Nanoparticle-Hydrogel Composites: Concept, Design, and Applications of These Promising, Multi-Functional Materials. — TEI-tagged view

Praveen ThoniyotpersName, Mein Jin TanpersName, Anis Abdul KarimpersName, David James YoungpersName, Xian Jun LohpersName (2015date). “Nanoparticle-Hydrogel Composites: Concept, Design, and Applications of These Promising, Multi-Functional Materials..” Advanced Sciencetitle·j.

Object of study — nanoparticle-hydrogel composites: their synthesis, design, potential applications and challenges

Research question — which approaches can produce structurally diverse nanoparticle-hydrogel composites, and which suits a desired composite

Contribution — a classification of synthetic approaches and applications to guide the design of new nanoparticle-hydrogel combinations

Full text — tagged

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Nanoparticle-Hydrogel Composites: Concept, Design, and Applications of These Promising, Multi-Functional Materials.

Abstract New technologies rely on the development of new materials, and these may simply be the innovative combination of known components. The structural combination of a polymer hydrogelterm·key network with a nanoparticleterm·key (metals, non‐metals, metal oxides, and polymeric moieties) holds the promise of providing superior functionality to the composite material with applications in diverse fields, including catalysisterm·key, electronics, bio‐sensing, drug deliveryterm·key, nano‐medicine, and environmental remediation. This mixing may result in a synergistic property enhancement of each component: for example, the mechanical strength of the hydrogelterm·key and concomitantly decrease aggregation of the nanoparticlesterm·key. These mutual benefits and the associated potential applications have seen a surge of interest in the past decade from multi‐disciplinary research groups. Recent advances in nanoparticleterm·key–hydrogelterm·key composites are herein reviewed with a focus on their synthesis, design, potential applications, and the inherent challenges accompanying these exciting materials.

Introduction Wichterlie and Lim 1 reported the first synthetic hydrogelsterm·key with control of properties such as swelling and shrinking over several orders of magnitude. This initial discovery provided the foundation for stimuli‐responsiveterm·key systems. The cross‐linked polymer network was highly sensitivity to stimuli such as solvent composition, solutes, pH, temperature, electric field, and light. This behavior of synthetic hydrogelsterm·key has been reviewed elsewhere. 2 Parallel to these developments in hydrogelsterm·key and their eventual reach of the biomedical and consumer care market, several types of nanoparticleterm·key and their composites have also been being developed over decades various material research groups. Today, nanoparticlesterm·key find their applications in common consumer products and appliances due to their differences in properties compared to bulk materials. This trend has generated public debate on the safety of nanoparticleterm·key technology and regulatory authorities have intervened in several countries. 3 The challenges in the application of nanoparticlesterm·key could potentially be overcome by incorporation into hydrogelsterm·key resulting in decreased risks to human health and the environment. In addition, innovative combination of these two entirely different types of materials was thought to generate not only structural diversity but also a plurality of property enhancements. Such property enhancements were the main focus of research on hydrogelterm·key‐nanoparticleterm·key composite materials that resulted in improved mechanical strength and stimuli response. For example, recently reported silica nanoparticleterm·key‐hydrogelterm·key composite made of silica nanoparticlesterm·key and modified poly ethylene glycol demonstrated remarkable improvements in tissue adhesive property, mechanical stiffness and bioactivity compared to hydrogelterm·key without nanoparticlesterm·key. 4 Similarly significant changes in mechanical property and thermal response were observed in poly N ‐isopropyl amide hydrogelsterm·key when gold nanoparticlesterm·key immobilized in the gel. 5 Thus the benefits of the combination of two different materials viz., nanoparticleterm·key and hydrogelsterm·key lead to advanced materials with unique properties absent in the individual components. This uniqueness has catalyzed intense research activity at the interface of nanoparticleterm·key hydrogelterm·key composites looking forward to numerous applications over the past decade.

One of the earliest investigations of such materials was reported by the Willner group, 6 in which gold nanoparticlesterm·key (Au‐NPs) were immobilized in polyacrylamide (PAAm) by swelling the dehydrated gel in the presence of Au‐NP solution, resulting in uniform distribution of the Au‐NPs in the gel matrix. Consequently, various approaches for realizing these structurally unique dispersions have been reported by researchers investigating potential applications in biomedicine and optics, optics etc. Structurally similar nano‐dispersions of Au in PAAm hydrogelsterm·key were obtained by in situ reduction of gold (III) chloride in the hydrogelterm·key network. 7 Three different supramolecular hydrogelterm·key‐nanoparticleterm·key designs can be proposed. They are: a) micro or nano‐gels stabilizing single/multiple nanoparticlesterm·key, b) nanoparticlesterm·key non‐covalently immobilized in an hydrogelterm·key matrix, and c) nanoparticlesterm·key covalently immobilized in an hydrogelterm·key matrix ( Figure 1 ). There are reviewsterm·mth on type (a) structures covering their applications in biomedicine (particularly drug deliveryterm·key), catalysisterm·key and electronics. 8 Bulk hydrogelsterm·key of type (b) and (c) have been reviewed by Schexnailder and Schmidt, 9 but since then there have been few accounts covering only very specific applications. 10 Concept for combination of nanoparticlesterm·key and hydrogelterm·key to form new functional materials. Three different structural designs exist: a) micro‐ or nano‐sized hydrogelterm·key particles stabilizing inorganic or polymer nanoparticlesterm·key, b) nanoparticlesterm·key non‐covalently immobilized in a hydrogelterm·key matrix, and c) nanoparticlesterm·key covalently immobilized in hydrogelterm·key matrix.

