpolymsci.2007.05.018. PMid:18670584.
http://dx.doi.org/10.1016/j.progpolymsci...

64 Chen, T., Ferris, R., Zhang, J., Ducker, R., & Zauscher, S. (2010). Stimulus-responsive polymer brushes on surfaces: Transduction mechanisms and applications. Progress in Polymer Science, 35(1-2), 94-112. http://dx.doi.org/10.1016/j.progpolymsci.2009.11.004.
http://dx.doi.org/10.1016/j.progpolymsci...
-6565 Liu, R., Fraylich, M., & Saunders, B. R. (2009). Thermoresponsive copolymers: From fundamental studies to applications. Colloid & Polymer Science, 287(6), 627-643. http://dx.doi.org/10.1007/s00396-009-2028-x.
http://dx.doi.org/10.1007/s00396-009-202...
]. The thermosensitive polymers are well-known by possessing a large alteration in their structure as a response to slight changes in temperature. When a polymer is dissolved in an appropriate solvent, it may become insoluble upon increase or decrease in temperature and, thus, precipitate from the solution[6666 Weber, C., Hoogenboom, R., & Schubert, U. S. (2012). Temperature responsive bio-compatible polymers based on poly(ethylene oxide) and poly(2-oxazoline)s. Progress in Polymer Science, 37(5), 686-714. http://dx.doi.org/10.1016/j.progpolymsci.2011.10.002.
http://dx.doi.org/10.1016/j.progpolymsci...
]. Solubility of most polymers increases with increasing temperature[5959 Dimitrov, I., Trzebicka, B., Müller, A. H. E., Dworak, A., & Tsvetanov, C. B. (2007). Thermosensitive water-soluble copolymers with doubly responsive reversibly interacting entities. Progress in Polymer Science, 32(11), 1275-1343. http://dx.doi.org/10.1016/j.progpolymsci.2007.07.001.
http://dx.doi.org/10.1016/j.progpolymsci...
,6363 Chaterji, S., Kwon, I. K., & Park, K. (2007). Smart polymeric gels: Redefining the limits of biomedical devices. Progress in Polymer Science, 32(8-9), 1083-1122. http://dx.doi.org/10.1016/j.progpolymsci.2007.05.018. PMid:18670584.
http://dx.doi.org/10.1016/j.progpolymsci...
]. When phase separation happens with decreasing temperature, polymer system presents an upper critical solution temperature(UCST)[6767 Schmaljohann, D. (2006). Thermo- and pH-responsive polymers in drug delivery. Advanced Drug Delivery Reviews, 58(15), 1655-1670. http://dx.doi.org/10.1016/j.addr.2006.09.020. PMid:17125884.
http://dx.doi.org/10.1016/j.addr.2006.09...
]. However, some polymers exhibit a peculiar behavior, in which a phase separation occurs with rising temperature. The temperature in which this occurs is called lower critical solution temperature (LCST)[4Kumar, A., Srivastava, A., Galaev, I. Y., & Mattiasson, B. (2007). Smart polymers: Physical forms and bioengineering applications. Progress in Polymer Science, 32(10), 1205-1237. http://dx.doi.org/10.1016/j.progpolymsci.2007.05.003.
http://dx.doi.org/10.1016/j.progpolymsci...
,1010 Maharjan, P., Woonton, B. W., Bennett, L. E., Smithers, G. W., De Silva, K., & Hearn, M. T. W. (2008). Novel chromatographic separation - The potential of smart polymers. Innovative Food Science & Emerging Technologies, 9(2), 232-242. http://dx.doi.org/10.1016/j.ifset.2007.03.028.
http://dx.doi.org/10.1016/j.ifset.2007.0...
,5959 Dimitrov, I., Trzebicka, B., Müller, A. H. E., Dworak, A., & Tsvetanov, C. B. (2007). Thermosensitive water-soluble copolymers with doubly responsive reversibly interacting entities. Progress in Polymer Science, 32(11), 1275-1343. http://dx.doi.org/10.1016/j.progpolymsci.2007.07.001.
http://dx.doi.org/10.1016/j.progpolymsci...
]. The LCST behavior in water has attracted much attention due to the great applicability[6666 Weber, C., Hoogenboom, R., & Schubert, U. S. (2012). Temperature responsive bio-compatible polymers based on poly(ethylene oxide) and poly(2-oxazoline)s. Progress in Polymer Science, 37(5), 686-714. http://dx.doi.org/10.1016/j.progpolymsci.2011.10.002.
http://dx.doi.org/10.1016/j.progpolymsci...
], such as in wastewater treatment[6868 Snowden, M. J., Thomas, D., & Vincent, B. (1993). Use of colloidal microgels for the absorption of heavy metal and other ions from aqueous solution. Analyst, 118(11), 1367-1369. http://dx.doi.org/10.1039/an9931801367.
http://dx.doi.org/10.1039/an9931801367...
], chromatographic separation[6969 Kanazawa, H., Yamamoto, K., Matsushima, Y., Takai, N., Kikuchi, A., Sakurai, Y., & Okano, T. (1996). Temperature-responsive chromatography using poly(. N-isopropylacrylamide)-modified silicaAnalytical Chemistry, 68(1), 100-105. http://dx.doi.org/10.1021/ac950359j. PMid:21619225.
http://dx.doi.org/10.1021/ac950359j...
], enzyme immobilization[7070 Palai, T., Kumar, A., & Bhattacharya, P. K. (2014). Synthesis and characterization of thermo-responsive poly-N-isopropylacrylamide bioconjugates for application in the formation of galacto-oligosaccharides. Enzyme and Microbial Technology, 55, 40-49. http://dx.doi.org/10.1016/j.enzmictec.2013.12.003. PMid:24411444.
http://dx.doi.org/10.1016/j.enzmictec.20...
] and tissue engineering[7171 Hopkins, S., Carter, S. R., Haycock, J. W., Fullwood, N. J., MacNeil, S., & Rimmer, S. (2009). Sub-micron poly(. N-isopropylacrylamide) particles as temperature responsive vehicles for the detachment and delivery of human cellsSoft Matter, 5(24), 4928-4937. http://dx.doi.org/10.1039/b909656f.
http://dx.doi.org/10.1039/b909656f...
].

From a thermodynamic point of view, the solubilization at low temperatures occurs due to the polymer-solvent hydrogen bonding that leads to a negative enthalpy of mixing. On the other hand, even with a moderate gain in compositional entropy as a consequence of the mixing process, the entropy of organization required to achieve this polymer-solvent hydrogen bonding is unfavorable (negative entropy). Thus, the free energy of dissolution,ΔG, given by ΔH-TΔS, can change from negative (solution) to positive (phase transition) as the temperature is increased[5959 Dimitrov, I., Trzebicka, B., Müller, A. H. E., Dworak, A., & Tsvetanov, C. B. (2007). Thermosensitive water-soluble copolymers with doubly responsive reversibly interacting entities. Progress in Polymer Science, 32(11), 1275-1343. http://dx.doi.org/10.1016/j.progpolymsci.2007.07.001.
http://dx.doi.org/10.1016/j.progpolymsci...
,6666 Weber, C., Hoogenboom, R., & Schubert, U. S. (2012). Temperature responsive bio-compatible polymers based on poly(ethylene oxide) and poly(2-oxazoline)s. Progress in Polymer Science, 37(5), 686-714. http://dx.doi.org/10.1016/j.progpolymsci.2011.10.002.
http://dx.doi.org/10.1016/j.progpolymsci...
,7272 Costa, R. O. R., & Freitas, R. F. S. (2002). Phase behavior of poly(. N-isopropylacrylamide) in binary aqueous solutionsPolymer, 43(22), 5879-5885. http://dx.doi.org/10.1016/S0032-3861(02)00507-4.
http://dx.doi.org/10.1016/S0032-3861(02)...
].

