北京化工大学：《材料导论》课程阅读材料（高分子材料）Smart_polymers_Physical_forms_and_bioengineering_applications.pdf

Prog. Polym. Sci. 32 (2007) 1205–1237 Smart polymers: Physical forms and bioengineering applications Ashok Kumara,b,, Akshay Srivastavaa , Igor Yu Galaevb , Bo Mattiassonb, a Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, 208016-Kanpur, India b Department of Biotechnology, Center for Chemistry and Chemical Engineering, Lund University, PO Box 124, SE-22100 Lund, Sweden Received 22 February 2007; received in revised form 22 May 2007; accepted 22 May 2007 Available online 2 June 2007 Abstract Smart polymers (SP) have become one important class of polymers and their applications have been increasing significantly. Last two to three decades have witnessed explosive growth in the subject. SP which are also known as stimuliresponsive soluble–insoluble polymers or environmentally sensitive polymers have been used in the area of biotechnology, medicine and engineering. The present review is aimed to highlight the applications of SP when these polymers are presented in three common physical forms (i) linear free chains in solution where polymer undergoes a reversible collapse after an external stimulus is applied, (ii) covalently cross-linked reversible gels where swelling or shrinking of the gels can be triggered by environmental change and (iii) chain adsorbed or surface-grafted form, where the polymer reversibly swells or collapses on surface, once an external parameter is changed. Though there are number of reviews coming up in this area in recent times, the present review mainly addresses the developments of SP in the last decade with specific application areas of bioseparations, protein folding, microfluidics and actuators, sensors, smart surfaces and membranes. r 2007 Elsevier Ltd. All rights reserved. Keywords: Smart polymer; Stimuli-responsive polymer; Bioseparation; Protein folding; Smart surfaces and membranes; Microfluidics and actuators Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1206 2. Polymers as linear free chains in solution. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1208 2.1. Bioseparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1208 2.1.1. Aqueous two-phase polymer system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1208 2.1.2. Affinity precipitation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1211 ARTICLE IN PRESS www.elsevier.com/locate/ppolysci 0079-6700/$ - see front matter r 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.progpolymsci.2007.05.003 Abbreviations: AA, acrylic acid; AML, affinity macroligand; ATPS, aqueous two-phase system; ATRP, atom transfer radical polymerizations; CP, critical point; ConA, concanavalin A; EDTA, ethylenediaminetetraacetic acid; EOPO, ethylene oxide propylene oxide; ELP, elastin like polymer; IPN, interpenetrating network; LCST, lower critical solution temperature; MAA, methacrylic acid; NiPAAm, N-isopropylacrylamide; PEG, poly(ethylene glycol); poly(AA), poly(acrylic acid); poly(DMAAM), poly(N, N0 -dimethylacrylamide); PMAA, poly(methacrylic acid); PNiPAAm, poly(N-isopropylacrylamide); PVCL, poly(vinylcaprolactam); poly(VDF), poly(vinylidene fluoride); SP, smart polymers; SPP, 3-[N-(3-methacrylamidopropyl)-N, N-dimethyl] ammonio-propane sulfonate Also to be corresponded to. Tel.: +91 512 2594010; fax: +91 512 2594051. Corresponding author. Tel.: +46 46 2228264; fax: +46 46 2224713. E-mail addresses: ashokkum@iitk.ac.in (A. Kumar), Bo.Mattiasson@biotek.lu.se (B. Mattiasson).