The current reviewterm·mth categorizes various approaches to the design of structurally diverse nanoparticleterm·key‐hydrogelterm·key composites. It will hopefully provide a tool for selecting an appropriate method for achieving a desired nanoparticleterm·key‐hydrogelterm·key composite. The potential applications and challenges in developing these materials are presented in parallel.

Design, Synthesis, and Properties A diverse range of nanoparticleterm·key–hydrogelterm·key composites have been developed with varying types of nanoparticleterm·key embedded in a bulk hydrogelterm·key framework. Five main approaches have been used to obtain a uniform distribution: 1) hydrogelterm·key formation in a nanoparticleterm·key suspension, 2) physically embedding the nanoparticlesterm·key into hydrogelterm·key matrix after gelation, 3) reactive nanoparticleterm·key formation within a preformed gel, and 4) cross‐linkingterm·key using nanoparticlesterm·key to form hydrogelsterm·key, and 5) gel formation using nanoparticlesterm·key, polymers, and distinct gelator molecules. A schematic illustration of these five approaches is given in Figure 2 . The approach chosen will be, in part, determined by the final application of nanoparticleterm·key‐hydrogelterm·key composite.

Five main approaches used to obtain hydrogelterm·key‐nanoparticleterm·key conjugates with uniform distribution: 1) hydrogelterm·key formation in a nanoparticleterm·key suspension, 2) physically embedding the nanoparticlesterm·key into hydrogelterm·key matrix after gelation, 3) reactive nanoparticleterm·key formation within a preformed gel, 4) cross‐linkingterm·key using nanoparticlesterm·key to form hydrogelsterm·key, 5) gel formation using nanoparticlesterm·key, polymers, and distinct gelator molecules.

Hydrogelterm·key Formation in a Nanoparticleterm·key Suspension The simplest approach to forming a nanoparticleterm·key–hydrogelterm·key composite is the gelation of a suspension of pre‐formed nanoparticlesterm·key in a hydrogelterm·key‐forming monomer solution. This approach has been utilized to form optically responsive opto‐mechanical nanoparticleterm·key‐hydrogelterm·key composites. 11 In an example of this approach, S. R. Sershen et al. 11 prepared gold nanoparticleterm·key (Au‐NP) hydrogelterm·key composites by adding nanoshell Au‐NPs into a solution of monomers (95/5 molar ratio of N ‐isopropylacrylamide/acrylamide (NIPAAm/AAm) followed by addition of the gelation initiator ammonium persulfate (APS) and accelerator tetramethylethylenediamine (TMEDA). The composite was subsequently cured. Ravi et al. used this approach to incorporate three different types of nanoparticlesterm·key: i) proteo‐mimetic PAAm nano‐gel, ii) bovine serum albumin, and iii) hydrophilized silica (Si), into a hydrogelterm·key matrix for intra‐ocular lens applications. 12 Other groups have adopted this simple approach to obtain hydrogelsterm·key containing Au or Si‐NPsterm·dom and thereby prevent aggregation. 13 This approach has certain drawbacks including the leaching of nanoparticlesterm·key out of the hydrogelterm·key matrix if the cross link density is low. 14 An advanced application of an hydrogelterm·key‐nanoparticleterm·key composite using a similar protocol was reported by Liu et al. for synthesizing photo‐modulable thermo‐responsive hydrogelsterm·key using unilamellar titania nanosheets (TiNSs) as photocatalytic cross linkers ( Figure 3 ). 15 In this synthesis, it was noted that the nanoparticlesterm·key act as photo‐catalysts rather than cross‐linkingterm·key agents and the use of bisfunctional monomer N , N '‐methylenebisacrylamide (MBAAm) was necessary for the formation of mechanically durable hydrogelsterm·key.

a) Schematic of titania nano sheets (Ti) acting as photo catalyst for gelation (difference in energy level of valence band and conduction band is shown). UV radiation with wavelength below 260 nm will produce hydroxyl free radicals causing gel formation reaction with vinyl monomers. b) List of vinyl monomers used for photo induced hydrogelation. c) Pictures before and after the hydrogelation using IPAAm (10.0 wt%) as monomer. The examples show hydrogelterm·key formation in a nanoparticleterm·key suspension. The nanoparticlesterm·key are retained in the hydrogelterm·key by non‐covalent interactions. Reproduced with permission. 15 Copyright 2013, Macmillan Publishers Ltd.

