Mechanical properties of PNIPAM based hydrogels: A

Materials Science and Engineering C 70 (2017) 842–855

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Materials Science and Engineering C journal homepage: www.elsevier.com/locate/msec

Review

Mechanical properties of PNIPAM based hydrogels: A review Muhammad Abdul Haq a,b, Yunlan Su a,⁎, Dujin Wang a a b

Beijing National Laboratory for Molecular Sciences, Key Laboratory of Engineering Plastics, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, PR China Laboratory of Food Engineering, Department of Food Science & Technology, University of Karachi, Karachi, Pakistan

a r t i c l e

i n f o

Article history: Received 8 June 2016 Received in revised form 13 September 2016 Accepted 29 September 2016 Available online 30 September 2016 Keywords: Poly(N-isopropylacrylamide) Hydrogel Smart material Mechanical properties

a b s t r a c t Materials which adjust their properties in response to environmental factors such as temperature, pH and ionic strength are rapidly evolving and known as smart materials. Hydrogels formed by smart polymers have various applications. Among the smart polymers, thermoresponsive polymer poly(N-isopropylacrylamide)(PNIPAM) is very important because of its well defined structure and property specially its temperature response is closed to human body and can be finetuned as well. Mechanical properties are critical for the performance of stimuli responsive hydrogels in diverse applications. However, native PNIPAM hydrogels are very fragile and hardly useful for any practical purpose. Intense researches have been done in recent decade to enhance the mechanical features of PNIPAM hydrogel. In this review, several strategies including interpenetrating polymer network (IPN), double network (DN), nanocomposite (NC) and slide ring (SR) hydrogels are discussed in the context of PNIPAM hydrogel. © 2016 Elsevier B.V. All rights reserved.

Contents 1. 2. 3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . Mechanical features of native PNIPAM hydrogel . . . . . . . . . . . Strategies to improve the mechanical strength of PNIPAM hydrogel . . . 3.1. Interpenetrating polymer network . . . . . . . . . . . . . . 3.2. Double network hydrogel . . . . . . . . . . . . . . . . . . 3.3. Slide ring hydrogel . . . . . . . . . . . . . . . . . . . . . 3.4. Nanocomposite PNIPAM hydrogel . . . . . . . . . . . . . . 3.5. Copolymerized PNIPAM based hydrogel . . . . . . . . . . . 4. Applications of PNIPAM hydrogels with improved mechanical strength . 4.1. Soft robotics . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Injectable hydrogel . . . . . . . . . . . . . . . . . . . . . 4.3. Shape memory hydrogel . . . . . . . . . . . . . . . . . . 5. Conclusion & future perspective . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Material science and technology has grown tremendously in last few decades. Smart materials which reversibly respond to the change in their environment are examples of these developments [1–4]. Although few low molecular weight compounds have been reported to possess smart properties [5–8], the majority of them are polymers. Polymers ⁎ Corresponding author. E-mail address: [email protected] (Y. Su).

http://dx.doi.org/10.1016/j.msec.2016.09.081 0928-4931/© 2016 Elsevier B.V. All rights reserved.

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are attractive candidates for smart materials because they may contain different domains or moieties. The affinity of these domains towards environment is altered under different conditions. This results in conformational change, e.g. from globule-to-coil or helix-to-random coil, which is associated with phase transition [9]. Many potential applications of smart materials are in aqueous medium. Polymers can form extended three dimensional structures which hold the solvent. Water insoluble crosslinked three dimensional network of polymer which hold water is known as hydrogel. Hydrogel microstructure resembles to natural tissue [10–12], therefore they can be

M.A. Haq et al. / Materials Science and Engineering C 70 (2017) 842–855

applied for various biomedical purposes e.g. drug delivery, tissue engineering and imaging [13–17]. Further applications of smart hydrogels include analytical separation and detection [4,18,19], antifouling coatings [20–22], flow controlling devices [23–25], soft mechanics [26–29] and water desalination using forward osmosis [30]. Smart hydrogels are capable of responding to the changes in temperature, pH, humidity, light, specific ions or molecules, electrical fields, solvent and ionic strength etc. Temperature and pH sensitive materials are most commonly studied because these parameters change naturally and can be easily controlled. Among them, thermoresponsive hydrogels prepared from thermosensitive polymers are widely studied. These polymers might be negatively or positively thermosensitive. The former possess a lower critical solution temperature (LCST) while the latter exhibit upper critical solution temperature (UCST). The LCST polymers contract upon increase in temperature beyond their critical temperature while UCST polymers show the similar behavior upon decrease in temperature [31,32]. More precisely, around critical temperature the polymer in solution exhibits a phase transition from a soluble state (i.e. random coil) to an insoluble state (i.e. collapsed or globule form). A well-known example of UCST polymer is gelatin which forms gel upon cooling. However, LCST polymers are more favorable for biomedical purposes because they can release the substance at human body temperature. Thermoresponsive phenomenon originates from the delicate balance between the hydrophobic and hydrophilic moieties in the monomer of the polymer. The interaction between polymer segments and water is altered by the small change in temperature due to shift in hydrophilic and hydrophobic forces [33]. Although copolymers such as poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) (PEO-b-PPO-b-PEO) block copolymer and poly(ethylene oxide)-bpoly(D,L-lactic acid-co-glycolic acid)-b-poly(ethylene oxide) (PEO-bPLGA-b-PEO) triblock copolymers have been reported as thermosensitive polymers, they are not extensively studied due to their difficulty in preparation, [34]. In thermoresponsive homopolymers, the monomer structure is generally hydrophilic which possesses some hydrophobic groups such as methyl, ethyl and propyl groups. Examples are N substituted poly(acrylamide) such as poly(Nisopropylacrylamide)(PNIPAM), poly(N,N-diethylacrylamide)(PDEAM), poly(N-ethylmethacrylamide)(PNEMAM) and others poly(methylvinylether)(PMVE), poly(2-ethoxyethylvinylether)(PEOVE), poly(Nvinylisobutyramide)(PNVIBAM) and poly(N-vinylcaprolactam) (PNVCa) [13]. Among the known thermosensitive polymers, PNIPAM is most promising because of its well defined structure and property specially its LCST is closed to human body and can be finetuned as well. There are numerous references referring to PNIPAM hydrogel. PNIPAM is characterized by amide (\\CONH\\) and propyl (\\CH(CH3)2) moieties in the monomer structure. When temperature is low, the hydrophilic amide group is solvated by the water molecules thus the polymer is soluble. This hydrogen bonding results in the highly structured hydration shell. When the temperature is elevated, the hydrogen bonding is weakened and subsequently, interactions among the hydrophobic groups (\\CH(CH3)2) become strong. This ultimately results in the release of water from the structure. Simultaneously the abrupt collapse of polymer chains happens, thus a volume phase transition (VPT) also occurs [12]. PNIPAM hydrogel exhibits VPT temperature at about 34 °C, which is somewhat higher than the LCST (≈32 °C) of the polymer in aqueous solution. In general, hydrogels exhibit low mechanical properties and PNIPAM hydrogel is not the exception. The situation is even more complex because thermoresponsive properties of the PNIPAM hydrogel are not good as well. The response of native PNIPAM hydrogels is very slow with respect to external temperature alterations. This is mainly because of the creation of an impenetrable surface structure, which slows down the outward flow of water throughout the hydrogel crumpling phenomenon. The response rate can be increased by the incorporation of pore forming additives e.g. sucrose-modified starches [35], silica particles [36] and poly(ethylene glycol) (PEG) [37] during the gel formation. Other strategies include the use of special