1206 A.Kumar et al.Prog.Polym.ScL.32(2007)1205-1237 2.2.Protein folding 1214 -linked,reversible and physical gels...... 32 art r SP in chain adsorbed or surface-grafted form (smart surfaces and membranes). 122 42 rt membranes with controlled r tion 1225 sity "che 1227 nowledgments 1229 References 1229 1.Introduction mechanical stress,will affect the level of various energy sources and alter molecular interactions at onse They underge presen hange state [141 re Irom a hydrophilic to imie these hic at the app itate fo variety of functional for ns to or orde the industrial and scientific pplications The the size and water content of stimuli-responsive synthetic polymers can be classified into different hydrogels [15].An appropriate proportion of categories based on their chemical properties.Out hydrophobicity and hydrophilicity in the molecular of these some special types of polymers have structure of the polymer is believed to be required as a very usefu clas ol polymers an for the phase transi n to occur en lowe er where pha ure threshold.Polv by su mers (SP)" .310 a thermally induced.reversible transition:they are soluble in a solvent (water)at tive"polymers [5].We shall use further on the name low temperatures but become insoluble as the smart polymer for such polymer systems in thi temperature rises above the LCST [161.The LCS review. he cha acteristi that actually the regioni the phase diagram at m ty to upy cont of water hye roge ht ch ang mer chain than th of th materials the d cture but also these transitions being of the en The responses are manifested as changes in one or principle.the LCST of a given polymer can be more of the following-shape,surface characteris. "tuned"as desired by variation in hydrophilic or tics,solubility,formation of an intricate molecula hydrophobic co-monomer content.Thermosensitive assembly,a sol-to-gel transition and others. polymers can be classified into dillerent groups depending on the mechanism and emistry of the either in i ature 6]or pH ar poly(N-alky su 0 nicals 181. 7.pe ce or cer charged polyme and ni mides)e of about according to molecular mass of electric [11]and magnetic field [12].light or polymer [18].There are other types of temperature radiation forces 1131 have also been reported as responsive polymers such as polv(ethylene oxide) stimuli for these polymers.The physical stimul poly(propylene oxide)o-poly (ethylene oxide) such as temperature,electric or magnetic fields,and co-polymer )which has the trade me

2.2. Protein folding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1214 3. Covalently cross-linked, reversible and physical gels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1216 3.1. Microfluidics and actuators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1217 3.2. Smart polymer hydrogels as sensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1219 4. SP in chain adsorbed or surface-grafted form (smart surfaces and membranes) . . . . . . . . . . . . . . . . . . . . . . 1221 4.1. Smart surfaces for tissue engineering. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1222 4.2. Smart surfaces for temperature controlled separations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1225 4.3. Smart membranes with controlled porosity: ‘‘chemical valve’’ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1227 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1229 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1229 1. Introduction Polymers such as proteins, polysaccharides and nucleic acids are present as basic components in living organic systems. Synthetic polymers, which are designed to mimic these biopolymers, have been developed into variety of functional forms to meet the industrial and scientific applications. The synthetic polymers can be classified into different categories based on their chemical properties. Out of these, some special types of polymers have emerged as a very useful class of polymers and have their own special chemical properties and applications in various areas. These polymers are coined with different names, based on their physical or chemical properties like, ‘‘stimuli-responsive polymers’’ [1] or ‘‘smart polymers (SP)’’ [2,3] or ‘‘intelligent polymers’’ [4] or ‘‘environmental-sensitive’’ polymers [5]. We shall use further on the name ‘‘smart polymers’’ for such polymer systems in this review. The characteristic feature that actually makes them ‘‘smart’’ is their ability to respond to very slight changes in the surrounding environment. The uniqueness of these materials lies not only in the fast macroscopic changes occurring in their structure but also these transitions being reversible. The responses are manifested as changes in one or more of the following—shape, surface characteristics, solubility, formation of an intricate molecular assembly, a sol-to-gel transition and others. The environmental trigger behind these transitions can be either change in temperature [6] or pH shift [7], increase in ionic strength [7], presence of certain metabolic chemicals [8], addition of an oppositely charged polymer [9] and polycation–polyanion complex formation [10]. More recently, changes in electric [11] and magnetic field [12], light or radiation forces [13] have also been reported as stimuli for these polymers. The physical stimuli, such as temperature, electric or magnetic fields, and mechanical stress, will affect the level of various energy sources and alter molecular interactions at critical onset points. They undergo