Physical Incorporation of Nanoparticlesterm·key into a Hydrogelterm·key Matrix after Gelation In order to study the solvent switchable electronic properties of hydrogelterm·key‐Au‐NPs, Pardo‐Yissar et al. 6 incorporated Au‐NPs into a PAAm gel after the electro polymerization formation of the hydrogelterm·key. Electro polymerization cannot be performed in the presence of the Au‐NPs because they readily aggregate under the influence of an electric field. To counter this problem, nanoparticlesterm·key were introduced into the gel matrix after the gel had already been formed via a “breathing in” mechanism. PAAm gels are highly swollen in aqueous solution, but shrink dramatically in an aprotic solvent such as acetone. Introduction of nanoparticlesterm·key into the gel “breathing” consisted of three steps, which were repeated several times to obtain the desired nanoparticleterm·key density ( Figure 4 ): a) the swollen gel was placed in acetone for 2 min, causing the gel to collapse with the expulsion of water (breathing out). b) the shrunken gel was then placed in an aqueous solution of citrate‐stabilized 13 nm diameter Au‐nanoparticlesterm·key (ca. 5 nM) for 2 min. This aqueous solution caused swelling of the gel in solution (breathing in), including breathing in the suspended nanoparticlesterm·key. Finally, the gel was washed thoroughly with water to remove any weakly surface‐adsorbed nanoparticlesterm·key. Upon the next “breathing out” cycle, the nanoparticlesterm·key remain attached inside the gel, possibly due to i) physical entanglement and ii) hydrogen bonding interactions between the polymer chains and the citrate surface of the nanoparticlesterm·key. These researchers confirmed the increasing presence of Au‐NPs in the gel with each “breathing” cycle by X‐ray photoelectron spectroscopy (XPS) and atomic absorption spectroscopy (AAS) measurements. 16 Guo et al. used a similar “breathing in” approach to form highly dispersed Au‐NPs in porous anodic aluminium oxide (AAO) films by incorporating Au and platinum (Pt) NPs in PAAm hydrogelsterm·key, followed by calcination. 17 Alternatively, embedding of nanoparticlesterm·key into pre‐formed colloidal micro‐gels could be achieved by repeated heating, centrifugation and re‐dispersion followed by annealing. 18 In a typical procedure, a solution containing various ratios of micro‐gel and colloidal Au was placed into a centrifuge tube and centrifuged. Au‐NP solution was added to the micro‐gel pellet obtained and re‐dispersed throughout the micro‐gel pellet by repeated heating, agitating, and sonication. The suspension was then re‐centrifuged and the protocol repeated before a final annealing.

The construction of a gold‐nanoparticleterm·key/hydrogelterm·key composite at the electrode interface by switching between its swollen and shrunken states. a) Electrochemical formation of acrylamide hydrogelterm·key film at the gold electrode showing its shrinking behavior in acetone and swelling behavior in water. b) Use of alternate cycles of swelling of the hydrogelterm·key gold nanoparticleterm·key suspension in water followed by shrinking in acetone to physically entrap nanoparticlesterm·key in the hydrogelterm·key. Adapted with permission. 6 Reactive Nanoparticleterm·key Formation Aided by the Hydrogelterm·key Network Langer's group developed this approach, which involves loading nanoparticleterm·key precursors into a gel, rather than preformed nanoparticlesterm·key. 7 In a typical procedure, crosslinking NIPAAm and co‐monomers containing thiol groups formed a hydrogelterm·key network containing embedded Au (III) ions. The thiol‐functionalized hydrogelterm·key matrix enabled the modulation of Au‐NP formation when a reducing agent such as sodium borohydride was added. The resulting hydrogelterm·key contained un‐aggregated nanoparticlesterm·key throughout the matrix. An improved procedure of nanoparticleterm·key formation within a gel without the use of thiol or phenol containing monomers was reported by Saravanan et al. ( Figure 5 ). 19 Free‐radical cross‐linkingterm·key polymerization of acrylamide monomer in an aqueous medium containing Ag + ions was conducted. The Ag + ions functionalized‐PAAm hydrogelterm·key matrix was then hydrolysed to yield Ag NPs within the hydrogelterm·key network. The size of the Ag NPs in the hydrogelterm·key were estimated to be 4–7nm and well‐dispersed. The intensity of surface plasmon bands display a symmetrical configuration with no band shift and proportional increases with the increase of Ag+ ion concentration. This showed that the size of Ag nanoparticlesterm·key did not vary on changing the Ag+ ion concentration and aggregation of particles are not present. These conclusions were confirmed with the electron microscopy results. This protocol has also been used for generating silver nanoparticlesterm·key in interpenetrating network hydrogelsterm·key. 20 Adopting a similar method, Xiang et al. synthesized pH‐responsive Ag‐NPterm·dom/poly(2‐hydroxyethyl methacrylate (HEMA)‐poly(ethylene glycol) methyl ether methacrylate (PEGMA)‐methacrylic acid (MAA)) composite hydrogelsterm·key by reducing Ag + ions anchored to free carboxylate groups in the matrix. 21 In a recent study, Varaprasad et al. reduced Ag + ions using green reducing agent (mint leaf extract) in a Carbopol 980 NF and acrylamide gelation mixture to produce composite hydrogelsterm·key for antibacterial applications. 22 In another recent example, Gema, M. et al. utilized redox active catechol side chain in acrylamide‐NIPAAm hydrogelsterm·key to reduce gold precursor to nanoparticlesterm·key to form nanoparticleterm·key‐hydrogelterm·key composites that mimic mussel adhesive protein. 5 A schematic of this approach is presented in Figure 5 (b). These hydrogelsterm·key were readily formed without an external reducing agent, and great reinforcement of mechanical property was observed for the resulting composite hydrogelterm·key.

a) Preparation of Ag/PAAm hydrogelterm·key nanocompositeterm·key without the use of thiols. Reproduced with permission. 19 Copyright 2007, Elsevier. b) Hydrogelterm·key formation and functionalization with Au NPs to obtain catalytic hydrogelsterm·key by redox active catechol groups. Adapted with permission. 5 Copyright 2014, American Chemical Society.