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solvents, high molecular weight crosslinker and control of polymerization temperature [31]. These methods generally do not improve the mechanical strength of the hydrogel [38]. Many applications of PNIPAM hydrogels are in aqueous medium in which they swell to a very high degree. This results in low density of the polymer chains which makes the gels extremely poor in physical strength. This is a great hurdle in their applications. For example in soft robotics applications, the robotic arm must be able to securely grip the objects [39]. In other applications such as filtration where permeate flux is directly proportional to applied pressure, the thermoresponsive antifouling coatings must be robust [40]. Similarly, in water purification by forward osmosis, thermoresponsive draw solutes must be capable of withstanding the high pressure (several MPa) of squeezing [41–43]. The mechanical profiles required in biological applications are even more diverse and difficult to achieve. For example, the mechanical properties of the scaffold for cell growth should match that of the host tissue [44]. Different tissues have very dissimilar mechanical strength, e.g. Young's modulus of brain tissues is reported to be in the range of 1 kPa [45] whereas bones exhibit Young's modulus in the range of GPa [46]. Thermally activated artificial muscles are another potential application of PNIPAM based hydrogels which are not explored yet due to low mechanical strength [47]. Moreover, in drug delivery application, the hydrogel has to be removed surgically because PNIPAM is non-biodegradable and it is very difficult to completely remove the fragile hydrogel by present surgical procedures. Therefore a number of techniques have been reported to enhance the mechanical properties of the PNIPAM hydrogel. 2. Mechanical features of native PNIPAM hydrogel PNIPAM hydrogels prepared by free radical redox polymerization technique are too weak and fragile to be accurately characterized using standard mechanical testing devices [48]. A number of parameters affect the mechanical properties e.g. initial monomer concentration, crosslinker ratio, polymerization and measurement temperature, degree of swelling at the time of measurement and the technique of measurement. This makes the precise comparison of any mechanical parameter very difficult. Nevertheless, different mechanical properties of PNIPAM hydrogel from various studies are presented in Table 1. The Young's modulus (E0) of PNIPAM hydrogel was first reported in 1997 by Takigawa et al. [48]. In a typical tensile test, they observed a linear stress-strain curve of the swollen as well as collapsed gel with the E0 about hundred times higher in collapsed state. The fracture strain was reported to be 35% in swollen state and 75% in collapsed state. The linearity of stress-strain curve beyond 35% strain was not observed in a later comprehensive study of mechanical and rheological properties of PNIPAM hydrogel by Puleo et al. [49] in 2013. They proposed the neoHookean model to explain the non-linear stress-strain curve (Fig. 1). The fracture strain was reported to be 79% in case of compression while it was only 30% in tensile (Fig. 2). They articulate that the difference in compressive and tensile testing is due to dissimilar water behavior in hydrogel matrix during two types of tests. In compression mode, water is redistributed in the matrix thus allows larger strain, which does not happen in tensile testing thus lower fracture strain is achieved. The Young's modulus calculated by complex modulus from rheological experiment was found to be 1.2 kPa under the assumptions of incompressibility, homogeneity and isotropy for the hydrogel, which is about one magnitude lower than those measured by tensile test. This shows that the technique of measurement greatly affects the magnitude of the mechanical parameter. The polymerization temperature also affects the mechanical strength. At low temperature the kinetics is slow and the material is formed via few polymer chains of high molecular weight, which results in high strength. In all the studies of Table 1, the polymerization temperature was room temperature (20–25 °C) except the report of Gundogan et al., who prepared the gel at 5 °C [50]. Unusually high compressive strength (81 kPa) is reported by Fei et al. in two

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Table 1 Mechanical properties of native PNIPAM hydrogel. Year

Monomer concentration (M)

Crosslinker ratioa

Measurement conditionb

Value (kPa)

