A review on nanocomposite hydrogels and their biomedical applications

2.1 Carbon nanotubes

The hydrophobic nature of carbon-based materials limits their interaction with hydrophilic polymers. For this reason, CNT surfaces are modified with various polar groups, such as amines (NH₂), hydroxyls (OH) and carboxyls (COOH), or grafted with different polymer chains in order to enhance their dispersion (Figure 2) [2].

Figure 2

The synthesis and fabrication of PGS-CNT nanocomposites. Reproduced from Ref. [8] with permission of The Royal Society of Chemistry.

CNTs can be used as reinforcing agents within hydrogel networks and, in some cases, make the hydrogel responsive to external electrical or thermal stimuli. The addition of 1% CNTs to poly glycerol sebacate (PGS)-based hydrogels reinforces the polymer network. The hydroxyl groups on the PGS esterifies with the carboxylic groups present on the COOH-functionalized CNTs. Here, the CNTs act as both physical and covalent crosslinkers. This covalent crosslinking between the CNTs and polymer chains results in a significant increase in the tensile and compression modulus compared to pure PGS, although the elasticity of the polymer network is not compromised. As a result, the addition of CNTs changes the ductile fracture property of PGS to a brittle fracture property and an elastomeric stiff nanocomposite is obtained (Figure 3) [8].

Figure 3

(A) The SEM image of the freeze-fractured surface of PGS-1% CNT nanocomposites showing uniform distribution of CNTs on the surface. (B) PGS-CNT nanocomposites showing high flexibility and can sustain bending and twisting. (C) The SEM images of the fractured surfaces of PGS-CNT nanocomposites after tensile testing. Reproduced from Ref. [8] with permission of The Royal Society of Chemistry.

2.2 Graphene/Graphene-oxide

Graphene sheets are treated with strong oxidizers in an intense acid environment or by radiation to attach oxygen-containing groups on their surface and obtain graphene oxide (GO). GO is more hydrophilic but less electro-conductive in comparison to graphene. GO sheets can be reduced again with reduction agents and the heating process but they will still contain oxygen-containing residuals.

In a recent report, gelatin methacrylate (GelMA) impregnated with functionalized GO (fGO) nanosheets, for the site-specific gene delivery of pro-angiogenic human vascular endothelial growth factor plasmid DNA (pDNA_VEGF) to damaged cardiac tissues [9].GOcan be used to deliver genes efficiently when bonded to cationic polymers such as polyethyleneimine (PEI). While low molecularweight, branched PEI is known to have low cytotoxicity and binds strongly to DNA, it is an acceptable material for gene transfer and can enhance gene delivery efficiency in combination with GO. This is how fGO is produced [10, 11, 12]. GelMA is also nontoxic to cells if its concentration and degree of methacrylate are optimized [13]. This combination promotes local myocardial neovascularization at the injected sites and reduces fibrosis. The heart ejection fraction (%EF) and thus the heart function, is also improved, as shown in Figure 4 [9].

Figure 4

The assessment of the in vivo scar areas and cardiac function of infarcted hearts treated with GG‘ hydrogel (GelMA hydrogel carrying fGO_VEGF (pDNA_VEGF bound to fGO)) therapy. (A) and (B) The scar area determination by morphometric analysis of the left ventricle in different groups. The representative images of the left ventricle myocardial sections stained with sirius red show the cardiac fibrosis regions (in red). Sham operated and untreated infarcted group were used as controls. The red area represents the ECM deposition in the scar tissue and the gray area represents the myocardium. (C) Echocardiographic assessment of cardiac function. The heart ejection fraction (EF%) was monitored at days 2 and 14 post-treatment. p < 0.0001; ^***p < 0.001, ^**p < 0.01, ^*p < 0.05 vs. time-matched control (n = 7). The p-values comparing time-matched GG′ and GG are indicated by ψ. This is an unofflcial adaption of Ref. [9] that appeared in an ACS publication. ACS has not endorsed the content of this adaption or the context of its use.

The dispersion of gold nanoparticles on GO or reduced GO (rGO) sheets or the encapsulation of gold clusters inside graphene-based cages generates a new class of hybrid materials for drug/gene delivery, bioimaging, electrochemical biosensing and photothermal therapy. The oxygen-containing functional groups on GO and rGO are essential for further chemical reactions and the integration of gold nanostructures through the electrostatic interactions, covalent linkage and π-π stacking [14]. A scheme is shown in Figure 5.

Figure 5

The decoration of GO and rGO with gold nanostructures using different interaction forces. Adapted from Ref. [14] with the permission of The Royal Society of Chemistry.

Although carbon-based hydrogels are able to imitate some of the functions of native tissues, their long-term cytotoxicity as tissue replacements in the body should be considered; it also requires further investigations under in vitro and in vivo conditions [2].