Cross‐Linkingterm·key using Nanoparticlesterm·key to Form Hydrogelsterm·key One particularly interesting example in the development of nanoparticleterm·key‐hydrogelterm·key composites involves the use of cross‐linkingterm·key groups present on the nanoparticleterm·key surface. Souza et al. produced bacteriophage molecular networks by the spontaneous assembly of phage with Au‐NPs. The resulting hydrogelterm·key network preserved the cell surface receptor binding and internalization attributes of the peptide. 23 The spontaneous arrangement of these networks could be further manipulated by incorporation of imidazole (Au–phage–imid), which induced changes in morphology, fractal structure and near‐infrared optical properties. The capacity to form multiple bonds within the gel networks (multivalencyterm·dom) would be a major advantage of nanoparticlesterm·key as cross‐linkers, rather than the two covalent bonds of a traditional hydrogelterm·key formation reaction. This concept was well demonstrated with collagen gel formation using the 1‐ethyl‐3‐(3‐dimethylaminopropyl)carbodiimide (EDC) crosslinking reaction of mercaptopropionyl glycine protected Au‐NPs. 24 Similarly, Zhao et al. used co‐polymerization of vinyl functionalized Au‐NPs to synthesize well‐dispersed Au‐NP‐PNIPAAm hydrogelterm·key composites with thermo‐switchable electrical properties. 25 The transition temperature of the composite could be adjusted from 0 °C to 40 °C by changing the concentration of Au‐NPs, the degree of cross‐linkingterm·key or the stoichiometry of the composite.

Prestwich et al. exploited the multivalencyterm·dom and thiophilicity of Au‐NPs to crosslink commercially available thiolated hyaluronic acid into printable, extrudable, cytocompatible and biodegradable hydrogelsterm·key. 26 In a very recent study, Zhang et al. synthesized semiconductor nanoparticleterm·key‐based hydrogelsterm·key by self‐initiated polymerization under light irradiation. 27 The system consisted of four components: i) water, ii) water soluble semiconductor nanoparticlesterm·key of zinc oxide (ZnO), titanium dioxide (TiO 2 ), iron(III) oxide (Fe 2 O 3 ), tin dioxide (SnO 2 ), zirconium dioxide (ZrO 2 ), cadmium selenide (CdSe) or cadmium telluride (CdTe), iii) N , N ‐dimethylacrylamide (DMAA), and iv) clay nanosheets. The semiconductor nanoparticlesterm·key functioned as inorganic initiators for the polymerization of DMAA. The authors demonstrated that CdSe and CdTe were able to form stable gels even under irradiation by visible light. The mechanism of gel formation and their visual and microscopic properties is shown in Figure 6 . Recently, incorporation of silica nanoparticlesterm·key were shown to result in increased interfacial binding between network and nanoparticlesterm·key leading to increased stiffness as well as excellent energy dissipation capability[[qv: 4b]] with orders of magnitude improvement in fracture resistance in compressive loading. The versatility of using nanoparticlesterm·key as cross‐linkingterm·key agent was further developed by Rose et al. for adhesion between two hydrogelsterm·key. 28 The authors demonstrated that strong, rapid adhesion between two hydrogelsterm·key could be achieved at room temperature by adding a droplet of a nanoparticleterm·key solution on to the surface of the gel and bringing the other gel into contact with it. This method relied on i) the nanoparticlesterm·key' ability to be adsorbed onto the polymer gels, ii) to act as a connector between polymer chains and iii) on the ability of the polymer chains to reorganize and dissipate energy under stress when adsorbed onto the nanoparticlesterm·key. Silica nanoparticlesterm·key (Si‐NPsterm·dom), surface‐modified carbon nanotubes or cellulose nano‐crystals were suitable for this purpose. Two samples of biological tissue (e.g., cut pieces of calf's liver) could be glued together using Si‐NPsterm·dom. This technology could have potential applications in surgery or tissue engineering.

Crosslinking using nanoparticlesterm·key to form nanoparticleterm·key‐hydrogelterm·key composites. Cross‐linkingterm·key using clay nanostructure (Clay‐NS) to form nanoparticleterm·key‐hydrogelterm·key composites with enhanced mechanical properties. The semiconductor NPs, monomer, and Clay‐NS are homogeneously dispersed in water. Upon photo activation semiconductor nanoparticlesterm·key produce free radicals initiating polymerization and crosslinking through clay‐NS. The photograph of the vials depicts optical images of the hydrogelation process. A mixture solution of ZnO nanoparticlesterm·key, DMAA (N,N‐dimethylacrylamide), and Clay‐NS before gelation, hydrogelation after 1 h of irradiation and the resultant elastic ZnO nanocompositeterm·key hydrogelterm·key taken out of the vial are shown. Adapted and reproduced with permission. 15 Copyright 2014, Macmillan Publishers Ltd.