1997 [48] 1997 [48] 2002 [50] 2002 [50] 2012 [52] 2013 [51] 2013 [49] 2013 [49] 2013 [56] 2013 [56]

0.87 0.87 0.71 0.71 1.07

1.66E-02 1.66E-02 1.18E-02 1.18E-02 2.97E-02

At equilibrium, TSc At collapsed state, TS, temp = 65 °C As prepared, CSd, strain = 15% At swollen state, TS, strain = 15% At swollen state, CS using DMAe, Strain = 10%

9.8 180 6.12 5.63 81

0.21 0.21 1.0 1.0

1.20E-02 1.20E-02 1.00E-02 1.00E-02

At swollen state, CS, strain = 15% At swollen state, TS, strain = 15% At swollen state, SFMg At collapsed state, SFM, temp = 40 °C

3.8f 7.3f 6.6 13.9

a b c d e f g

Crosslinker ratio (moles of crosslinker/mol of monomers). Temperature of measurement is room temperature unless otherwise stated. TS = tensile strength. CS = compressive strength. DMA = dynamic mechanical analysis. Neo-hookean. SFM = scanning force microscopy.

studies [51,52]. This might be due to the fact that they used highest concentration of crosslinker among all studies. 3. Strategies to improve the mechanical strength of PNIPAM hydrogel 3.1. Interpenetrating polymer network As mentioned above, the low polymer density in swollen state is one of the reasons of poor mechanical properties of the PNIPAM hydrogel. The simplest approach to overcome is to incorporate another polymer in the hydrogel matrix. This new polymer establishes its own thermodynamic equilibrium and thus total polymer density is increased. The combination of polymers produces a multicomponent polymeric system with enhanced properties. The formal definition of “interpenetrating polymer network (IPN)” states that at least one of the monomers must be polymerized in the presence of the second polymer (semi IPN) and the polymers must not be attached to each other by covalent bond [53,54]. Alternatively, both polymers can be synthesized from their monomers in one pot (Full IPN). Polymers in IPN cannot be separated without breaking the chemical bonds [54]. Incorporation of second polymer into PNIPAM hydrogel network generally results in the formation of channels from which water diffuses easily during swelling and deswelling. This channel effect is further enhanced in IPN because the second polymer is usually more hydrophilic than PNIPAM. About 35 studies have been reported so far for the IPN

of PNIPAM (Table 2). Most of them were focused on improvement in swelling and deswelling rates rather than mechanical properties. For example, Zhang et al. [55] prepared a thermoresponsive PNIPAM based IPN hydrogel with poly(vinylalcohol)(PVA). Although the LCST was not altered, the response rate was greatly enhanced in IPN. Incorporation of merely 10 wt% PVA resulted in loss of about 95% water within 1 min at 40 °C. Under similar conditions PNIPAM gel liberated only 50% water even in 2 h. The effect of matrix structure independent of polymer hydrophilicity was demonstrated by Zhang et al. [57] using an IPN prepared by crosslinked and linear PNIPAM i.e. both polymers were PNIPAM. IPN containing only 10 wt% linear chain with molecular weight of 33,000 released about 98% water in 18 min compared to pure PNIPAM hydrogel which did not lose even 50% water in 38 min. This emphasizes that PNIPAM chains are itself not responsible for slow response. It is the three dimensional structure of the hydrogel that hinders the water transport. Therefore, any attempt to improve the mechanical structure of the PNIPAM hydrogel with IPN strategy must consider the microporosity of the resulting hydrogel. Direct comparison of original gels and IPN gels is difficult due to different swelling ratio. The modulus of hydrogel (E0) varies with the equilibrium swelling ratio (ESR) and it should be calculated to the dry state (E0dr) for comparison. The swelling ratio, which is a function of polymer volume fraction, links the moduli in swollen (E0sw) and dry states. The relation is: E0dr = E0sw × (ESR−1/3), which is entirely based on geometrical considerations. However at low concentration, there is a profound competition between stretching strands and thus

Fig. 1. Tensile strength curve of PNIPAM hydrogel. Fitted curves are: linear hookean at 15% strain (green); neo-hookean (red); Mooney–Rivlin (magenta). Inset is strain between 0% and 15%. Reproduced with permission from [49].


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Fig. 2. Compressive strength curves of PNIPAM hydrogel. Fitted curves are: neo-hookean (red); linear hookean at 15% strain (green); Mooney–Rivlin (magenta). Inset is strains between 0% and 30%. Reproduced with permission from [49].

the value of exponent of ESR in equation is increased, the extent of which depends on polymer-solvent interaction. The mechanical strength of PNIPAM hydrogel with IPN reinforcement has been reported to be between 20 and 100 kPa (Table 3), which is a substantial increase over pure PNIPAM hydrogel. Djonlagic et al. [58] prepared a series of semi IPN with neutral, anionic and cationic poly(acrylamide) (PAAM). They characterized the hydrogel by dynamic mechanical analyses under compression as well tensile mode. The tensile strength of neutral and cationic PAAM containing hydrogels was twice that of pure PNIPAM gel. The stretchability of the IPN hydrogels was also about 20% higher than pure PNIPAM hydrogel. On the other hand the tensile strength of hydrogel containing anionic PAAM was found to be approximately one magnitude lower than of the pure PNIPAM hydrogel. It was due to the fact that these hydrogels had the higher swelling ratio than PNIPAM. This result confirms that low density of polymer chains is a contributing factor in poor mechanical strength of PNIPAM hydrogels. The same group [59] prepared the semi IPN with poly(N-vinylpyrrolidone) (PVP). They

Table 2 Polymers used for IPN with PNIPAM. Synthetic

Epoxy [66] Poly(acrylic acid) [79–81] Poly(acrylamide) [58,89–94] Poly(aniline) [103]