The N-alkyl-substituted polyacrylamides are an especially relevant family of thermosensitive polymers, as seen by a huge numbers of publications. Interestingly, the LCST in this group of polymers varies according to the type of N-substituted groups, ranging from materials insoluble at room temperature to other with high LCST[6565 Liu, R., Fraylich, M., & Saunders, B. R. (2009). Thermoresponsive copolymers: From fundamental studies to applications. Colloid & Polymer Science, 287(6), 627-643. http://dx.doi.org/10.1007/s00396-009-2028-x.
http://dx.doi.org/10.1007/s00396-009-202...
]. They include poly (N-isopropylacrylamide)[2Gil, E. S., & Hudson, S. M. (2004). Stimuli-reponsive polymers and their bioconjugates. Progress in Polymer Science, 29(12), 1173-1222. http://dx.doi.org/10.1016/j.progpolymsci.2004.08.003.
http://dx.doi.org/10.1016/j.progpolymsci...
,5656 Medeiros, S. F., Santos, A. M., Fessi, H., & Elaissari, A. (2011). Stimuli-responsive magnetic particles for biomedical applications. International Journal of Pharmaceutics, 403(1-2), 139-161. http://dx.doi.org/10.1016/j.ijpharm.2010.10.011. PMid:20951779.
http://dx.doi.org/10.1016/j.ijpharm.2010...
,6262 Bajpai, A., Shukla, S., Saini, R. & Tiwari, A. (2010). Stimule responsive drug delivery systems: from introduction to application. Shawbury: iSmithers.,6565 Liu, R., Fraylich, M., & Saunders, B. R. (2009). Thermoresponsive copolymers: From fundamental studies to applications. Colloid & Polymer Science, 287(6), 627-643. http://dx.doi.org/10.1007/s00396-009-2028-x.
http://dx.doi.org/10.1007/s00396-009-202...
,7373 Sousa, R. G., & Freitas, R. F. S. (1995). Determinação do diagrama de fases do gel termossensível poli(-isopropilacrilamida). NPolímeros: Ciência e Tecnologia, 5(3), 32-37.

74 Feijó, F. D., Magalhães, W. F., Freitas, R. F. S., & Sousa, R. G. (1999). Estudo da influência das concentrações de monômero principal e de agente reticulante na estrutura do gel poli(. N-isopropilacrilamida) através de espectroscopia de aniquilação de pósitronsPolímeros: Ciência e Tecnologia, 9(4), 33-38. http://dx.doi.org/10.1590/S0104-14281999000400006.
http://dx.doi.org/10.1590/S0104-14281999...
-7575 Ortega, J. A. C. (2013). Síntesis de hidrogeles termosensibles de poli(‑isopropilacrilamida)-co-poli(,-dimetilacrilamida). NN,NPolímeros: Ciência e Tecnologia, 23(2), 189-195. http://dx.doi.org/10.4322/polimeros.2013.080.
http://dx.doi.org/10.4322/polimeros.2013...
], poly (N,N-diethylacrylamide)[2Gil, E. S., & Hudson, S. M. (2004). Stimuli-reponsive polymers and their bioconjugates. Progress in Polymer Science, 29(12), 1173-1222. http://dx.doi.org/10.1016/j.progpolymsci.2004.08.003.
http://dx.doi.org/10.1016/j.progpolymsci...
,5656 Medeiros, S. F., Santos, A. M., Fessi, H., & Elaissari, A. (2011). Stimuli-responsive magnetic particles for biomedical applications. International Journal of Pharmaceutics, 403(1-2), 139-161. http://dx.doi.org/10.1016/j.ijpharm.2010.10.011. PMid:20951779.
http://dx.doi.org/10.1016/j.ijpharm.2010...
,5959 Dimitrov, I., Trzebicka, B., Müller, A. H. E., Dworak, A., & Tsvetanov, C. B. (2007). Thermosensitive water-soluble copolymers with doubly responsive reversibly interacting entities. Progress in Polymer Science, 32(11), 1275-1343. http://dx.doi.org/10.1016/j.progpolymsci.2007.07.001.
http://dx.doi.org/10.1016/j.progpolymsci...
,6262 Bajpai, A., Shukla, S., Saini, R. & Tiwari, A. (2010). Stimule responsive drug delivery systems: from introduction to application. Shawbury: iSmithers.], poly (2-carboxyisopropylacrylamide), poly (N-(L)-(1-hydroxymethyl) propylmethacrylamide, poly (N-acryloyl-N’-propilpiperazine)[2Gil, E. S., & Hudson, S. M. (2004). Stimuli-reponsive polymers and their bioconjugates. Progress in Polymer Science, 29(12), 1173-1222. http://dx.doi.org/10.1016/j.progpolymsci.2004.08.003.
http://dx.doi.org/10.1016/j.progpolymsci...
], poly (N-ethylacrylamide), poly (N-methyl-N-ethylacrylamide), poly (N-n-propylacrylamide)[5656 Medeiros, S. F., Santos, A. M., Fessi, H., & Elaissari, A. (2011). Stimuli-responsive magnetic particles for biomedical applications. International Journal of Pharmaceutics, 403(1-2), 139-161. http://dx.doi.org/10.1016/j.ijpharm.2010.10.011. PMid:20951779.
http://dx.doi.org/10.1016/j.ijpharm.2010...
,6565 Liu, R., Fraylich, M., & Saunders, B. R. (2009). Thermoresponsive copolymers: From fundamental studies to applications. Colloid & Polymer Science, 287(6), 627-643. http://dx.doi.org/10.1007/s00396-009-2028-x.
http://dx.doi.org/10.1007/s00396-009-202...
], poly (N-ethylmethacrylamide), poly (N-methyl-N-isopropylacrylamide), poly (N-isopropylmethacrylamide), poly (N-n-propylmethacrylamide), poly (N-methyl-N-isopropylacrylamide), poly (N-cyclopropylacrylamide), poly (N-cyclopropymethacrylamide)[5656 Medeiros, S. F., Santos, A. M., Fessi, H., & Elaissari, A. (2011). Stimuli-responsive magnetic particles for biomedical applications. International Journal of Pharmaceutics, 403(1-2), 139-161. http://dx.doi.org/10.1016/j.ijpharm.2010.10.011. PMid:20951779.
http://dx.doi.org/10.1016/j.ijpharm.2010...
], poly (N,N-bis(2-methoxyethyl) acrylamide), poly (N-(3-methoxypropyl)acrylamide), poly (ethoxypropylacrylamide)[6565 Liu, R., Fraylich, M., & Saunders, B. R. (2009). Thermoresponsive copolymers: From fundamental studies to applications. Colloid & Polymer Science, 287(6), 627-643. http://dx.doi.org/10.1007/s00396-009-2028-x.
http://dx.doi.org/10.1007/s00396-009-202...
] and poly (aminomethoxypropylacrylamide)[7676 Uğuzdoğan, E., & Kabasakal, O. S. (2010). Synthesis and characterization of thermally-sensitive polymer: Poly(aminomethoxypropylacrylamide). Colloids and Surfaces. A, Physicochemical and Engineering Aspects, 368(1-3), 129-136. http://dx.doi.org/10.1016/j.colsurfa.2010.07.026.
http://dx.doi.org/10.1016/j.colsurfa.201...
].

Thermosensitive polymers that do not contain acrylamide-based repeat units have also attracted significant attention, such as poly (N-vinylcaprolactam)[5959 Dimitrov, I., Trzebicka, B., Müller, A. H. E., Dworak, A., & Tsvetanov, C. B. (2007). Thermosensitive water-soluble copolymers with doubly responsive reversibly interacting entities. Progress in Polymer Science, 32(11), 1275-1343. http://dx.doi.org/10.1016/j.progpolymsci.2007.07.001.
http://dx.doi.org/10.1016/j.progpolymsci...
,6262 Bajpai, A., Shukla, S., Saini, R. & Tiwari, A. (2010). Stimule responsive drug delivery systems: from introduction to application. Shawbury: iSmithers.,6565 Liu, R., Fraylich, M., & Saunders, B. R. (2009). Thermoresponsive copolymers: From fundamental studies to applications. Colloid & Polymer Science, 287(6), 627-643. http://dx.doi.org/10.1007/s00396-009-2028-x.
http://dx.doi.org/10.1007/s00396-009-202...
], poly (2-ethyl-2-oxazoline)[6565 Liu, R., Fraylich, M., & Saunders, B. R. (2009). Thermoresponsive copolymers: From fundamental studies to applications. Colloid & Polymer Science, 287(6), 627-643. http://dx.doi.org/10.1007/s00396-009-2028-x.
http://dx.doi.org/10.1007/s00396-009-202...
], poly (vinyl methyl ether)[5959 Dimitrov, I., Trzebicka, B., Müller, A. H. E., Dworak, A., & Tsvetanov, C. B. (2007). Thermosensitive water-soluble copolymers with doubly responsive reversibly interacting entities. Progress in Polymer Science, 32(11), 1275-1343. http://dx.doi.org/10.1016/j.progpolymsci.2007.07.001.
http://dx.doi.org/10.1016/j.progpolymsci...
,6565 Liu, R., Fraylich, M., & Saunders, B. R. (2009). Thermoresponsive copolymers: From fundamental studies to applications. Colloid & Polymer Science, 287(6), 627-643. http://dx.doi.org/10.1007/s00396-009-2028-x.
http://dx.doi.org/10.1007/s00396-009-202...
], poly (2-isopropyl-2-oxazoline), poly ((2-dimethylamino)ethyl methacrylate), poly (propylene oxide)[6565 Liu, R., Fraylich, M., & Saunders, B. R. (2009). Thermoresponsive copolymers: From fundamental studies to applications. Colloid & Polymer Science, 287(6), 627-643. http://dx.doi.org/10.1007/s00396-009-2028-x.
http://dx.doi.org/10.1007/s00396-009-202...
] and poly (N-acryloylpiperidine)[5656 Medeiros, S. F., Santos, A. M., Fessi, H., & Elaissari, A. (2011). Stimuli-responsive magnetic particles for biomedical applications. International Journal of Pharmaceutics, 403(1-2), 139-161. http://dx.doi.org/10.1016/j.ijpharm.2010.10.011. PMid:20951779.
http://dx.doi.org/10.1016/j.ijpharm.2010...
]. There are also polymers derived from natural sources with LCST behavior, such as methylcellulose, ethyl(hydroxyethyl)cellulose and hydroxypropylcellulose, that are of great interest for biomedical applications[6565 Liu, R., Fraylich, M., & Saunders, B. R. (2009). Thermoresponsive copolymers: From fundamental studies to applications. Colloid & Polymer Science, 287(6), 627-643. http://dx.doi.org/10.1007/s00396-009-2028-x.
http://dx.doi.org/10.1007/s00396-009-202...
]. Some of thermoresponsive polymer structures are presented in Figure 1.