Using Nanoparticlesterm·key, Polymers and Distinct Gelator Molecules Wu et al. has reported incorporation of Si‐NPsterm·dom into a conducting polymer hydrogelterm·key for Si‐based anodes. 29 The hydrogelterm·key was polymerized in situ to produce a well‐connected three dimensional network structure consisting of Si‐NPterm·dom coated with the conducting polymer. This hydrogelterm·key framework combined multiple positive features, including a continuous electrically conductive polyaniline network, binding with the Si surface through either hydrogen bonding with phytic acid or electrostatic interaction with the positively charged polymer, and porous space for volume expansion. Formation of this hydrogelterm·key was achieved with a scalable solution phase synthesis by mixing Si NPs with phytic acid and aniline in water followed by the addition of an oxidizer (for example, ammonium persulphate). The aniline oxidised rapidly and polymerized to form cross‐linked polyaniline and the mixture formed a dark green viscous gel due to the presence of the phytic acid gelator. The viscous gel was then bladed onto a copper foil current collector and dried to form a uniform film over a large area for electrochemical applications ( Figure 7 ).

Nanoparticleterm·key‐Hydrogelterm·key composite with gelator molecules to form electrodes. a) Each (silicon‐nanoparticleterm·key) Si‐NPterm·dom is encapsulated within a conductive polymer surface coating and is further connected to the highly porous hydrogelterm·key framework. b) Dispersion of Si‐NPsterm·dom in the hydrogelterm·key precursor solution containing the crosslinker (phytic acid), the monomer aniline and the initiator ammonium per sulphate. c) Cross‐linked viscous gel formed after several minutes of chemical reaction, d) the hydrogelterm·key gel bladed onto a 520 cm 2 copper foil current collector and dried to form the electrode. Reproduced with permission. 29 Copyright 2013, Macmillan Publishers Ltd.

Types of NP‐Hydrogelterm·key Composites and Their Applications The innovative combination of nanoparticlesterm·key and hydrogelsterm·key create synergistic, unique and potentially useful properties that are not found in the individual components. Properties imparted to the composites depend on the type of nanoparticlesterm·key incorporated, which in turn is determined by the proposed application of the designed composite. Different types of nanoparticleterm·key‐hydrogelterm·key composites and their associated properties and applications are described below.