Natural/biodegradable Carbohydrate

Protein

Alginate [60,67–75] Cellulose [82–86] Chitosan [95–98]

Gelatin [76–78]

Cyclodextrin [104,105] Guar gum [110] Hyaluronic acid [112,113] Pullulan [115]

Poly(ethylene oxide) [109] Poly(N-acryloxysuccinimide) [111] Poly(N-isopropylacrylamide) [114] Poly(N-isopropylmethacrylamide) Salecan [117] [57,116] Poly(N-vinylcaprolactam) [114] Xanthan gum [77,118,119] Poly(N-vinylpyrrolidone) [59,120,121] Poly(methacrylic acid) [122,123] poly(styrene sulfonic acid) [124] Poly(vinyl alcohol) [55,125–129] Polyurethane [130–134]

Poly(aspartic acid) [87,88] Silk protein [61,62,99–102] Soy protein [106–108]

found a relation between E0dr and E0sw as: E0dr = E0sw × (ESR−1.19) in case of PAAM and E0d r = E0sw × (ESR−1.25) in case of PVP. Petrusic et al. [60] prepared the PNIPAM hydrogel with calcium alginate. They observed that the glass transition temperature is increased (20–30 °C) by the addition of calcium alginate into crosslinked PNIPAM. This shows that the polymers interact at molecular level in IPN which results in improved mechanical strength. Two studies using silk protein are reported by Gil et al. [61,62]. In their first attempt, although the silk protein enhanced the mechanical properties but the swelling kinetics was hindered. Incorporation of microporous structure by freezing during IPN formation drastically increased the rate of swelling and deswelling. In fact they have reported the shortest (40 s) swelling time among all the IPN studies (Table 3). 3.2. Double network hydrogel Double network hydrogels (DN) are particular type of IPN hydrogels. In this type of IPN the degree of crosslinking of two networks are asymmetrical. More specifically, the first network consists of dense structure (highly crosslinked), while the second network is sparsely crosslinked or uncrosslinked. Since the first report of DN hydrogel by Gong et al. [63] using ionizable polymer poly(2-acrylamido-2methylpropanesulfonicacid) (PAMPS) as 1st network and neutral polymer polyacrylamide (PAAM) as 2nd network, a number of double network hydrogels have been reported using non-thermoresponsive polymers. However, only three reports have been published so far with thermoresponsive PNIPAM [51,52,64]. These attempts are reported by Fei et al. [51,52], who tried only one response i.e. temperature and Li et al. [64] who added another response of pH by incorporation of polyacrylic acid (PAA) in PNIPAM DN hydrogel. In the first report of Fei et al. [51], PNIPAM was used for both networks. By changing the concentration of crosslinking agent (N,N′-Methylenebisacrylamide-, Bis), they achieved the asymmetric structure required in DN hydrogel. The hydrogel formed using this strategy resulted in improved mechanical strength by a factor of about 2 without altering the equilibrium swelling and kinetics. However, this improvement level was still not as high as usually achieved in DN hydrogels. This is due to the fact that in DN the 1st network must swell into the 2nd network in order to extraordinarily increase in strength [65]. To improve the swelling of the first network, the authors added an ionic comonomer i.e. AMPS with NIPAM during the polymerization of first network [52] (Fig. 3). In this way the compressive strength was increased by a factor of about 4, without changing the volume phase transition temperature of composite

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Table 3 Mechanical properties of IPN PNIPAM hydrogel. Polymer

PNIPAM (%)

ESR (swollen state)

ESR (collapsed state)

Swelling time (min)

Strength (kPa) (swollen state)

Strength (kPa) (collapsed state)

Calcium alginate [60] Cellulose [84] Poly(acrylamide) [89] Poly(acrylamide) [58] PNIPAM [52] P(NIPAM-co-AMPS) [52] Poly(N-vinylpyrrolidone) [59] Silk fibroin [62] Silk fibroin [61]

83 25 12.3 90 100 75 90 90 90

24.50 16 6.75 11 7.8 10 6.7 9.5 9.0

1.23 5 6.25 NR NR NR 1.95 0.555 1.75

30 NR NR NR 25 12 190 250 0.66

120b 55a 101a 42.3e 188a 341a 20.5d 100c 40a

250b NR 120a NR NR NR NR NR 80a

NR, not reported. a CS. b E0, DMA, Frequency Hz 100. c Storage modulus by dynamic shear rheology. d Dynamic shear rheology. e Elastic modulus by DMA.

hydrogel. Using scanning electron microscope they demonstrated that AMPS increases the pore size of the hydrogel which results in the enhanced thermosensitivity. However, due to the ionic nature of the AMPS, these hydrogels retained higher water during deswelling as well. Instead of copolymerizing with AMPS, Li et al. [64] used the PNIPAM as a highly crosslinked 1st network, ionic polymer polyacrylic acid (PAA) as a lightly crosslinked 2nd network and graphene oxide (GO) as nanoparticle (Fig. 4). In this way they attained a hydrogel with both temperature and pH sensitivity and high compressive strength up to 3.6 MPa. However volume phase transition temperature was decreased to 29 °C. 3.3. Slide ring hydrogel Rotaxane is a mechanically interlocked molecular architecture in which a cyclic molecule is trapped within another molecule by the host guest mechanism. If the guest is a polymer, the rotaxane is called polyrotaxane (PR). More specifically, the cyclic molecule for example α-

cyclodextrin (α-CD) is threaded in to a linear polymer chain e.g. polyethylene glycol (PEG), which is followed by capping the ends of polymer chain by bulky groups [135]. Interactions between these cyclic moieties result in the formation a figure eight configuration (known as pulley) and this is the basis of crosslinking in slide ring hydrogels (SR) (Fig. 5). The cyclic molecule is trapped by physical forces within the polymer chain and thus it slides along the chain, hence the name slide ring. The rings might be physically or chemically attached to each other. The crosslinking points (junction zone) slide along the polymer chain; therefore effectively distribute the applied stress. This results in extremely high stretchability-up to 24 times of their original length. Although their Young's modulus is low due to physical nature of the interaction between the cyclodextrin molecules involved in the crosslinking. This homogeneity is also reflected in extremely high volume change (up to 24,000 times) during swelling. Under repeated cyclic mechanical tests SR hydrogel could completely recover without any hysteresis loop, which is unique to them [135]. The formation of inclusion complex with cyclic molecule and polymer is limited by the geometry of the molecules and must be