Figure 1
Chemical structure of some thermosensitive polymers: (a) poly (N-isopropylacrylamide); (b) poly (N,N-diethylacrylamide); (c) poly (N-ethylacrylamide); (d) poly (2-carboxyisopropylacrylamide); (e) poly (N-(L)-(1-hydroxymethyl) propylmethacrylamide; (f) poly (N-acryloyl-N’-propilpiperazine); (g) poly (N-vinylcaprolactam); (h) poly ((2-dimethylamino)ethyl methacrylate); (i) poly (2-ethyl-2-oxazoline); (j) poly (2-isopropyl-2-oxazoline); (k) poly (vinyl methyl ether); (l) poly (propylene oxide); (m) methylcellulose; (n) ethyl(hydroxylethyl)cellulose.

Despite the vast variety of thermoresponsive polymers, poly (N-isopropylacrylamide) (PNIPAM) is the most extensively studied one, as seen by the huge amount of publications dealing with this polymer. PNIPAM presents a LCST that lies between 30 and 35°C, depending on the precise microstructure of the macromolecule[7777 Schild, H. G. (1992). Poly(-isopropylacrylamide): experiment, theory and application. NProgress in Polymer Science, 17(2), 163-249. http://dx.doi.org/10.1016/0079-6700(92)90023-R.
http://dx.doi.org/10.1016/0079-6700(92)9...
]. PNIPAM brings together an abrupt and reversible thermosensitive nature[7878 Recillas, M., Silva, L. L., Peniche, C., Goycoolea, F. M., Rinaudo, M., & Argüelles-Monal, W. M. (2009). Thermoresponsive behavior of chitosan-g-N-isopropylacrylamide copolymer solutions. Biomacromolecules, 10(6), 1633-1641. http://dx.doi.org/10.1021/bm9002317. PMid:19364095.
http://dx.doi.org/10.1021/bm9002317...
], with biocompatibility and LCST close to the human body[2424 Brun-Graeppi, A. K. A. S., Richard, C., Bessodes, M., Scherman, D., & Merten, O. W. (2010). Thermoresponsive surfaces for cell culture and enzyme-free cell detachment. Progress in Polymer Science, 35(11), 1311-1324. http://dx.doi.org/10.1016/j.progpolymsci.2010.07.007.
http://dx.doi.org/10.1016/j.progpolymsci...
], which turns it especially attractive in biomedical applications[7979 Cole, M. A., Voelcker, N. H., Thissen, H., & Griesser, H. J. (2009). Stimuli-responsive interfaces and systems for the control of protein-surface and cell-surface interactions. Biomaterials, 30(9), 1827-1850. http://dx.doi.org/10.1016/j.biomaterials.2008.12.026. PMid:19144401.
http://dx.doi.org/10.1016/j.biomaterials...
].

At temperatures below the LCST of PNIPAM, water-polymer interactions are dominant, leading to dissolution or swelling in water[7878 Recillas, M., Silva, L. L., Peniche, C., Goycoolea, F. M., Rinaudo, M., & Argüelles-Monal, W. M. (2009). Thermoresponsive behavior of chitosan-g-N-isopropylacrylamide copolymer solutions. Biomacromolecules, 10(6), 1633-1641. http://dx.doi.org/10.1021/bm9002317. PMid:19364095.
http://dx.doi.org/10.1021/bm9002317...
]. With rising temperature, the polymer-solvent hydrogen bonds are being disrupted, whereas polymer-polymer interactions are greatly increased, resulting in collapsed structures at the LCST[8080 Han, J., Wang, K., Yang, D., & Nie, J. (2009). Photopolymerization of methacrylated chitosan/PNIPAAm hybrid dual-sensitive hydrogels as carrier for drug delivery. International Journal of Biological Macromolecules, 44(3), 229-235. http://dx.doi.org/10.1016/j.ijbiomac.2008.12.009. PMid:19146871.
http://dx.doi.org/10.1016/j.ijbiomac.200...
,8181 Al-Manasir, N., Zhu, K., Kjøniksen, A. L., Knudsen, K. D., Karlsson, G., & Nyström, B. (2009). Effects of temperature and pH on the contraction and aggregation of microgels in aqueous suspensions. The Journal of Physical Chemistry B, 113(32), 11115-11123. http://dx.doi.org/10.1021/jp901121g. PMid:19618921.
http://dx.doi.org/10.1021/jp901121g...
]. Above the transition temperature, the globules are aggregated into a few PNIPAM chains at very dilute solutions, while higher polymer concentrations result in colloidal dispersions or even macroscopic precipitates[2323 Pelton, R. (2010). Poly(-isopropylacrylamide) (PNIPAM) is never hydrophobic. NJournal of Colloid and Interface Science, 348(2), 673-674. http://dx.doi.org/10.1016/j.jcis.2010.05.034. PMid:20605160.
http://dx.doi.org/10.1016/j.jcis.2010.05...
,8282 Chan, K., Pelton, R., & Zhang, J. (1999). On the formation of colloidally dispersed phase-separated poly(-isopropylacrylamide). NLangmuir, 15(11), 4018-4020. http://dx.doi.org/10.1021/la9812673.
http://dx.doi.org/10.1021/la9812673...
,8383 Kujawa, P., Aseyev, V., Tenhu, H., & Winnik, F. M. (2006). Temperature-sensitive properties of poly(. N-isopropylacrylamide) mesoglobules formed in dilute aqueous solutions heated above their demixing pointMacromolecules, 39(22), 7686-7693. http://dx.doi.org/10.1021/ma061604b.
http://dx.doi.org/10.1021/ma061604b...
].

Furthermore, as a consequence of LCST dependence on the balance between attractive polymer-polymer and polymer-solvent interactions[2424 Brun-Graeppi, A. K. A. S., Richard, C., Bessodes, M., Scherman, D., & Merten, O. W. (2010). Thermoresponsive surfaces for cell culture and enzyme-free cell detachment. Progress in Polymer Science, 35(11), 1311-1324. http://dx.doi.org/10.1016/j.progpolymsci.2010.07.007.
http://dx.doi.org/10.1016/j.progpolymsci...
,6565 Liu, R., Fraylich, M., & Saunders, B. R. (2009). Thermoresponsive copolymers: From fundamental studies to applications. Colloid & Polymer Science, 287(6), 627-643. http://dx.doi.org/10.1007/s00396-009-2028-x.
http://dx.doi.org/10.1007/s00396-009-202...
], the transition temperature of PNIPAM can be adjusted by changing its molecular weight and concentration, by means of copolymerization of NIPAM with other comonomers, as well as through and addition of salts, surfactants and co-solvents[2424 Brun-Graeppi, A. K. A. S., Richard, C., Bessodes, M., Scherman, D., & Merten, O. W. (2010). Thermoresponsive surfaces for cell culture and enzyme-free cell detachment. Progress in Polymer Science, 35(11), 1311-1324. http://dx.doi.org/10.1016/j.progpolymsci.2010.07.007.
http://dx.doi.org/10.1016/j.progpolymsci...
,6262 Bajpai, A., Shukla, S., Saini, R. & Tiwari, A. (2010). Stimule responsive drug delivery systems: from introduction to application. Shawbury: iSmithers.,6565 Liu, R., Fraylich, M., & Saunders, B. R. (2009). Thermoresponsive copolymers: From fundamental studies to applications. Colloid & Polymer Science, 287(6), 627-643. http://dx.doi.org/10.1007/s00396-009-2028-x.
http://dx.doi.org/10.1007/s00396-009-202...
,8282 Chan, K., Pelton, R., & Zhang, J. (1999). On the formation of colloidally dispersed phase-separated poly(-isopropylacrylamide). NLangmuir, 15(11), 4018-4020. http://dx.doi.org/10.1021/la9812673.
http://dx.doi.org/10.1021/la9812673...