Metal NP‐Hydrogelterm·key Composites Silver NP‐Hydrogelterm·key Composites Silver (Ag) NPs are known for their antimicrobial properties and have been widely used in dental fillings and, more recently in wound and burn dressings to prevent infections. 30 Ag‐NPsterm·dom bind non‐specifically to bacterial membranes and other components, inducing structural changes that increase membrane permeabilityterm and mitochondrial dysfunction. 31 Controlled release of Ag‐NPsterm·dom is necessary to sustain antimicrobial efficacy. As such, design of Ag NP‐hydrogelterm·key composites was expected to provide functional coatings for various applications ( Figure 8 a). 32 Furthermore, properties such as mechanical toughness, swelling ratio, stimuli responsiveness and bio‐compatibility/degradability would need to be investigated and optimized in such composites for effective application. Ag‐NPsterm·dom have been incorporated into PAAm, 33 polyacrylic acid (PAA), 34 NIPAAm, 35 methyl methacrylate 36 and polyvinyl alcohol (PVA) based hydrogelsterm·key. 37 These Ag NP‐hydrogelterm·key composites show promise as functional anti‐microbial coatings. Semi‐interpenetrating network (IPN) hydrogelsterm·key offer an excellent alternative for applications requiring higher mechanical toughness. These materials also acted as templates for the synthesis of small (2–5nm) and uniformly distributed Ag‐NPsterm·dom. 20 Efforts in recent years have shifted to utilizing naturally occurring materials such as chitosan, 38 carbohydrate polymers such as gum acacia and dextran 39 and gelatin 40 to produce bio‐compatible/degradable composite materials that have potential applications as implantable dressings. The controlled‐release of Ag‐NPsterm·dom provides consistent protection for a period of time, without the need to remove the dressings. Tokarev et al. demonstrated that Ag‐NPsterm·dom enhance the efficacy of surface plasmon resonance (SPR)‐based sensors. 41 Ag‐NPsterm·dom incorporated into pH‐responsive hydrogelsterm·key with the enzyme glucose oxidase function as glucose concentration sensors (Figure 8 b). The swelling‐shrinking transition of Ag‐NPterm·dom filled hydrogelsterm·key alter the inter‐particle distance and so affect the optical response of SPR‐based sensors, leading to sensitive glucose detection. 42 Additionally, Ag‐NPsterm·dom have been incorporated into hydrogelsterm·key to form electrically conducting hydrogelsterm·key. The relationship between initial precursor Ag + ions concentration and swelling ratio of the hydrogelterm·key have a direct impact on conductivity. A higher concentration of Ag + ions resulted in better conductivity, but reduced swelling ratios, and vice versa. 19 High conductivity without affecting the swelling ratio could potentially be achieved with Ag nanowires (1D nano‐structures) rather than Ag NPs (0D nano‐structures). 43 a) Overview of potential medical applications for Ag NP‐hydrogelterm·key composites. Reproduced with permission. 37 Copyright 2013, Elsevier. b) Ag NPs incorporated into pH‐responsive hydrogelterm·key based glucose oxidase activity sensor. c) Shifts in silver nanoparticleterm·key absortion maxima (Δλ max ) as functions of glucose concentration for the plasmonic sensing device. d) Spectrophotometric glucose sensing. Change in absorption at 470 nm. Adapted with permission. 48 Gold NP‐Hydrogelterm·key Composites Stimuli‐responsiveterm·key and switchable conductive Au‐NP‐hydrogelterm·key composites have been demonstrated by several groups. 25 , 44 External stimuli such as temperature or pH cause a change in conductivity of the hydrogelterm·key due to the change in inter‐particle distance. Even though Au‐NP‐hydrogelterm·key composites have shown efficacy in SPR based sensors 45 and anti‐bacterial applications, 46 the high cost of gold has so far prevented wide‐scale adoption of Au‐NPs for such applications. Irradiation of light at the Au plasmonic peak induces localized heating within a temperature‐responsive gel matrix. 47 This phenomenon can be used for remote‐controlled drug deliveryterm·key. If the temperature rises above the lower critical solution temperatureterm·dom (LCSTterm·dom) of the gel matrix, the gel structure collapses resulting in an on‐demand burst release of drugs as opposed to a diffusion‐controlled release. Shiotani and co‐workers have demonstrated this concept using a system ( Figure 9 a) of Au nanorods‐NIPAAm composite hydrogelsterm·key and rhodamine‐based materials. 48 They reported a fast and reversible shrinking and re‐swelling of this composite hydrogelterm·key. The fast response was attributed to heat generation within the gel matrix, rather than external to the matrix. Cytotoxicity studies of these composite gels on cultured cells are underway, with clinical trials expected in the near future. 48 Different sized or structured Au‐NPs immobilized in a thermo‐responsive hydrogelterm·key matrix can also function as remote‐controlled microfluidic valves. The principle behind this application relies on the variation of thermal response with nanoparticleterm·key size. 49 The use of different excitation wavelengths renders opening of different valves when the correct amount of energy is delivered by matching the plasmonic resonant peaks of the NPs. On irradiation with 532nm light, Au‐colloids (3–10 nm diameter) with plasmonic peak at 532nm collapse the hydrogelterm·key network, opening the valve. Valves containing Au‐nanoshell (diameter 120nm, shell thickness 10nm) hydrogelterm·key composites remain unaffected. Opening of these valves containing Au‐nanoshells could be achieved upon illumination at 832nm (Figure 9 b). 50 a) Photo‐thermal effect of laser irradiated Au‐nano rods, causing localized collapse of hydrogelterm·key. White arrow indicates position of Au‐nano rods and laser irradiation. Reproduced with permission. 57 Copyright 2007, American Chemical Society. b) T‐junction of a microfluidic device with Au‐colloid hydrogelterm·key (right valve) and Au nano shell hydrogelterm·key (left valve) with 100 μM wide channels i) When the device is illuminated with 532nm green light the left valve opened ii) when the device is illuminated with 832nm IR light the right valve opened. iii) The absorption spectra of gold nano particles and gold nano shells. Adapted and reproduced with permission. 50 Other Metal NP‐Hydrogelterm·key Composites Although the majority of metal NP‐hydrogelterm·key composite studies involve Ag and Au‐NPs, several other metallic NPs also show promise in various fields including catalysisterm·key, magnetic components and environmental nanotechnology. Platinum (Pt) metal is well‐known as a hydrogenation catalyst. Pt‐NPs in a bola‐amphiphile hydrogelterm·key was found to be an efficient catalyst for the hydrogenation of p‐nitroaniline. 51 This procedure can be used for templated, in situ synthesis of nanoparticlesterm·key leading to uniform distribution and high loadings. Magnetic NPs of cobalt (Co) or nickel (Ni) have also been incorporated into hydrogelsterm·key to form soft, magnetic field driven actuators for muscle‐like applications. 52 Ni and Ni‐nickel oxide core‐shell NPs incorporated into PVA hydrogelsterm·key were responsive to magnetic fields and used for separating and concentrating of chemical species from a mixture. 53 Copper (Cu) has been investigated as a cost effective alternative to Ag and Au‐NP anti‐microbial agents. Cometa and co‐workers have demonstrated an effective Cu‐NP‐poly(ethylene glycol diacrylate) hydrogelterm·key anti‐microbial coating, where the combined effect of the high surface/volume ratio of Cu‐NPs and charged quaternary ammonium salts led to potent bactericidal activity. 54 In situ synthesis of bi‐metallic NPs provides interesting nanocompositeterm·key hybrid materials. Fe‐Co bimetallic NPs, for example, were synthesized in a PAAm hydrogelterm·key network to form magnetic hydrogelsterm·key for waste removal applications. 55 Poly(2‐acrylamido‐2‐methyl‐1‐propansulfonic) acid has been used as a template for the synthesis of Co:Ni bimetallic NPs, which can catalyse the hydrolysis of sodium borohydride (NaBH 4 ) for hydrogen production and are also magnetically responsive, to be sequestered when not required. 56 Zhang et al. recently used a poly(ethylene oxide propylphosphonamidate) (PEOPPA) hydrogelterm·key bearing multi‐amine groups to carry out in situ reduction with concomitant nanoparticleterm·key formation. Uniform immobilization of noble metal nanoparticlesterm·key (Au, Ag, Pd, Pt and Ru) were obtained in the absence of any other reducing agents and stabilizers. 57 These nanoparticleterm·key‐infused hydrogelsterm·key were used for the reduction of nitro aromatics in the presence of NaBH 4 . This system showed excellent recyclability with retention of catalytic activity because aggregation induced deactivation was prevented by the hydrogelterm·key network.