Fig. 3. Systematic representation of P(NIPAM-co-AMPS)/PNIPAM double network (DN) hydrogels. Formation of single network (a), Formation of 2nd network (b), Compressive strength of hydrogels (c). DN hydrogels are represented as “DN-X%” where X% mentions the wt% of AMPS in the 1st network. Reproduced with permission from [52].


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Fig. 4. Systematic representation of pH and temperature responsive PNIPAM/AA/GO DN hydrogels (a), compressive strength of hydrogels with different amounts of AA (b) and different amounts of GO (c). Reproduced with permission from [64].

finetuned to make the host guest interaction possible which is not easy [137]. PNIPAM is too bulky to be threaded by the α- and β-CDs. In fact it has been utilized as end capping agent in the preparation of α- and βCDs based PRs. Large size CD i.e. γ-CD has been used to form the inclusion complex with PNIPAM [138–143]. But no attempt was done to prepare the hydrogel from this inclusion complex, probably due to low CD content in resulting PR [138–143]. However, in a series of investigations using the PEG-CD complex as crosslinker of PNINAM chains, Bin Imran et al. [144– 146] have reported the SR PNIPAM hydrogel. In this type of SR structure, the junction zones have limited flexibility as compared to total freedom in case of true SR hydrogel. In their first attempt [144], they modified the cyclodextrin by 2-acryloyloxyethyl isocyanate to make it compatible with PNIPAM (Fig. 6). However, the mechanical properties of the resulting

PNIPAM hydrogel using the modified PEG-CD crosslinker were marginally improved. They explain this insignificant improvement by the fact that cyclodextrin was in slender shape in the hydrogel. In their follow up study, addition of ionic monomer sodium acrylic acid during the polymerization of NIPAM drastically improved the properties [146]. Although the Young's modulus of this modified hydrogel was low (43.2 kPa), tensile strength (40.9 kPa) and elongation at break (912%) was high. Small Young's modulus with high stretchability is the eminent property of SR hydrogels. The presence of ionic groups allowed the polyrotaxane crosslinkers to fully expand in the polymer network. These hydrogels also exhibited high rate of swelling and deswelling (ca. 50% lose in water in 20 min). 3.4. Nanocomposite PNIPAM hydrogel

Fig. 5. Schematic representation of the SR hydrogel. Reproduced with permission from [136].

Incorporation of fillers into polymer has been long known to boost the properties of the resulting composite [147]. In recent decades, it has been realized that reducing the size of the filler particles to nanometer level greatly enhances the properties of the materials. Small size of the filler results in better dispersion and large interface for the interaction between polymer and the particle. These new materials are called nanocomposite (NC) materials. Haraguchi et al. in 2002 first reported the use of nanoparticles (clay) in hydrogel (nanocomposite hydrogel NC gel) and thus extended the concept of nanocomposite to the soft materials [148] (Table 4).These NC gels show some extraordinary properties e.g. transparency even at high clay content which shows the homogeneity of the structure. They exhibit high tensile strength comparable to industrial rubber despite low modulus and high stretchability (elongation at break N 1000%). This reveals that NC gels are soft and flexible yet tough material. In NC gels the ends of the polymer chains are adsorbed on the clay platelets by coordination and ionic interactions and thus clay particles act as multifunctional crosslinkers (Fig. 7). Glass transition temperature (Tg) of original PNIPAM gels is elevated by the increase in chemical crosslinking which shows that chains are restricted in original gels. However Tg of NC gel is not affected by the clay content. Interestingly, amide group

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Fig. 6. Preparation of water-soluble hydroxypropylated polyrotaxane crosslinker (HPR-C) from hydroxypropylated polyrotaxane (HPR), 2-acryloyloxyethyl isocyanate, dibutyltin dilaurate-DBTDL (catalyst) and butyl hydroxyl toluene-BHT (polymerization inhibitor) (a). Preparation of the P(NIPA-AAcNa-HPR-C) hydrogel, NIPA is main monomer, AAcNa is comonomer, HPR-C is crosslinker, APS is initiator and TEMED is accelerator (b). Reproduced with permission from [146].

containing monomers such as NIPAM dimethylacetamide (DMAA) and acrylamide (AAM) show superior enhancement in clay based NC gels. This is most probably due to sufficient interaction with the clay surface [149]. Nanoparticles also form fine water channels in the polymer matrix and thus enhance the swelling and deswelling rate. Water swellable clays which are easily exfoliated have been used e.g. hectorite, montmorillonite

and synthetic mica [149]. However, in clay based NC gels, hectorite has shown better mechanical performance [149]. The mechanical properties of hectorite based NC gels can be improved by increasing the clay content [148,151,152]. However when the concentration of clay is high, the dispersion is too viscous to handle efficiently. High viscosity of the clay dispersions is believed to be due to

Table 4 Mechanical properties of nanocomposite PNIPAM hydrogel. Nanoparticle

Concentration (%)a

ESR (swollen state)

ESR (collapsed state)