fast, reversible changes in microstructure from a hydrophilic to a hydrophobic state [14]. These changes are apparent at the macroscopic level as precipitate formation from a solution or order-of-magnitude changes in the size and water content of stimuli-responsive hydrogels [15]. An appropriate proportion of hydrophobicity and hydrophilicity in the molecular structure of the polymer is believed to be required for the phase transition to occur. Temperature-sensitive polymers exhibit lower critical solution temperature (LCST) behavior where phase separation is induced by surpassing a certain temperature threshold. Polymers of this type undergo a thermally induced, reversible phase transition; they are soluble in a solvent (water) at low temperatures but become insoluble as the temperature rises above the LCST [16]. The LCST corresponds to the region in the phase diagram at which the enthalpy contribution of water hydrogenbonded to the polymer chain becomes less than the entropic gain of the system as a whole and thus is largely dependent on the hydrogen-bonding capabilities of the constituent monomer units. In principle, the LCST of a given polymer can be ‘‘tuned’’ as desired by variation in hydrophilic or hydrophobic co-monomer content. Thermosensitive polymers can be classified into different groups depending on the mechanism and chemistry of the groups. These are (a) poly(N-alkyl substituted acrylamides) e.g. poly(N-isopropylacrylamide) with LCST of 32 1C [17] and (b) poly (N-vinylalkylamides) e.g. poly(N-vinylcaprolactam) with a LCST of about 32–35 1C according to molecular mass of polymer [18]. There are other types of temperatureresponsive polymers such as poly(ethylene oxide)106- poly(propylene oxide)70-poly (ethylene oxide)106 co-polymer [19], which has the trade name Pluronics ARTICLE IN PRESS 1206 A. Kumar et al. / Prog. Polym. Sci. 32 (2007) 1205–1237

A.Kumar et al.Prog.Polym.Sci.32 (2007)1205-1237 1207 SP can be orized into the ive polymers versible collap after an rnal stim us which involves elastin like polymers (ELPs)[21]. The specific LCST of all these different polymeric sible or physical gels,which can be either micro- systems show potential applications in bioengineer- scopic or macroscopic networks and for which ing and biotechnology. swelling behavior is environmentally triggered and On the other hand in a typical pH-sensitive (chain adsorbed or surface-grafted form,where tion/depro the polyme rever s or on charge over the mole atteenerml interfac strongly on the nT nci tor is odified.SPs in a the three fo tion of pH-sensitive polymer tends to be very sharp can be and usually switches within 0.2-0.3 unit of pH.Co conjugated with biomolecules,thereby widening polymers of methylmethacrylate and methacrylic their potential scope of use in many interesting acid undergo sharp conformational transition and ways Biological molecules that may be conjugated collapse at low pH around 5,while co-polymers of with SPs include proteins and oligopeptides,sugars methylmethacrylate dim thy and polys ou lub ightly and DN dru field and magnetic field the els of which lecule hybrid sys 、is able of re onding to can shrink/swell in response to external electric or biological.physical and chemical stimuli.Hoffman magnetic field stimuli.Polythiophene or sulpho- and colleagues have pioneered the work in combin- nated-polystyrene-based conducting polymers have ing SPs with a wide variety of biomolecules [35-38] shown bending in response to external field The The SPs can be conjugated randomly or site magnetic field-responsive ge specifically prot An earlier the biomolecules. ame journal has their b tha ve polymeed for These responses of polymer systems show use. fulness in bio-related applications such as drug delivery [5.22],bioseparation [3].chromatography [4.23,24]and cell culture [25].Some systems have been eloped to combine two or more stimuli system S 26-281 polymers ma M could beppled in order to nsive poly- mer systems [291.Recently.biochemical stimuli have been considered as another strategy,which biochemical agents [32].There is a great Fig.1.Classification of the polymers by their physical form:(i out ainer form chains in solutio where und beyo the an inkedrever ole gels where s For de gh of the and bo chain d or surf grafted form.where the poly rec ent chapters [33.34]. evers collapses on surface.once an extern

F127 and poly lactic acid-co–poly ethylene glycol– poly lactic acid (PLLA)/PEG/PLLA triblock copolymers [20]. Another interesting class of temperature-responsive polymers have recently emerged which involves elastin like polymers (ELPs) [21]. The specific LCST of all these different polymeric systems show potential applications in bioengineering and biotechnology. On the other hand in a typical pH-sensitive polymer, protonation/deprotonation events occur and impart the charge over the molecule (generally on carboxyl or amino groups), therefore it depends strongly on the pH. The pH-induced phase transition of pH-sensitive polymer tends to be very sharp and usually switches within 0.2–0.3 unit of pH. Copolymers of methylmethacrylate and methacrylic acid undergo sharp conformational transition and collapse at low pH around 5, while co-polymers of methylmethacrylate with dimethylaminoethyl methacrylate are soluble at low pH but collapse and aggregate under slightly alkaline conditions. Other types of responsive polymers involve electric field [11] and magnetic field [12], the gels of which can shrink/swell in response