83 Kujawa, P., Aseyev, V., Tenhu, H., & Winnik, F. M. (2006). Temperature-sensitive properties of poly(. N-isopropylacrylamide) mesoglobules formed in dilute aqueous solutions heated above their demixing pointMacromolecules, 39(22), 7686-7693. http://dx.doi.org/10.1021/ma061604b.
http://dx.doi.org/10.1021/ma061604b...

84 Durand, A., & Hourdet, D. (1999). Synthesis and thermoassociative properties in aqueous solution of graft copolymers containing poly(N-isopropylacrylamide) side chains. Polymer, 40(17), 4941-4951. http://dx.doi.org/10.1016/S0032-3861(98)00698-3.
http://dx.doi.org/10.1016/S0032-3861(98)...

85 Hofmann, C., & Schönhoff, M. (2009). Do additives shift the LCST of poly (N-isopropylacrylamide) by solvent quality changes or by direct interactions?Colloid & Polymer Science, 287(12), 1369-1376. http://dx.doi.org/10.1007/s00396-009-2103-3.
http://dx.doi.org/10.1007/s00396-009-210...

86 Schild, H. G., & Tirrell, D. A. (1990). Microcalorimetric detection of lower critical solution temperatures in aqueous polymer solutions. Journal of Physical Chemistry, 94(10), 4352-4356. http://dx.doi.org/10.1021/j100373a088.
http://dx.doi.org/10.1021/j100373a088...

87 Durand, A., & Hourdet, D. (2000). Thermoassociative graft copolymers based on poly(. N-isopropylacrylamide): effect of added co-solutes on the rheological behaviorPolymer, 41(2), 545-557. http://dx.doi.org/10.1016/S0032-3861(99)00212-8.
http://dx.doi.org/10.1016/S0032-3861(99)...

88 Dumitriu, R. P., Mitchell, G. R., & Vasile, C. (2011). Rheological and thermal behaviour of poly(-isopropylacrylamide)/alginate smart polymeric networks. NPolymer International, 60(9), 1398-1407.

89 Rubira, A. F., Muniz, E. C., Guilherme, M. R., Paulino, A. T., & Tambourgi, E. B. (2009). Morphology of temperature-sensitive and pH-responsive IPN-hydrogels for application as biomaterial for cell growth. Polímeros: Ciência e Tecnologia, 19(2), 105-110. http://dx.doi.org/10.1590/S0104-14282009000200006.
http://dx.doi.org/10.1590/S0104-14282009...

90 Lü, S., Liu, M., & Ni, B. (2011). Degradable, injectable poly(-isopropylacrylamide)-based hydrogels with low gelation concentrations for protein delivery application. NChemical Engineering Journal, 173(1), 241-250. http://dx.doi.org/10.1016/j.cej.2011.07.052.
http://dx.doi.org/10.1016/j.cej.2011.07....

91 Bokias, G., Mylonas, Y., Staikos, G., Bumbu, G. G., & Vasile, C. (2001). Synthesis and aqueous solution properties of novel thermoresponsive graft copolymers based on a carboxymethylcellulose backbone. Macromolecules, 34(14), 4958-4964. http://dx.doi.org/10.1021/ma010154e.
http://dx.doi.org/10.1021/ma010154e...
-9292 Alvarez-Lorenzo, C., Blanco-Fernandez, B., Puga, A. M., & Concheiro, A. (2013). Crosslinked ionic polysaccharides for stimuli-sensitive drug delivery. Advanced Drug Delivery Reviews, 65(9), 1148-1171. http://dx.doi.org/10.1016/j.addr.2013.04.016. PMid:23639519.
http://dx.doi.org/10.1016/j.addr.2013.04...
].

3 pH-sensitive Polymers

pH-sensitive polymers experience abrupt alterations in their polymer-polymer and polymer-solvent interactions in response to small variations in the environmental pH[6161 Bajpai, A. K., Shukla, S. K., Bhanu, S., & Kankane, S. (2008). Responsive polymers in controlled drug delivery. Progress in Polymer Science, 33(11), 1088-1118. http://dx.doi.org/10.1016/j.progpolymsci.2008.07.005.
http://dx.doi.org/10.1016/j.progpolymsci...
]. This behavior is attributed to the presence of pendant weak basic or acid groups in the polymeric chains, that either accept or release protons, respectively, as a result of slight changes in the pH of the medium[6262 Bajpai, A., Shukla, S., Saini, R. & Tiwari, A. (2010). Stimule responsive drug delivery systems: from introduction to application. Shawbury: iSmithers.]. This occurs because the degree of ionization of weak acids or bases is highly modified by changing the pH around their pKa value. Then, a large alteration in the hydrodynamic volume of the polymeric chains takes place, as a result of the quick variation in the charges of the pendant groups[2Gil, E. S., & Hudson, S. M. (2004). Stimuli-reponsive polymers and their bioconjugates. Progress in Polymer Science, 29(12), 1173-1222. http://dx.doi.org/10.1016/j.progpolymsci.2004.08.003.
http://dx.doi.org/10.1016/j.progpolymsci...
,6363 Chaterji, S., Kwon, I. K., & Park, K. (2007). Smart polymeric gels: Redefining the limits of biomedical devices. Progress in Polymer Science, 32(8-9), 1083-1122. http://dx.doi.org/10.1016/j.progpolymsci.2007.05.018. PMid:18670584.
http://dx.doi.org/10.1016/j.progpolymsci...
].

There are many polymers responsive to the environmental pH (Figure 2), including synthetic ones, such as poly (acrylic acid), poly (2-ethyl acrylic acid), poly (N,N-diethyl aminoethyl methacrylate) and poly (vinyl imidazole)[2Gil, E. S., & Hudson, S. M. (2004). Stimuli-reponsive polymers and their bioconjugates. Progress in Polymer Science, 29(12), 1173-1222. http://dx.doi.org/10.1016/j.progpolymsci.2004.08.003.
http://dx.doi.org/10.1016/j.progpolymsci...
], and those from natural sources, such as alginate[8888 Dumitriu, R. P., Mitchell, G. R., & Vasile, C. (2011). Rheological and thermal behaviour of poly(-isopropylacrylamide)/alginate smart polymeric networks. NPolymer International, 60(9), 1398-1407.,8989 Rubira, A. F., Muniz, E. C., Guilherme, M. R., Paulino, A. T., & Tambourgi, E. B. (2009). Morphology of temperature-sensitive and pH-responsive IPN-hydrogels for application as biomaterial for cell growth. Polímeros: Ciência e Tecnologia, 19(2), 105-110. http://dx.doi.org/10.1590/S0104-14282009000200006.
http://dx.doi.org/10.1590/S0104-14282009...
], carboxymethylcellulose[9090 Lü, S., Liu, M., & Ni, B. (2011). Degradable, injectable poly(-isopropylacrylamide)-based hydrogels with low gelation concentrations for protein delivery application. NChemical Engineering Journal, 173(1), 241-250. http://dx.doi.org/10.1016/j.cej.2011.07.052.
http://dx.doi.org/10.1016/j.cej.2011.07....
,9191 Bokias, G., Mylonas, Y., Staikos, G., Bumbu, G. G., & Vasile, C. (2001). Synthesis and aqueous solution properties of novel thermoresponsive graft copolymers based on a carboxymethylcellulose backbone. Macromolecules, 34(14), 4958-4964. http://dx.doi.org/10.1021/ma010154e.
http://dx.doi.org/10.1021/ma010154e...
]and chitosan[9292 Alvarez-Lorenzo, C., Blanco-Fernandez, B., Puga, A. M., & Concheiro, A. (2013). Crosslinked ionic polysaccharides for stimuli-sensitive drug delivery. Advanced Drug Delivery Reviews, 65(9), 1148-1171. http://dx.doi.org/10.1016/j.addr.2013.04.016. PMid:23639519.
http://dx.doi.org/10.1016/j.addr.2013.04...

93 Kimura, I. Y., Gonçalves, A. C., Jr,, Stolberg, J., Laranjeira, M. C. M., & Fávere, V. T. (1999). Efeito do pH e do tempo de contato na adsorção de corantes reativos por microesferas de quitosana. Polímeros: Ciência e Tecnologia, 9(3), 51-57. http://dx.doi.org/10.1590/S0104-14281999000300010.
http://dx.doi.org/10.1590/S0104-14281999...