Swelling time (min)

Strength (kPa) (swollen state)

Elongation at break (%)

Graphene oxide [64] Graphene oxide [155] Laponite XLG [156] Laponite XLG [151]

2 5 20 19.8

22 32 25 NR

2 2 NR NR

9 10 800 80

125 NR 1632 1112

Laponite XLG [152] Laponite XLG [157]

11.8 23.2

NR NR

NR NR

NR NR

Laponite XLG [148]

6.6

18

2

10

Laponite XLG Graphene oxide [158] PNIPAM [38] Starch 300 nm [159] Starch 300 nm [159] Tetramethoxysilane [160] Au [161] Fe2O3 [162]

Clay = 10 GO = 1 12.65 100 25 50 4 70

25

2.5

125

TS = 250 CS = 216 TS = 42.3 TS = 69 E0 = 3.8 TS = 130 TS = 1600 E0 = 43,200 TS = 41 E0 = 1.5 CS = 3000

80 17.2 40.4 20 NR NR

2 NR NR 2.70 NR NR

2 5 5 10 NR NR

1400 NA NA NR NR NR

Fe2O3 [163] Laponite XLG

Fe2O3 = 10 Clay = 50

25

7

100

TS = 200 CS = 8440 CS = 2570 NR E0 = 6726 CS = 190 E0 = 218 CS = 50,000

a

Based on NIPAM.

1500 741 857 NR

NR


Fig. 7. Representation of the nanocomposite hydrogels. Dic is interparticle distance of exfoliated clay. g1, g2 and χ represent grafted chain, looped chain and crosslinked chain respectively. Reproduced with permission from [150].

the formation of “house of card” structure originating from the electrostatic attractions between surfaces and edges of clay discs (Fig. 8) [153]. Thus the highest content of native hectorite clay, that has been used is 6.8 wt% based on water [151]. The maximum solubility of NIPAM in water is about 20 wt% [154]. High molecular weight of the resulting polymer is desirable for improved mechanical property therefore NIPAM is usually used at its highest concentration. This means that hectorite clay can be used up to maximum 35 wt% based on NIPAM. This limitation was overcome by Liu et al. [153] through the use of modified hectorite clay (tetrasodium pyrophosphate modification). This modification gives the negative charge to the end of clay disc and thus surfaces and edges have the same charge therefore repel each other (Fig. 9). This results in low viscosity dispersion. Therefore it was possible to use the modified clay suspension of 15 wt% based on water. Under this condition, they achieved a PNIPAM hydrogel having the tensile strength of 1 MPa with very high elongation at break (1348%) and modulus (74.14 kPa). However, as expected swelling was restricted (swelling ratio 26) due to high clay content. These gels deswelled initially and then began to swell during the subsequent period. After a definite time, the gels deswelled again. This complex deswelling kinetics was due to competition between the swelling of PNIPAM and swelling of ionic pyrophosphate in the clay. Other than clay, silica, starch, graphene oxide, PNIPAM and metal based nanoparticles has been reported (Table 4). A novel and very

849

efficient approach to combine the multifunctional ability of nanoparticles with the strong covalent bonding of chemical crosslinking is reported by Xia et al. [38]. They prepared the PNIPAM nanoparticles by precipitation polymerization (at 60 °C) of NIPAM in the presence of crosslinker Bis. The high ratio of NIPAM to Bis (25:1) and low polymerization time (10–40 min) permitted the partial reaction of the unsaturated bonds in Bis. This resulted in nanoparticles with functionality to form chemical crosslinking in subsequent polymerization (Fig. 10). Thus hydrogels with high elongation (up to 1400%) and high tensile strength (up to 200 kPa in swollen and 1.5 MPa in collapsed state) were achieved. The other authors dealing with PNIPAM based NC gels have not reported the mechanical properties in collapsed state. These hydrogels also showed extremely high (ESR up to 80) and rapid swelling- within 10 min about 100% swelling was achieved. A unique layer by layer nanocomposite hydrogel inspired by nacre (mother of pearl) with exceptional mechanical properties was developed by Wang et al. [157]. Suspension of clay and NIPAM was vacuum filtered to build up the layers. NIPAM was subsequently polymerized using UV initiation, which resulted in layered hydrogel (L-NC gel) (Fig. 11). The transmission electron microscopy (TEM) image showed the distinct aligned structure with alternating soft polymer and hard clay layers. These gels exhibited a unique tensile behavior with a yielding phenomenon. Initially the gels deformed linearly which was followed by yielding behavior and then hardening. The tensile strength and elastic modulus was found to increase with clay content (up to 1.6 MPa and 43.2 MPa respectively).The elongation was decreased although it was still 740% at maximum clay content of 23.2 wt% at which the highest tensile strength and elastic modulus was achieved. The excellent mechanical properties were articulated to the unique layered structure consisting of alternative polymer and clay network. In their work the clay was orderly distributed which led to a narrow uniform distribution of the crosslinking. Hence in the uniform polymer-clay network the stress was spread over many polymer chains homogenously. Metal (i.e. Ag, Au, Fe) based nanoparticles (MNP) are also widely studied for composing them in hydrogel because they can provide additional functionality such as electrical conductance, magnetic response and anti-microbial properties [164]. Among metals superparamagnetic iron oxide is of particular interest. Their presence allow remote and localized heating for phase transition which is essential in some applications such as targeted drug delivery and advantageous in others such as water purification because it can avoid the bulk heating and thus save energy [165]. However, most of the studies are not focused on mechanical properties. This is due to the fact that PNIPAM is hydrophobic and cannot efficiently trap the MNPs due to the absence of hydrogen bonding. Therefore, unlike clay they cannot act as multifunctional crosslinkers and thus the enhancement in mechanical strength is not so high. Furthermore, the mesh size of PNIPAM hydrogel lies between 10 and 20 nm which is larger than most of the MNPs (5–10 nm) [166]. Poor mechanical properties of MNP composite PNIPAM hydrogel are addressed by functionalizing the PNIPAM [161] or MNP [162] or combining MNP with clay nanocomposite [163]. Marcelo et al. [161] functionalized the PNIPAM network with catechol groups using crosslinking polymerization of NIPAM with a catechol methacrylamide monomer. Catechol group reduced the HAuCl4 to Au nanoparticles. In this way combined effect of crosslinking and nanoparticle on

Fig. 8. Gel formation of pure hectorite in water. A single disc of clay (a); gel formation in the form of house of cards (b). Reproduced with permission from [153].