to external electric or magnetic field stimuli. Polythiophene or sulphonated-polystyrene-based conducting polymers have shown bending in response to external field. The magnetic field-responsive gel which can be obtained by dispersing magnetic colloidal particle in poly (N-isopropylacrylamide-co-poly vinylalcohol) hydrogel matrix and get aggregated in external nonuniform magnetic field [12]. These responses of polymer systems show usefulness in bio-related applications such as drug delivery [5,22], bioseparation [3], chromatography [4,23,24] and cell culture [25]. Some systems have been developed to combine two or more stimuliresponsive mechanisms into one polymer system. For instance, temperature-sensitive polymers may also respond to pH changes [26–28]. Two or more signals could be simultaneously applied in order to induce response in so called dual-responsive polymer systems [29]. Recently, biochemical stimuli have been considered as another strategy, which involves the responses to antigen [30], enzyme [31] and biochemical agents [32]. There is a great deal of literature available about different forms of SP, but it is beyond the scope and aim of the present review to describe it in detail here. For more details, readers are advised to go through some of the recent reviews and book chapters [33,34]. SP can be categorized into three classes according to their physical forms (Fig. 1). They are (i) linear free chains in solution, where polymer undergoes a reversible collapse after an external stimulus is applied, (ii) covalently cross-linked gels and reversible or physical gels, which can be either microscopic or macroscopic networks and for which swelling behavior is environmentally triggered and (iii) chain adsorbed or surface-grafted form, where the polymer reversibly swells or collapses on a surface, converting the interface from hydrophilic to hydrophobic and vice versa, once a specific external parameter is modified. SPs in all the three forms—in solution, as hydrogels and on surfaces can be conjugated with biomolecules, thereby widening their potential scope of use in many interesting ways. Biological molecules that may be conjugated with SPs include proteins and oligopeptides, sugars and polysaccharides, single- and double-stranded oligonucleotides and DNA plasmids, simple lipids and phospholipids, and other recognition ligands and synthetic drug molecules. The polymer–biomolecule hybrid system is capable of responding to biological, physical and chemical stimuli. Hoffman and colleagues have pioneered the work in combining SPs with a wide variety of biomolecules [35–38]. The SPs can be conjugated randomly or sitespecifically to protein biomolecules. An earlier review published in the same journal has described various forms of stimuli-responsive polymers and their bioconjugates that have been utilized for ARTICLE IN PRESS S T I M U L U S Fig. 1. Classification of the polymers by their physical form: (i) linear free chains in solution where polymer undergoes a reversible collapse after an external stimulus is applied; (ii) covalently cross-linked reversible gels where swelling or shrinking of the gels can be triggered by environmental change; and (iii) chain adsorbed or surface-grafted form, where the polymer reversibly swells or collapses on surface, once an external parameter is changed. A. Kumar et al. / Prog. Polym. Sci. 32 (2007) 1205–1237 1207

1208 A.Kumar et al.Prog.Polym.ScL.32(2007)1205-1237 different applications [33].This review focuses on LCST.whereas the poly-SPP block exhibits an the various potential applications of sps within the opriate above three defined categories.The main aim of the review is to highlight the recent developments polymers which stay in solution in the ful within last decade of SPs for applications 100C.Both oseparation,protein ing.micronu these polymers in water at d engin pli chemical valves and tissue at hig atu 2.Polymers as linear free chains in solution th poly-SPP block. and at low poly-SPP block forms colloidal polar ags gates In aqueous solution,the delicate balance between that are kept in solution by the PNiPAAm block.In hydrophobic-hydrophilic conditions controls phase this way.colloidal aggregates which switch rever transition of the polymer.As hydrophobic condi tions increas solub S conver pH-respon as Eu vhich the dragit (co-po ylmetha rylate with wate h chitosa (de.y vlated chitin)as th these polymers become increasingly protonated and Aqueous solutions of thermoresponsive polymers hydrophobic,and eventually precipitate and this are characterized by an inverse dissolution beha. transition can be sharp.For example Eudragi S-100 precipitates from aqueous solution on acid 21.The ons are homogenous at fica ar und pH erea dap a10 precipit at vely hig LCST emperature of the in soluti p nd it is ted that sp honthe phertion atures at play a role in the new direction like rotein folding also called These application areas are discussed here. demixtion,will be denoted "Ta"or critical point (CP). Poly-N-isopropylacrylamide (PNiPAAm) 2.1.Bioseparation gained its popularity mainly ecause of the sharp LCST of about 32 the eds 4A3 proces 144-461 or addition of surfactants [44.47.48]to the mprove the purity of the roduct.Use of SPma polymer solution.When heated above 32C.the contribute to the simple and cost-effective processes polymer becomes hydrophobic and precipitates out to separate target molecules.The separation of from solution and below LCST it becomes com- target substance can be performed in different ways pletely soluble because of hydrophilic state and using these polymers,like aqueous two-phas forms a clear solution. Water-soluble block co- polymer system (ATPS),affinity precipitation or mer ofr prepare polym nic atograpny. he thermor sponsive be ma pyD-N N-dimethyll at there. (SPP)by sequential free radical polymerization via the reversible addition-fragmentation chain transfer 2.1.1.Aqueous two-phase polymer system (RAFT)process.Such block co-polymers with two ATPS is an aqueous,liquid-liquid,biphasic hydrophilic blocks exhibit double thermoresponsive system which is obtained by mixing of aqueous behavior in water:the PNiPAAm block shows a solution of two polymers,or a polymer and a salt at