94 Oliveira, S. P. D., Mahl, C. R. A., Simões, M. R., & Silva, C. F. (2012). Chitosan as flocculant agent for clarification of stevia extract. Polímeros: Ciência e Tecnologia, 22(4), 401-406. http://dx.doi.org/10.1590/S0104-14282012005000066.
http://dx.doi.org/10.1590/S0104-14282012...

95 Maciel, V. B. V., Franco, T. T., & Yoshida, C. M. P. (2012). Alternative intelligent material for packaging using chitosan films as colorimetric temperature indicators. Polímeros: Ciência e Tecnologia, 22(4), 318-324. http://dx.doi.org/10.1590/S0104-14282012005000054.
http://dx.doi.org/10.1590/S0104-14282012...

96 Josué, A., Laranjeira, M. C. M., Fávere, V. T., Kimura, I. Y., & Pedrosa, R. C. (2000). Controlled release of eosin impregnated in microspheres of chitosan/poly(acrylic acid) copolymer. Polímeros: Ciência e Tecnologia, 10(3), 116-121.
-9797 Gonçalves, V. L., Laranjeira, M. C. M., Fávere, V. T., & Pedrosa, R. C. (2005). Effect of crosslinking agents on chitosan microspheres in controlled release of diclofenac sodium. Polímeros: Ciência e Tecnologia, 15(1), 6-12. http://dx.doi.org/10.1590/S0104-14282005000100005.
http://dx.doi.org/10.1590/S0104-14282005...
]. The pH-responsive polymers can also be classified as: (i) polyacids, which contain pendant weak acid groups, such as -COOH and -SO3H; (ii) polybases, that possess pendant weak basic groups (-NH2) in their chains[2Gil, E. S., & Hudson, S. M. (2004). Stimuli-reponsive polymers and their bioconjugates. Progress in Polymer Science, 29(12), 1173-1222. http://dx.doi.org/10.1016/j.progpolymsci.2004.08.003.
http://dx.doi.org/10.1016/j.progpolymsci...
,1010 Maharjan, P., Woonton, B. W., Bennett, L. E., Smithers, G. W., De Silva, K., & Hearn, M. T. W. (2008). Novel chromatographic separation - The potential of smart polymers. Innovative Food Science & Emerging Technologies, 9(2), 232-242. http://dx.doi.org/10.1016/j.ifset.2007.03.028.
http://dx.doi.org/10.1016/j.ifset.2007.0...
]; or (iii) polyamphoterics, that bear both weak acid and basic groups[6262 Bajpai, A., Shukla, S., Saini, R. & Tiwari, A. (2010). Stimule responsive drug delivery systems: from introduction to application. Shawbury: iSmithers.].

Figure 2
Chemical structure of some pH-responsive polymers: (a) poly (acrylic acid); (b) poly (methacrylic acid); (c) poly (2-ethyl acrylic acid); (d) poly (N,N-dimethyl aminoethyl methacrylate); (e) poly (N,N-diethyl aminoethyl methacrylate); (f) poly (vinyl imidazole); (g) chitosan; (h) alginate.

When applying pH-responsive polymers, the polysaccharides are preferred in many applications, because they join pH-sensitiveness with inherent biological properties. One of the most outstanding pH-sensitive biopolymer is chitosan[9898 Grem, I. C. S., Lima, B. N. B., Carneiro, W. F., Queirós, Y. G. C., & Mansur, C. R. E. (2013). Chitosan microspheres applied for removal of oil from produced water in the oil industry. Polímeros: Ciência e Tecnologia, 23(6), 705-711. http://dx.doi.org/10.4322/polimeros.2014.008.
http://dx.doi.org/10.4322/polimeros.2014...
,9999 Fernandes, L. L., Resende, C. X., Tavares, D. S., Soares, G. A., Castro, L. O., & Granjeiro, J. M. (2011). Cytocompatibility of chitosan and collagen-chitosan scaffolds for tissue engineering. Polímeros: Ciência e Tecnologia, 21(1), 1-6. http://dx.doi.org/10.1590/S0104-14282011005000008.
http://dx.doi.org/10.1590/S0104-14282011...
], a polysaccharide which naturally occurs in certain fungi[100100 Campana, S. P., Fo., & Signini, R. (2001). Efeito de aditivos na desacetilação de quitina. Polímeros: Ciência e Tecnologia, 11(4), 169-173. http://dx.doi.org/10.1590/S0104-14282001000400006.
http://dx.doi.org/10.1590/S0104-14282001...
], but is extensively obtained by the deacetylation of chitin[5858 Carreira, A. S., Goncalves, F. A. M. M., Mendonca, P. V., Gil, M. H., & Coelho, J. F. J. (2010). Temperature and pH responsive polymers based on chitosan: applications and new graft copolymerization strategies based on living radical polymerization. Carbohydrate Polymers, 80(3), 618-630.,101101 Santos, J. E., Soares, J. P., Dockal, E. R., Campana, S. P., Fo., & Cavalheiro, É. T. G. (2003). Characterization of commercial chitosan from different suppliers. Polímeros: Ciência e Tecnologia, 13(4), 242-249.,102102 Dash, M., Chiellini, F., Ottenbrite, R. M., & Chiellini, E. (2011). Chitosan - A versatile semi-synthetic polymer in biomedical applications. Progress in Polymer Science, 36(8), 981-1014. http://dx.doi.org/10.1016/j.progpolymsci.2011.02.001.
http://dx.doi.org/10.1016/j.progpolymsci...
], which is extracted from the shells of crustaceans, from the exoskeleton of many arthropods and from some fungi[103103 Kasaai, M. R. (2009). Various methods for determination of the degree of N-acetylation of chitin and chitosan: a review. Journal of Agricultural and Food Chemistry, 57(5), 1667-1676. http://dx.doi.org/10.1021/jf803001m. PMid:19187020.
http://dx.doi.org/10.1021/jf803001m...
]. Despite the massive annual production and easy availability, due to its poor solubility in almost all common solvents, chitin does not find practical applications, except for being a source for obtaining chitosan[102102 Dash, M., Chiellini, F., Ottenbrite, R. M., & Chiellini, E. (2011). Chitosan - A versatile semi-synthetic polymer in biomedical applications. Progress in Polymer Science, 36(8), 981-1014. http://dx.doi.org/10.1016/j.progpolymsci.2011.02.001.
http://dx.doi.org/10.1016/j.progpolymsci...

103 Kasaai, M. R. (2009). Various methods for determination of the degree of N-acetylation of chitin and chitosan: a review. Journal of Agricultural and Food Chemistry, 57(5), 1667-1676. http://dx.doi.org/10.1021/jf803001m. PMid:19187020.
http://dx.doi.org/10.1021/jf803001m...

104 Pillai, C. K. S., Paul, W., & Sharma, C. P. (2009). Chitin and chitosan polymers: Chemistry, solubility and fiber formation. Progress in Polymer Science, 34(7), 641-678. http://dx.doi.org/10.1016/j.progpolymsci.2009.04.001.
http://dx.doi.org/10.1016/j.progpolymsci...
-105105 Abreu, F. O. M. S., Cavalcante, L. G., Doudement, P. V., Castro, A. M., Nascimento, A. P., & Matos, J. E. X. (2013). Development of new method to obtain chitosan from the exoskeleton of crabs using microwave radiation. Polímeros: Ciência e Tecnologia, 23(5), 630-635. http://dx.doi.org/10.4322/polimeros.2013.042.
http://dx.doi.org/10.4322/polimeros.2013...
].

Chitosan is a linear copolymer composed of two repeating units i.e. N-acetyl-2-amino-2-D-glucopyranose and 2-amino-2-deoxy-D-glucopyranose, linked by β-(1→4)-glycosidic bonds. Generally, when the content of 2-amino-2-deoxy-D-glucopyranose (degree of deacetylation – DD) in the polysaccharide chain is higher than 50 %, it becomes soluble in an aqueous acidic medium, as a result of the protonation of its amino groups and, in these conditions, it is named chitosan[106106 Rinauldo, M. (2008). Main properties and current applications of some polysaccharides as biomaterials. Polymer International, 57(3), 397-430. http://dx.doi.org/10.1002/pi.2378.
http://dx.doi.org/10.1002/pi.2378...
,107107 Fernandes, S. C. M., Freire, C. S. R., Silvestre, A. J. D., Pascoal, C., No., & Gandini, A. (2011). Novel materials based on chitosan and cellulose. Polymer International, 60(6), 875-882. http://dx.doi.org/10.1002/pi.3024.
http://dx.doi.org/10.1002/pi.3024...
]. As a polysaccharide, chitosan exhibits attractive properties such as biocompatibility and biodegradability. Also, its degradation products are non-toxic, non-immunogenic and non-carcinogenic[6262 Bajpai, A., Shukla, S., Saini, R. & Tiwari, A. (2010). Stimule responsive drug delivery systems: from introduction to application. Shawbury: iSmithers.,106106 Rinauldo, M. (2008). Main properties and current applications of some polysaccharides as biomaterials. Polymer International, 57(3), 397-430. http://dx.doi.org/10.1002/pi.2378.
http://dx.doi.org/10.1002/pi.2378...
].