850


Fig. 9. Dispersion of tetrasodium pyrophosphate modified hectorite clay (Clay-S) in water. A single disc of Clay-S (a); stable dispersion of Clay-S in water (b). Reproduced with permission from [153].

mechanical strength was observed (storage modulus up to 6.7 MPa). Scott et al. [162] prepared an injectable PNIPAM superparamagnetic iron oxide nanoparticle (SPION) composite hydrogel by functionalizing the PNIPAM with hydrazide. The resulting PNIPAM- hydrazide efficiently peptized the SPION. Dextran-aldehyde was used as second polymer to form the hydrogel. In this structure, SPION- PNIPAM- hydrazide actually acted as multifunctional crosslinker for dextran-aldehyde. Increasing the dextran-aldehyde initially resulted in increase in compressive strength up to 190 kPa then decreased to 23 kPa with opposite trend in strain at break. Li et al. [163] combined the IPN (alginate), clay (laponite XLG) and MNP (iron oxide) with PNIPAM to get highly stretchable (strain at break N 95% in compression) and tough (compressive strength up to 50 MPa) magnetically responsive hydrogel. 3.5. Copolymerized PNIPAM based hydrogel Copolymerizing PNIPAM with other polymers provides a means to incorporate a wide range of functionality in addition to thermoresponse. These functionalities include but not limited to biocompatibility, antifouling, control release, pH and photo sensitivity

(Table 5). Random copolymerization is usually done to alter the LCST and swelling behavior. Grafting with other macromolecule and incorporation of PNIPAM in a layered structure, on the other hand, is performed for a variety of purposes. However, not all the grafting results in “gelable” polymer [167]. The properties of the grafted supermolecule depend on a number of factors such as nature of polymer, grafting ratio and architecture and thus it is not necessary that the mechanical strength is increased. In fact despite the huge number of researches on grafted PNIPAM, only few studies have reported any mechanical parameter. Grafting the PNIPAM to bio-polymer not only renders the supermolecule more compatible with biological systems but also provide a reversible cell adhesion and detachment mechanism. For example complete adhesion and detachment via thermal treatment is demonstrated for PNIPAM grafted gelatin by Morikawa and Matsuda [168]. Ohya et al. [169] studied the relationship between microscopic structure and mechanical property of surface regions (by AFM) of PNIPAM grafted gelatin and found that surface elastic modulus greatly affects the cell culture on this type of hydrogel. Furthermore, the modulus was found to be higher (up to 240 kPa) at higher grafting densities of PNIPAM.

Fig. 10. Schematics representation of nano structured hydrogel (NSG). NIPAM and Bis (a). Activated nanogels (ANG) prepared by precipitation polymerization of NIPAM and Bis, (b). Chemical structure of the ANG representing the double bonds of the un-reacted Bis (c). Optical image of NSG (d). NSG hydrogel with nano-structured architecture in the swollen state at temperature below the LCST (e) and in the collapsed state at temperature above the LCST (f). Reproduced with permission from [38].


851

Fig. 11. Method of preparation of layered nanocomposite (L-NC) hydrogel films (a). Layers consisting of monomer, clay, and initiator (b). Model of layered PNIPAM/clay hydrogels. The clay acts as multifunctional crosslinkers. PNIPAM adopts a coiled configuration(c). Optical photograph of the freestanding L-NC gel film (d). Cross-section morphology of a dried L-NC gel film, showing a layered arrangement (e). TEM image showing ordered piles with alternating soft polymer layers and hard clay(f). Reproduced with permission from [157].

Therefore, in this study grafting the PNIPAM actually enhanced the mechanical strength of gelatin hydrogel. Similar result was later observed in compression testing by same group [190]. Barnes et al. [210] grafted more cytocompatible N-vinylpyrrolidone and combined it with collagen to form a full IPN with tuneable mechanical properties. Furthermore, different concentrations of this polymer led to a range of hydrogels with shear moduli ranging from 105 Pa down to less than 102 Pa, similar to the soft tissues in the body.

4. Applications of PNIPAM hydrogels with improved mechanical strength Although the comprehensive narrative of the applications of PNIPAM hydrogel is beyond the scope of this review, three studies will be discussed here to highlight the importance of mechanical properties in applications.