different applications [33]. This review focuses on the various potential applications of SPs within the above three defined categories. The main aim of the review is to highlight the recent developments within the last decade of SPs for applications in areas like bioseparation, protein folding, microfluidics and actuators, chemical valves and tissue engineering applications. 2. Polymers as linear free chains in solution In aqueous solution, the delicate balance between hydrophobic–hydrophilic conditions controls phase transition of the polymer. As hydrophobic conditions increase the polymer precipitates forming an altogether different phase. This conversion from soluble to insoluble form can be achieved by either reducing the number of hydrogen bonds which the polymer forms with water or by neutralizing the electric charges present on the polymeric network. Aqueous solutions of thermoresponsive polymers are characterized by an inverse dissolution behavior, their isobaric phase diagrams presenting a LCST [39–42]. The solutions are homogenous at low temperature and a phase separation appears when the temperature exceeds a definite value. The LCST is the minimum of the phase diagram of the system, and in the practical cases to be treated in the following, the phase separation temperatures at which the phase transition occurs, also called demixtion, will be denoted ‘‘Td’’ or critical point (CP). Poly-N-isopropylacrylamide (PNiPAAm) gained its popularity mainly because of the sharpness of its phase transition, LCST of about 32 1C which is close to the physiological temperature, and the easiness to vary its phase separation temperature by co-polymerization [42,43], addition of salts [44–46], or addition of surfactants [44,47,48] to the polymer solution. When heated above 32 1C, the polymer becomes hydrophobic and precipitates out from solution and below LCST it becomes completely soluble because of hydrophilic state and forms a clear solution. Water-soluble block copolymers were prepared from the non-ionic monomer of N-isopropylacrylamide (NiPAAm) and the zwitterionic monomer 3-[N-(3-methacrylamidopropyl)-N,N-dimethyl] ammonio-propane sulfonate (SPP) by sequential free radical polymerization via the reversible addition–fragmentation chain transfer (RAFT) process. Such block co-polymers with two hydrophilic blocks exhibit double thermoresponsive behavior in water: the PNiPAAm block shows a LCST, whereas the poly-SPP block exhibits an upper critical solution temperature. Appropriate design of the block lengths leads to block copolymers which stay in solution in the full temperature range between 0 and 100 1C. Both blocks of these polymers dissolve in water at intermediate temperatures, whereas at high temperatures, the PNiPAAm block forms colloidal hydrophobic associates that are kept in solution by the poly-SPP block, and at low temperatures, the poly-SPP block forms colloidal polar aggregates that are kept in solution by the PNiPAAm block. In this way, colloidal aggregates which switch reversibly can be prepared in water [49]. Another type of soluble SPs which respond to microchanges in pH are the ‘‘pH-responsive polymers’’—such as Eudragit S-100 (co-polymer of methylmethacrylate and methacrylic acid) and the natural polymer, chitosan (deacetylated chitin). As the pH is lowered, these polymers become increasingly protonated and hydrophobic, and eventually precipitate and this transition can be sharp. For example Eudragit S-100 precipitates from aqueous solution on acidification to around pH 5.5 whereas chitosan precipitates at a relatively higher pH of about 7. Such class of SP in solution phase has various applications, such as bioseparation of proteins, cells and bioparticles and it is also investigated that SP play a role in the new direction like protein folding. These application areas are discussed here. 2.1. Bioseparation The production of macromolecules and separation of biomolecules in purified form, through the process of bioseparation needs special efforts to bring down the overall cost of production and improve the purity of the product. Use of SP may contribute to the simple and cost-effective processes to separate target molecules. The separation of target substance can be performed in different ways using these polymers, like aqueous two-phase polymer system (ATPS), affinity precipitation or thermoresponsive chromatography. The thermoresponsive chromatography comes under smart surfaces and membranes section and will be discussed there. 2.1.1. Aqueous two-phase polymer system ATPS is an aqueous, liquid–liquid, biphasic system which is obtained by mixing of aqueous solution of two polymers, or a polymer and a salt at ARTICLE IN PRESS 1208 A. Kumar et al. / Prog. Polym. Sci. 32 (2007) 1205–1237