Metal Oxide NP‐Hydrogelterm·key Composites Metal oxide NPs hydrogelterm·key composites have been developed for their ferromagnetic and semi‐conducting properties. Iron oxideterm·dom (FexOyterm·dom) is a commonly synthesized ferromagnetic material that has recently been incorporated into hydrogelsterm·key to form ferrogelsterm·dom. 58 Ferrogelsterm·dom made from poly(acrylamide‐co‐maleic acid), 59 pNIPAAm, 60 4‐vinylpyridine, 61 chitosan blends with PAA 62 and methacrylate co‐polymers 63 loaded with magnetite NPs are effective absorbents for toxic ions such as lead (Pb 2+ ), chromium (Cr 2+ ) and arsenic (As 5+ ). The embedded pollutants can then be collected magnetically. 64 Similarly, Ozay et al. ( Figure 10 a) used a poly(2‐acrylamido‐2‐methyl‐1‐propansulfonic acid‐co‐vinylimidazole) hydrogelterm·key loaded with Fe(II)oxide magnetite NPs to absorb and remove Cu 2+ ions from solution. 65 Ferrogelsterm·dom can also be magnetically driven actuators to mimic muscle movement. Caykara and co‐workers prepared Fe 3 O 4 NPs immobilized in poly(N‐tert‐butylacrylamide‐co‐acrylamide) hydrogelsterm·key by in situ oxidation of iron precursor in an alkaline medium. 66 These ferrogelsterm·dom displayed actuation under magnetic field (Figure 10 b), suggesting that further research could lead to devices exhibiting human‐like actuation. Magnetite NPs embedded in thermo‐responsive hydrogelsterm·key can be employed for drug deliveryterm·key and microfluidic valve control in a similar fashion to that described above for light activated Ag and Au NP composites. 38 In this case, alternating magnetic fields (AMFs) result in a localized temperature change around the NP, stimulating the hydrogelterm·key matrix. 67 Titanium oxide and ZnO NPs, have been developed for their UV protective and photocatalytic properties. These materials have potential applications in skin care products and self‐cleaning surfaces. 68 a) Removal of Cu2+ ions in aqueous medium, i) Ferrogelterm·dom in solution of Cu2+ ions, ii) Magnetic rod attracts ferrogelterm·dom, iii) Removal of ferrogelterm·dom is accompanied by the removal of Cu 2+ ions as well. Reproduced with permission. 65 Copyright 2010, Elsevier. b) Bending of ferrogelterm·dom under varying magnetic field. i) No bending under no field. (ii–iv) Increasing bending observed as magnetic field is increased from 0.5T to 1.3T. Magnetic field strength is indicated in the pictures. Reproduced with permission. 66 Non‐Metal NP‐Hydrogelterm·key Composites Non‐metal based NPs such as carbon‐based materials (graphene oxide, nanodots, nanotubes), quantum dots (CdTe) and Si have been used to create composite materials with unique properties and functions. Si‐NPsterm·dom have been traditionally used as a support for catalysts or functional materials. Yang et al. incorporated Si‐NPsterm·dom as cross‐linkingterm·key centers in PAA based hydrogelsterm·key that resulted in excellent mechanical strengtheningterm ( Figure 11 a). 69 Si‐NPterm·dom‐hydrogelterm·key composites have also been shown to have higher drug release efficiency when loaded with a drug such as doxorubicin. 70 Alvarez and co‐workers developed an antibiotic loaded (gentamicin) Si‐NPterm·dom‐collagen composite hydrogelterm·key that exhibited prolonged antibacterial activity and increased mechanical strength. 71 Similarly, Lee and co‐workers used Si‐NPsterm·dom‐collagen hydrogelterm·key composites for delivering nerve growth factors for neural tissue engineering. 72 Annaka and co‐workers developed a hydrophobically modified polyethylene glycol containing an hydrophilized Si‐NPsterm·dom hydrogelterm·key composite for injectable intraocular applications. 73 In a similar approach Liu et. al, designed an injectable tissue adhesive using dopamine‐modified four‐armed poly(ethylene glycol and with a synthetic nanosilicate, Laponite.[[qv: 4a]] A subcutaneous implantation study of these materials in rats demonstrated improvement in mechanical and adhesive properties with enhanced cellular infiltration and minimum inflammatory response. Carbon nanotubes, 74 graphene oxide 75 and even melanin, 76 when placed in hydrogelsterm·key act as NIR light absorbing materials useful for photo‐thermal drug deliveryterm·key. These materials present synthetic alternatives to Au or Ag‐NPterm·dom based remote‐controlled photo‐thermal systems. Semiconductor quantum dots CdSe/ZnS and CdSe/CdS have been incorporated into hydrogelsterm·key to produce fluorescent hydrogelsterm·key bio‐markers. Chang and co‐workers prepared highly fluorescent, robust cellulose‐QD hydrogelsterm·key (Figure 11 b) 77 while Salcher and co‐workers made CdSe/CdS QDs/PNIPAAm hydrogelterm·key beads for cell labelling. 78 a) Left: Physical demonstration of extreme elasticity of Si‐NPsterm·dom hydrogelsterm·key by stretching. Right: Stress‐strain plots showing excellent toughness by Si‐NPterm·dom hydrogelsterm·key. SNP 0.09 indicate gels made with 0.09mg/mL surface treated silica nanoparticleterm·key, SNP0.009 a indicate gels made with same amount of silica without surface treatment. CC1 is the hydrogelterm·key without silica nanoparticlesterm·key. Reproduced with permission. 69 Copyright 2013, Royal Society of Chemistry. b) Demonstration of cellulose networks in the hydrogelsterm·key protecting the CdSe/ZnS structure and preserving the quantum dots characteristics. Appearances of the Quantum dot (QD) ‐cellulose hydrogelsterm·key under a 302 nm UV lamp (left), and Photoluminescence spectra of CdSe/ZnS (core/shell) QDs with average diameter 2.8 nm (green), 3.0 nm (yellowish‐green), 3.2 nm (yellow) and 3.6 nm (red) respectively in buffer solution. QD‐cellulose hydrogelterm·key emission peaks are matching with (right, bottom) with emission peaks of the free quantum dots in buffer. Adapted and reproduced with permission. 77 Copyright 2009, Royal Society of Chemistry.