The pH-responsive property of chitosan is a consequence of protonation–deprotonation equilibrium of its amino groups (pKa around 6) in aqueous media[5858 Carreira, A. S., Goncalves, F. A. M. M., Mendonca, P. V., Gil, M. H., & Coelho, J. F. J. (2010). Temperature and pH responsive polymers based on chitosan: applications and new graft copolymerization strategies based on living radical polymerization. Carbohydrate Polymers, 80(3), 618-630.,102102 Dash, M., Chiellini, F., Ottenbrite, R. M., & Chiellini, E. (2011). Chitosan - A versatile semi-synthetic polymer in biomedical applications. Progress in Polymer Science, 36(8), 981-1014. http://dx.doi.org/10.1016/j.progpolymsci.2011.02.001.
http://dx.doi.org/10.1016/j.progpolymsci...
,108108 Martins, G. V., Mano, J. F., & Alves, N. M. (2011). Dual responsive nanostructured surfaces for biomedical applications. Langmuir, 27(13), 8415-8423. http://dx.doi.org/10.1021/la200832n. PMid:21639130.
http://dx.doi.org/10.1021/la200832n...
]. Besides, the presence of -OH and -NH2 reactive groups makes of this polysaccharide very attractive for chemical modifications[109109 Goy, R. C., Britto, D., & Assis, O. B. G. (2009). A review of the antimicrobial activity of chitosan. Polímeros: Ciência e Tecnologia, 19(3), 241-247. http://dx.doi.org/10.1590/S0104-14282009000300013.
http://dx.doi.org/10.1590/S0104-14282009...
,110110 Torres, M. A., Vieira, R. S., Beppu, M. M., & Santana, C. C. (2005). Production and characterization of chemically modified chitosan microspheres. Polímeros: Ciência e Tecnologia, 15(4), 306-312. http://dx.doi.org/10.1590/S0104-14282005000400016.
http://dx.doi.org/10.1590/S0104-14282005...
].

4 Combination of pH and Thermosensitive Properties Through Graft Copolymerization of Chitosan with PNIPAM

Nowadays, grafting PNIPAM side chains on the chitosan backbone constitutes a crescent area of research, since it bonds the most studied thermosensitive polymer with the most outstanding cationic polysaccharide, to reach dual temperature and pH responsive materials with remarkable properties[3333 Wang, Y., Wang, J., Ge, L., Liu, Q., Jiang, L., Zhu, J., Zhou, J., & Xiong, F. (2013). Synthesis, properties and self-assembly of intelligent core-shell nanoparticles based on chitosan with different molecular weight and . N-isopropylacrylamideJournal of Applied Polymer Science, 127(5), 3749-3759. http://dx.doi.org/10.1002/app.37648.
http://dx.doi.org/10.1002/app.37648...
,111111 Bao, H., Li, L., Leong, W. C., & Gan, L. H. (2010). Thermo-responsive association of chitosan-graft-poly(N-isopropylacrylamide) in aqueous solutions. The Journal of Physical Chemistry B, 114(32), 10666-10673. http://dx.doi.org/10.1021/jp105041z. PMid:20734475.
http://dx.doi.org/10.1021/jp105041z...

112 Seetapan, N., Mai-ngam, K., Plucktaveesak, N., & Sirivat, A. (2006). Linear viscoelasticity of thermoassociative chitosan--poly(. gN-isopropylacrylamide) copolymerRheologica Acta, 45(6), 1011-1018. http://dx.doi.org/10.1007/s00397-005-0055-1.
http://dx.doi.org/10.1007/s00397-005-005...

113 Huang, C. H., Wang, C. F., Don, T. M., & Chiu, W. Y. (2013). Preparation of pH- and thermo-sensitive chitosan-PNIPAAm core-shell nanoparticles and evaluation as drug carriers. Cellulose (London, England), 20(4), 1791-1805. http://dx.doi.org/10.1007/s10570-013-9951-1.
http://dx.doi.org/10.1007/s10570-013-995...
-114114 Li, G., Guo, L., Wen, Q., & Zhang, T. (2013). Thermo- and pH-sensitive ionic-crosslinked hollow spheres from chitosan-based graft copolymer for 5-fluorouracil release. International Journal of Biological Macromolecules, 55, 69-74. http://dx.doi.org/10.1016/j.ijbiomac.2012.12.048. PMid:23313823.
http://dx.doi.org/10.1016/j.ijbiomac.201...
].

To achieve those dual-responsive copolymers, researchers have applied some strategies. One of them involves a coupling reaction between PNIPAM bearing a reactive end group and chitosan, by using a condensing agent[115115 Prabaharan, M., & Mano, J. F. (2006). Stimuli-responsive hydrogels based on polysaccharides incorporated with thermo-responsive polymers as novel biomaterials. Macromolecular Bioscience, 6(12), 991-1008. http://dx.doi.org/10.1002/mabi.200600164. PMid:17128423.
http://dx.doi.org/10.1002/mabi.200600164...
]. These condensing agents can catalyze the formation of amide bonds between carboxylic acid group of a carboxyl-terminated PNIPAM and amine groups of chitosan. In these cases, an end-functionalized PNIPAM has to be prepared before the graft copolymerization[116116 Mao, Z., Ma, L., Yan, J., Yan, M., Gao, C., & Shen, J. (2007). The gene transfection efficiency of thermoresponsive N,N,N-trimethyl chitosan chloride-g-poly(N-isopropylacrylamide) copolymer. Biomaterials, 28(30), 4488-4500. http://dx.doi.org/10.1016/j.biomaterials.2007.06.033. PMid:17640726.
http://dx.doi.org/10.1016/j.biomaterials...
,117117 Lee, E. J., & Kim, Y. H. (2010). Synthesis and thermo-responsive properties of chitosan-g-poly (-isopropylacrylamide) and HTCC-g-poly(-isopropylacrylamide) copolymers. NNFibers and Polymers, 11(2), 164-169. http://dx.doi.org/10.1007/s12221-010-0164-z.
http://dx.doi.org/10.1007/s12221-010-016...
]. For instance, Rejinold et al. (2011) prepared PNIPAAM-COOH by using azobisisobutyronitrile (AIBN) and 3-mercaptopropionic acid, in isopropyl alcohol, at 75 °C; then, they grafted PNIPAAM-COOH chains onto chitosan backbone by using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride/N-hydroxysuccinimide (EDC/NHS) as the condensing agents, in acid medium, at room temperature. The resulting nanoparticles were loaded with curcumin. The in vitro drug release was effective only above LCST, which was attributed to higher polymer-polymer interaction than polymer-drug interaction when phase transition was reached. The drug loaded nanoparticles also showed cell uptake, cytocompatibility and specific toxicity on cancer cells, indicating that theses sensitive materials could be effective nanovehicles for controlled curcumin delivery[118118 Rejinold, N. S., Sreerekha, P. R., Chennazhi, K. P., Nair, S. V., & Jayakumar, R. (2011). Biocompatible, biodegradable and thermo-sensitive chitosan-g-poly (N-isopropylacrylamide) nanocarrier for curcumin drug delivery. International Journal of Biological Macromolecules, 49(2), 161-172. http://dx.doi.org/10.1016/j.ijbiomac.2011.04.008. PMid:21536066.
http://dx.doi.org/10.1016/j.ijbiomac.201...
].

Some others research groups have been preparing poly (N-isopropylacrylamide)-co-poly (acrylic acid) (PNIPAM-co-PAA) copolymers to be further anchored onto chitosan backbone by coupling reactions[119119 Saitoh, T., Sugiura, Y., Asano, K., & Hiraide, M. (2009). Chitosan-conjugated thermo-responsive polymer for the rapid removal of phenol in water. Reactive & Functional Polymers, 69(10), 792-796. http://dx.doi.org/10.1016/j.reactfunctpolym.2009.06.011.
http://dx.doi.org/10.1016/j.reactfunctpo...
,120120 Saitoh, T., Asano, K., & Hiraide, M. (2011). Removal of phenols in water using chitosan-conjugated thermo-responsive polymers. Journal of Hazardous Materials, 185(2-3), 1369-1373. http://dx.doi.org/10.1016/j.jhazmat.2010.10.057. PMid:21074940.
http://dx.doi.org/10.1016/j.jhazmat.2010...
]. Proceeding in this method, PNIPAM-co-PAA copolymers were prepared by the redox pair ammonium persulfate/ N,N,N’,N’-tetramethylethylenediamine (APS/TEMED). Then, the PNIPAM-co-PAA side chains were bonded to chitosan by a coupling reaction, with the aid of EDC. The final copolymer was evaluated by means of its ability in removing phenol of aqueous solution. Phenol was oxidized by enzymatic reaction, aiming to produce compounds that could react with the amino groups of the chitosan derivative, forming Schiff bases or Michael-type adducts. Through heating and shaking the solution, the copolymer containing highly concentrated oxidized compounds deposited and agglutinated to a condensed coagulate. By increasing polymer concentration and chitosan content in the copolymer, the removal of phenol and its oxidized compounds was increased[119119 Saitoh, T., Sugiura, Y., Asano, K., & Hiraide, M. (2009). Chitosan-conjugated thermo-responsive polymer for the rapid removal of phenol in water. Reactive & Functional Polymers, 69(10), 792-796. http://dx.doi.org/10.1016/j.reactfunctpolym.2009.06.011.
http://dx.doi.org/10.1016/j.reactfunctpo...
].