4.1. Soft robotics The thermoresponsive deformation movements of PNIPAM hydrogels provide a means to control the bending/unbending of the hydrogel which can be used to grip the objects and thus act as soft robots. Compared to conventional hard robot (consist of stiff materials such as metals and ceramics and actuated by electrical, hydraulic or pneumatic means), soft robots have unique advantages. They can be easily used in aqueous environments and mimic the biological functions. A number of PNIPAM based actuating systems has been reported in the literature [211]. However most of them are unsuitable for practical situations due to their low hardness. For example Yoon et al. [39] prepared a layered PNIPAM-co-acrylic acid self-folding hydrogel using asymmetrical crosslinking in different layers. Although the hydrogel showed some gripping of the objects (beads) but they were very floppy and the beads often fall out of their clutch. Recognizing the importance of the mechanical strength, the same group later used a stiff polymer polypropylene fumarate (modulus = 16 MPa) as one layer of the bi-layered PNIPAM based hydrogel [203]. The combined structure showed sufficient strength to excise cells from a real tissue clump. This is a

huge step towards demonstration of concept type studies to the actual application. 4.2. Injectable hydrogel Injectable hydrogels provide ultimate flexibility in targeted drug delivery and tissue engineering systems. They must be biocompatible as well as have enough strength to stay in place for a reasonable time. The strength becomes critically important when they are used as scaffold in tissue engineering for bone repairing [212]. Most of the injectable hydrogels formed by natural polymers or their derivatives do not possess the mechanical strength due to physical nature of the crosslinking involved in the gelation [213]. Recently Bai et al. [212] prepared a selfreinforcing injectable hydrogel based on non-covalent (achieved by host quest interaction of β-CD-g-PNIPAM and adamantine), and Diels– Alder (DA) chemical dual crosslinking. The sol-gel transition of PNIPAM enabled the quick formation of gel after injection. DA chemical crosslinking via furfurylamine grafted chondroitin sulfate (ChS-F) and maleimido-terminated poly(ethylene glycol) subsequently increased the mechanical strength (modulus ~25 MPa) of the hydrogel. The hydrogel exhibited bone repairing without using cells or growth factors. 4.3. Shape memory hydrogel There is an emerging trend in the PNIPAM based shape changing or “shape memory” material. The ability to undergo large, reversible changes in volume, when stimulated by heat, renders the PNIPAM a promising material to create the structures which change their shapes in different environment. This is achieved by either non-uniform heating [201], asymmetrical distribution of crosslinking in to hydrogel [26,175,183,184] or combining the PNIPAM with other polymers in a variety of bilayer, trilayer and sandwiched configurations [194,198, 203]. The simplest approach to create the PNIPAM based shape changing hydrogel is to asymmetrically distribute the crosslinking, for example by controlling the intensity and the area of exposure of UV light in photo-initiated polymerization. Most of the hydrogels prepared by this strategy are very poor in mechanical properties because their polymeric networks are chemically crosslinked by small molecules [26,214].

852


Table 5 Copolymerized PNIPAM based hydrogel with various functionality. Biocompatibility

Antifouling

Control release

pH-sensitivity

Shape memory

Others

Alginate [170,171] Chitosan [178,179] Dextrin [186] Gelatin [167–169,190,191] Hyaluronan [196,197] Starch [200]

Chitosan [172] Methacrylate [180] PETa [40] PVDFb [192]

Alginate [173] AMPSc [181] Itaconic acid [187] NVPd [193]

Alginate [171] Chitosan [182] Itaconic acid [188]

Acrylic acid [174,175] Benzophenone [183,184] Clay [26] PAAM [194] PE [198] Polyamide [201] PPFf [203] PUe [205]

APMS [176,177] Allylamine [185] Acrylamide [189] Acrylic acid [195] Carrageenan [199] Chitosan [178,202] Polystyrene [204] Silicon [206] Chlorophyllin [207–209]

a b c d e f

Poly(ethylene terephthalate). Poly(vinylidene fluoride). 2-Acrylamido-2-methylpropanesulfonic acid. N-vinyl-2-pyrrolidinone. Polyureathan. Polypropylene fumarate.

Yao et al. [26] recently prepared the PNIPAM based hydrogel with excellent shape changing ability as well as mechanical strength (tensile strength = 400 kPa), using uneven distribution of multifunctional cross linker i.e. clays across the hydrogel thickness. The asymmetry was achieved by the layering of different concentration of clay during photo polymerization. However this technique can be used to prepare limited number of shapes. Layering the swellable PNIPAM hydrogel with a non-swellable stiff polymer e.g. low-density polyethylene [198] or polypropylene fumarate [203] allows more detailed patterning and thus further complex structure [203]. The stiff polymer layer also greatly enhances the mechanical strength of the composite.

5. Conclusion & future perspective Mechanical properties of PNIPAM based hydrogel have been substantially improved over the past few decades. However simultaneous improvement in mechanical properties and quick thermoresponse is still a challenge especially in complex applications such as injectable hydrogel. Additional design considerations in combination with mechanical strength, such as reproducibility in robotics applications, controlled degradation in biological applications and chemo-mechanical stability in sensor applications, are still needed to be addressed carefully. Although number of publications on PNIPAM based hydrogels are tremendously increasing, there is a need for theoretical background to understand the probable functionality ahead of experimental outcomes. For example the effect of nature of crosslinking junction zone i.e. chemical, physical or ionic of first network is unclear in the PNIPAM based interpenetrating hydrogels. The tough hydrogels must dissipate mechanical energy efficiently under large deformation while maintain their original configuration. So far most of the attempts to achieve this goal have relied on single mechanism e.g. either interpenetrating network, slide ring or multifunctional crosslinkers. Combination of these methods will direct the future research on PNIPAM based tough hydrogel. For example, enhancement in mechanical strength is expected by fabricating a rigid nanocomposite hydrogel within a loose network by interpenetration technique. Moreover, there is a great potential for non-clay based nanocomposite PNIPAM hydrogels using functionalized nanoparticles. For example nanoparticles can be tuned to interact differently in swollen and collapsed state. The role of molecular weight of PNIPAM in nanocomposite hydrogel is still not clear. Another area of neglected research is the rheological and mechanical characterization of micro and nanoPNIPAM hydrogel. The applications of thermoresponse functionality are very diverse and every application requires specific mechanical profile. Therefore upcoming efforts on tough PNIPAM based hydrogel must focus on specific application.

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