Polymeric NP‐Hydrogelterm·key Composites Polymeric NPs composed of micelles, 79 nano‐gels, 80 core‐shell particles, 81 dendrimers, 82 hyper‐branched polymers, 83 and liposomes 84 have been developed for a variety of applications. The inclusion of these particles in a hydrogelterm·key imparts multi‐functionality because the polymer particles themselves possess multiple functional groups. Many designs have biomedical applications including drug deliveryterm·key and bio‐sensing. Zhong et al. enhanced the biological stability of collagen by the physical incorporation of poly amidoamine dendritic NPs. 85 Such physical incorporation resulted in enhanced mechanical properties due to the numerous interactions within the hydrogelterm·key network which, in turn, increased human conjunctival fibroblast proliferation. Zhang et al. overcame the limitation of poor drug loading and lack of control over the lower generation dendritic NPs by using generation 5, hyper‐branched polyamine ester nanoparticleterm·key in an hydrogelterm·key network. 86 These hydrogelsterm·key allowed week‐long, controlled release of active ingredients which was not possible with hydrogelsterm·key that did not possess NPs. The use of polymeric NPs for reinforcement of hydrogelsterm·key is not restricted to biomedical applications. Polystyrene (PS), a material commonly used for packaging and storage, could be used as filler in hydrogelsterm·key to impart mechanical strength. 87 Bait et al. developed an acrylamide and hydroxyethyl methacrylate hydrogelterm·key with PS‐NP fillers for superior elasticity in dermatological patches. 88 Thevenot et al. developed hybrid materials with differing elastic moduli by using alternating layers of PAAm hydrogelterm·key composites with and without PS‐NP fillers. Physical deformation of this bi‐layer gel produced an electrical potential, useful in developing soft tactile‐sensing devices ( Figure 12 ). 89 Polypyrrole (PPy) is a semi‐conducting conjugated polymer used in organic‐based optoelectronic devices. Luo et al. developed an agarose/alginate double network hydrogelterm·key incorporating PPy NPs for use as an infrared responsive releasing system, much like those employing reduced graphene oxide NPs. 38 a) Mechanical compression of bilayer gels with and without poly styrene nanoparticlesterm·key (PSNPs) Gel 1: without PS NP (top) and Gel 2: with 26% PS NP (bottom part of the cylindrical gel) are attached together and compression is given from top (arrow). b) Time profile of deformation ΔL 1 /L and ΔL 2 /L (top) and electric potential ΔV generated (bottom) upon deformation. Reproduced with permission. 89 Copyright 2007, Royal Society of Chemistry.

Conclusions and Outlook We have reviewed nanoparticleterm·key‐hydrogelterm·key composites as a state‐of‐the‐art, versatile class of materials suitable for a wide range of applications. Synthetic methods and strategies and the unique synergistic properties of the composite that is absent in individual components, together with their applications, have been summarized. Nanoparticleterm·key‐hydrogelterm·key composites exhibit multi‐functional and stimuli responsiveterm·key properties, making them ideal for “smart” materials, including i) antimicrobial gels/barriers/matrices; ii) photo thermally active hydrogelsterm·key; iii) soft material catalysts; iv) environmental absorbents; v) drug deliveryterm·key vehicles; vi) optical detection sensors and vii) soft actuators. Potential applications include i) safe, clinically implantable nanoparticleterm·key‐hydrogelterm·key composite systems for bio‐sensing and therapy; ii) environmental remediation systems for catalytic oxidation of toxins/removal of pollutants; iii) recyclable catalytic nanoparticleterm·key hydrogelterm·key composites for chemical synthesis and iv) composite hydrogelterm·key patches for cosmetic applications.

We expect that the classification of synthetic approaches and applications of nanoparticleterm·key‐hydrogelterm·key composites presented in this reviewterm·mth provide a better understanding of the system and enable the reader to design innovative combinations for new applications. Control of the covalent and supra molecular interactions by synthetic design and prediction of the resultant properties in the nanoparticleterm·key‐hydrogelterm·key composite are major areas to be developed in this emerging field. Such predictions upon experimental validation will form the foundation of design for the next generation nanoparticleterm·key‐hydrogelterm·key composites with optimal properties for a desired application. In the coming years, such design of nanoparticleterm·key‐hydrogelterm·key composites will not only result in advanced applications, but will also steer the fundamental understanding of material interactions, aiding computational prediction of properties of new composites from existing components.