Core-shell nanoparticles, based on PNIPAM-co-PAA as core and chitosan as shell were designed, by means of previously copolymerization of N-isopropylacrylamide (NIPAM) with acrylic acid (AA), using sulfate persulfate as initiator and N,N-methylenebisacrylamide (MBA) as crosslink agent, at 75 °C in water medium, followed by coupling reaction between PNIPAM-co-PAA with chitosan, using EDC as the condensing agent, at 25 °C in aqueous media. The particles size was reduced from 380 to 25 nm as the temperature of the medium increased. While PNIPAM-co-PAA did not present thermosensitivity, core-shell smart nanoparticles showed temperature responsiveness and might also be more biocompatible than PNIPAM-co-PAA itself due to polysaccharide shell[121121 Jung, H., Jang, M.-K., Nah, J., & Kim, Y.-B. (2009). Synthesis and characterization of thermosensitive nanoparticles based on PNIPAAm core and chitosan shell structure. Macromolecular Research, 17(4), 265-270. http://dx.doi.org/10.1007/BF03218690.
http://dx.doi.org/10.1007/BF03218690...
].

Chitosan-g-PNIPAM smart copolymers have also been prepared through radiation-based methods[8080 Han, J., Wang, K., Yang, D., & Nie, J. (2009). Photopolymerization of methacrylated chitosan/PNIPAAm hybrid dual-sensitive hydrogels as carrier for drug delivery. International Journal of Biological Macromolecules, 44(3), 229-235. http://dx.doi.org/10.1016/j.ijbiomac.2008.12.009. PMid:19146871.
http://dx.doi.org/10.1016/j.ijbiomac.200...
,122122 Don, T. M., & Chen, H. R. (2005). Synthesis and characterization of AB-crosslinked graft copolymers based on maleilated chitosan and . N-isopropylacrylamideCarbohydrate Polymers, 61(3), 334-347. http://dx.doi.org/10.1016/j.carbpol.2005.05.025.
http://dx.doi.org/10.1016/j.carbpol.2005...

123 Cai, H., Zhang, Z. P., Sun, P. C., He, B. L., & Zhu, X. X. (2005). Synthesis and characterization of thermo- and pH- sensitive hydrogels based on Chitosan-grafted N-isopropylacrylamide via γ-radiation. Radiation Physics and Chemistry, 74(1), 26-30. http://dx.doi.org/10.1016/j.radphyschem.2004.10.007.
http://dx.doi.org/10.1016/j.radphyschem....
-124124 Fan, J., Chen, J., Yang, L., Lin, H., & Cao, F. (2009). Preparation of dual-sensitive graft copolymer hydrogel based on -maleoyl-chitosan and poly(. NN-isopropylacrylamide) by electron beam radiationBulletin of Materials Science, 32(5), 521-526. http://dx.doi.org/10.1007/s12034-009-0077-x.
http://dx.doi.org/10.1007/s12034-009-007...
]. Zhao and collaborators prepared pH and temperature sensitive smart hydrogels by exposing the mixture of allylated chitosan, NIPAM and the photoinitiator, 2,2-dimethoxy-2-phenylacetophenone (DMPA), in acid medium, to UV irradiation[125125 Zhao, S. P., Zhou, F., & Li, L. Y. (2012). pH- and temperature-responsive behaviors of hydrogels resulting from the photopolymerization of allylated chitosan and -isopropylacrylamide, and their drug release profiles. NJournal of Polymer Research, 19(9), 9944. http://dx.doi.org/10.1007/s10965-012-9944-z.
http://dx.doi.org/10.1007/s10965-012-994...
]. Swelling kinetics was dependent on pH, temperature and composition of the hydrogels. The in vitro release of the model drug methyl orange (MO) from the hydrogels was strongly pH dependent, being gradually released at pH 7.4 and rather low released in pH 2.0. This occurred due to the lack of ionic attractive interactions between MO and hydrogels at pH 7.4 and strong ionic attractive interactions between –SO3− groups of MO molecules and –NH3 + groups of chitosan at acid medium[125125 Zhao, S. P., Zhou, F., & Li, L. Y. (2012). pH- and temperature-responsive behaviors of hydrogels resulting from the photopolymerization of allylated chitosan and -isopropylacrylamide, and their drug release profiles. NJournal of Polymer Research, 19(9), 9944. http://dx.doi.org/10.1007/s10965-012-9944-z.
http://dx.doi.org/10.1007/s10965-012-994...
].

Grafting vinyl monomers onto the polysaccharide backbone using free radical polymerization (FRP) is a very common route to obtain chitosan-g-poly (N-isopropylacrylamide) responsive copolymers. Ceric ammonium nitrate (CAN), 2,2’-azoisobutyronitrile (AIBN) and persulfates (XPS) are some of the most employed initiators, which can be thermally activated, or using a redox initiation system[5858 Carreira, A. S., Goncalves, F. A. M. M., Mendonca, P. V., Gil, M. H., & Coelho, J. F. J. (2010). Temperature and pH responsive polymers based on chitosan: applications and new graft copolymerization strategies based on living radical polymerization. Carbohydrate Polymers, 80(3), 618-630.,115115 Prabaharan, M., & Mano, J. F. (2006). Stimuli-responsive hydrogels based on polysaccharides incorporated with thermo-responsive polymers as novel biomaterials. Macromolecular Bioscience, 6(12), 991-1008. http://dx.doi.org/10.1002/mabi.200600164. PMid:17128423.
http://dx.doi.org/10.1002/mabi.200600164...
].

There are many proposals regarding the anchored points for grafted chains when free radicals are used as initiators. When using CAN, for instance, some authors have exhibited a mechanism in which the chitosan units are predominantly oxidized through C2–C3 bond cleavage induced by Ce+4 ions, producing free-radicals sites onto the polysaccharide[126126 Chung, H. J., Bae, J. W., Park, H. D., Lee, J. W., & Park, K. D. (2005). Thermosensitive chitosans as novel injectable biomaterials. Macromolecular Symposia, 224(1), 275-286. http://dx.doi.org/10.1002/masy.200550624.
http://dx.doi.org/10.1002/masy.200550624...
,127127 Pourjavadi, A., Mahdavinia, G. R., Zohuriaan-Mehr, M. J., & Omidian, H. (2003). Modified chitosan. I. Optimized cerium ammonium nitrate-induced synthesis of chitosan-graft-polyacrylonitrile. Journal of Applied Polymer Science, 88(8), 2048-2054. http://dx.doi.org/10.1002/app.11820.
http://dx.doi.org/10.1002/app.11820...
]. Others researchers suggest that the graft copolymerization of chitosan in the presence of CAN occurs onto amino groups of chitosan[7878 Recillas, M., Silva, L. L., Peniche, C., Goycoolea, F. M., Rinaudo, M., & Argüelles-Monal, W. M. (2009). Thermoresponsive behavior of chitosan-g-N-isopropylacrylamide copolymer solutions. Biomacromolecules, 10(6), 1633-1641. http://dx.doi.org/10.1021/bm9002317. PMid:19364095.
http://dx.doi.org/10.1021/bm9002317...
,128128 Caner, H., Yilmaz, E., & Yilmaz, O. (2007). Synthesis, characterization and antibacterial activity of poly(-vinylimidazole) grafted chitosan. NCarbohydrate Polymers, 69(2), 318-325. http://dx.doi.org/10.1016/j.carbpol.2006.10.008.
http://dx.doi.org/10.1016/j.carbpol.2006...
,129129 Joshi, J. M., & Sinha, V. K. (2006). Graft copolymerization of 2-hydroxyethylmethacrylate onto carboxymethyl chitosan using CAN as an initiator. Polymer, 47(6), 2198-2204. http://dx.doi.org/10.1016/j.polymer.2005.11.050.
http://dx.doi.org/10.1016/j.polymer.2005...
]. Initiation by persulfate has been also presented as occurring at different sites of chitosan backbone[130130 Najjar, A. M. K., Yunus, W. M. Z. W., Ahmad, M. B., & Rahman, M. Z. A. (2000). Preparation and characterization of poly(2-acrylamido-2-methylpropane-sulfonic acid) grafted chitosan using potassium persulfate as redox initiator. Journal of Applied Polymer Science, 77(10), 2314-2318. http://dx.doi.org/10.1002/1097-4628(20000906)77:10<2314::AID-APP25>3.0.CO;2-7.
http://dx.doi.org/10.1002/1097-4628(2000...

131 Prashanth, K. V. H., & Tharanathan, R. N. (2003). Studies on graft copolymerization of chitosan with synthetic monomers. Carbohydrate Polymers, 54(3), 343-351. http://dx.doi.org/10.1016/S0144-8617(03)00191-7.
http://dx.doi.org/10.1016/S0144-8617(03)...

132 Mun, G. A., Nurkeeva, Z. S., Dergunov, S. A., Nam, I. K., Maimakov, T. P., Shaikhutdinov, E. M., Lee, S. C., & Park, K. (2008). Studies on graft copolymerization of 2-hydroxyethyl acrylate onto chitosan. Reactive & Functional Polymers, 68(1), 389-395. http://dx.doi.org/10.1016/j.reactfunctpolym.2007.07.012.
http://dx.doi.org/10.1016/j.reactfunctpo...
-133133 Ganji, F., & Abdekhodaie, M. J. (2008). Synthesis and characterization of a new thermosensitive chitosan–PEG diblock copolymer. Carbohydrate Polymers, 74(3), 435-441. http://dx.doi.org/10.1016/j.carbpol.2008.03.017.
http://dx.doi.org/10.1016/j.carbpol.2008...
].

Duan and collaborators prepared chitosan-g-PNIPAM nanogels via free radical copolymerization at 80 °C, using APS as initiator and MBA as a crosslink agent. They suggested a synthetic route in which sulfate anion radicals, produced by thermal homolytic cleavage of APS, interacted with the hydroxyl groups of the polysaccharide to form alkoxy radicals, which then initiated the graft copolymerization of N-isopropylacrylamide (NIPAM) onto the backbone with MBA as a crosslinking agent. The final nanogels were loaded with oridonin (ORI), a powerful anticancer agent in chinese traditional medicine. The in vitro tests, performed at 37 °C, demonstrated a much faster drug release at acid condition than in pH 7.4. ORI loaded nanogels also presented better anti-tumor activity under acid media, as showed by both MTT assay and cellular morphological analysis, indicating that these nanogels are good candidates for pH-sensitive drug release of hydrophobic anticancer drugs, such as ORI[134134 Duan, C., Zhang, D., Wang, F., Zheng, D., Jia, L., Feng, F., Liu, Y., Wang, Y., Tian, K., Wang, F., & Zhang, Q. (2011). Chitosan-g-poly(N-isopropylacrylamide) based nanogels for tumor extracellular targeting. International Journal of Pharmaceutics, 409(1-2), 252-259. http://dx.doi.org/10.1016/j.ijpharm.2011.02.050. PMid:21356283.
http://dx.doi.org/10.1016/j.ijpharm.2011...
].

More recently, our group evaluated the stability and rheological behavior of suspensions of PNIPAM, chitosan-g-PNIPAM and chitosan-g-(PNIPAM-co-PAA) particles, which were prepared by using potassium persulfate (50 °C) as initiator and MBA as a crosslinking agent. Differences on particle-particle and particle-solvent attractive interactions were obtained by changing the composition of the particles and also pH and temperature environment, demonstrating that the particles stability can be adjusted depending on the desired application. The presence of chitosan onto the chemical network had particular importance on the particles behavior, as even at high pHs, in which chitosan is not protonated, the rigidity of polysaccharide chains helped to control stability of the particles[135135 Nascimento, N. N., Curti, P. S., Maia, A. M. S., & Balaban, R. C. (2013). Temperature and pH effects on the stability and rheological behavior of the aqueous suspensions of smart polymers based on . N-isopropylacrylamide, chitosan, and acrylic acidJournal of Applied Polymer Science, 129(1), 334-345. http://dx.doi.org/10.1002/app.38750.
http://dx.doi.org/10.1002/app.38750...
].

Great attention has also been paid on controlled/living radical polymerization methods (CLRP), which include, mainly, atom transfer radical polymerization (ATRP), reversible addition fragmentation transfer (RAFT) and stable free radical polymerization (SFRP). The CLRP methods are based on a dynamic equilibrium between active species and dormant species, aiming to minimize the chance of termination reactions during the polymerization by decreasing the concentration of active species and, as a result, being able to produce polymers with precise architectures and compositions[5858 Carreira, A. S., Goncalves, F. A. M. M., Mendonca, P. V., Gil, M. H., & Coelho, J. F. J. (2010). Temperature and pH responsive polymers based on chitosan: applications and new graft copolymerization strategies based on living radical polymerization. Carbohydrate Polymers, 80(3), 618-630.,136136 Oh, J. K., Lee, D. I., & Park, J. M. (2009). Biopolymer-based microgels/nanogels for drug delivery applications. Progress in Polymer Science, 34(12), 1261-1282. http://dx.doi.org/10.1016/j.progpolymsci.2009.08.001.
http://dx.doi.org/10.1016/j.progpolymsci...

137 Cayre, O. J., Chagneux, N., & Biggs, S. (2011). Stimulus responsive core-shell nanoparticles: Synthesis and applications of polymer based aqueous systems. Soft Matter, 7(6), 2211-2234. http://dx.doi.org/10.1039/C0SM01072C.
http://dx.doi.org/10.1039/C0SM01072C...
-138138 Braunecker, W. A., & Matyjaszewski, K. (2007). Controlled/living radical polymerization: Features, developments, and perspectives. Progress in Polymer Science, 32(1), 93-146. http://dx.doi.org/10.1016/j.progpolymsci.2006.11.002.
http://dx.doi.org/10.1016/j.progpolymsci...
].

Chen and collaborators synthesized dual pH and temperature responsive chitosan-g-PNIPAM copolymers via ATRP. In order to protect the amino groups of chitosan, N-phthaloyl chitosan (PHCS) was firstly prepared, followed by the synthesis of the macroinitiator bromoisobutyryl-terminated N-phthaloyl chitosan (PHCS-Br), through the reaction of PHCS with 2-bromoisobutyryl bromide, in the presence of triethylamine, in dimethylfomamide (DMF) medium; then, PHCS-g-PNIPAM was prepared by combining PHCS-Br macroinitiatior with NIPAM, 2,2’-Bipyridyl and cuprous chloride (CuCl), in DMF at 70 °C and under nitrogen atmosphere; finally, deprotection was made by the reaction of PHCS-g-PNIPAM with hydrazine hydrate in water medium, under nitrogen atmosphere. The LCST of chitosan-g-PNIPAM in aqueous solution was 33 °C at pH 6.3 and 35 °C at pH 5.0, which indicated that the thermoresponsive behavior is also pH dependent in these materials, since the lowest pH implies on a more hydrophilic material[139139 Chen, C., Liu, M., Gao, C., Lü, S., Chen, J., Yu, X., Ding, E., Yu, C., Guo, J., & Cui, G. (2013). A convenient way to synthesize comb-shaped chitosan-graft-poly (-isopropylacrylamide) copolymer. NCarbohydrate Polymers, 92(1), 621-628. http://dx.doi.org/10.1016/j.carbpol.2012.09.014. PMid:23218344.
http://dx.doi.org/10.1016/j.carbpol.2012...
].

5 Conclusions

In this paper, the stimuli-sensitive polymer systems are described, by means of their behavior and applications. The pH-responsive, thermoresponsive and the dual pH and thermoresponsive copolymers were presented, giving focus on the combination of chitosan with poly (N-isopropylacrylamide) by graft copolymerization, obtained via different routes and their properties. Chitosan-g-PNIPAM copolymers are very promising materials especially on biomedical applications, such as in drug delivery systems and tissue engineering. The pH-sensitiveness and biological favorable properties from chitosan associated to the thermosensitive properties from PNIPAM lead to a powerful responsive material that can be synthesized to a target physical-chemical behavior, as well as with an enhanced therapeutic efficiency and reduced side effects.

6. Acknowledgements

The authors are grateful to CAPES, a Brazilian Government entity targeting the training of human resources, for their financial support.

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Publication Dates

  • Publication in this collection
    May-Jun 2015

History

  • Received
    10 Apr 2014
  • Reviewed
    19 Aug 2014
  • Accepted
    14 Nov 2014
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