3.1 Dendrimers/Hyperbranched polymers

Dendrimers have high reactivity and loading efficiency due to the multiple functional groups on their periphery and their highly branched porous structure [2]. The stiffness of the hydrogels, the degradation properties, and the hydration kinetics are affected by the dendrimer concentration. The resulting nanocomposite hydrogels containing dendrimers show high stress absorbing capacity, which is crucial for cartilage tissue engineering applications. The globular morphology of chondrocytes encapsulated within the hydrogel nanocomposite is retained, and a significant increase is observed in the production of type II collagen and proteoglycans [18]. In another work, collagen-grafted nanocomposite films showed significant improvements in cell adhesion and proliferation due to the changes in wettability, surface morphology and new functional groups on the surface [19].

It has been observed that photocrosslinkable hyper-branched polyester (HPE) hydrogels can encapsulate hydrophobic drug molecules as a result of the hydrophobic structure inside their cavities. As the concentration of HPE increased, the functionalization of HPE with photocrosslinkable acrylate moieties resulted in formation of hydrogels with a highly porous interconnected structure, mechanically tough network and better attachment of fibroblasts on the surface (Figures 6 and 7) [20].

Figure 6

The representative phase contrast and fluorescent images of fibroblasts on the surface of the HPE hydrogels. Cells readily attached and spread on hydrogels with higher HPE concentration. Adapted with permission from Ref. [20]. Copyright (2013) American Chemical Society.

Figure 7

The effect of HPE macromolecule concentration on the microstructure of freeze-dried hydrogel network evaluated using SEM. Adapted with permission from Ref. [20], Copyright (2013) American Chemical Society.

3.2 Liposomes

A liposome is a tiny bubble made out of the same material as a cell membrane (phospholipids). When membrane phospholipids are disrupted, they can reassemble themselves into tiny spheres, smaller than a normal cell, either as bilayers or monolayers. The bilayer structures are liposomes. The monolayer structures are called micelles. Liposomes are hydrophilic at the core and surface but hydrophobic at the shell layer. Hence, they can be loaded with hydrophobic and/or hydrophilic molecules, such as drugs, bioactive agents, DNA, RNA, and genes [21]. Drug-loaded liposomes, can be mixed with materials, such

as degradable polymers, acting as a matrix or carrier in the system and then crosslinked to obtain nanocomposite hydrogels to deliver the molecules to a site of action (Figure 8).

Figure 8

The structure of a liposome and its drug delivery mechanism. Image available at Ref. [21].

3.3 Nanogels

Nanosize hydrogels (nanogels) can trap bioactive compounds inside their nanoscale core. They respond to microenvironmental elements, such as temperature or pH, because of their nano-dimensions. Various methods are used to prepare nanogels based on their cross-linking route. They can be crosslinked either with covalent bonds (chemically) (Figure 9) or with hydrogen bonds as well as electrostatic and hydrophobic interactions (physically). For example, the amphiphilic block copolymers can self-assemble mono dispersive polymer micelles in water. Nanogels have been obtained by covalent cross-linking of the hydrophilic or hydrophobic polymer chains in these polymer micelles either at core or shell (Figure 9-A) [5].

Figure 9

The chemically prepared nanogel by: (A) Crosslinking of amphiphilic block copolymer at core or shell of the polymer micelles in water. (B) Emulsion polymerization with/without emulsion. (C) Using liposome as a template. Adapted from Ref. [5], Copyright (2010) with permission from John Wiley & Sons, Inc.

Another route to obtain nanogels with a well-controlled size is through nano or microemulsion polymerization. This polymerization occurs within the core of oil-in-water or water-in-oil nano or microemulsions in the presence of surfactants (Figure 9-B). Monodispersed nanogels of various sizes have been synthesized using atom transfer radical polymerization (ATRP) in water-in-oil nanoemulsion. Water-soluble drugs, including anticancer drugs (e.g. doxorubicin) and bioactive macromolecules (e.g. DNA and proteins) can be easily incorporated into nanogels using this method [5, 22].

In a recent work, Poly(D, L-lactide-co-glycolide) (PLGA) micro/nanoparticles have been prepared using oil-in-oil emulsion/solvent evaporation in the presence of surfactants. Results indicate that the mean size of PLGA micro/nano particles is influenced by the polymer and surfactant concentration, stirring speed, impeller type and dropping size [23]. In addition, nanogels can be obtained using the aqueous cores of liposomes as reaction vessels. Nanogels with the size of the liposomal template are obtained after the removal of the lipid molecules covering the hydrogel. The lipid-coated nanogels can be used as nanocarriers (Figure 9-C) [24].

Nanogels can be used as nanoparticles in the construction of a hydrogel. Nanogel-integrated hydrogels (nanogel cross-linked gels) are attractive for drug delivery systems, regenerative medicine and bioimaging [5]. In an interesting application, synthesized poly(n-isopropylacrylamide) (PNIPAAm), a temperature-responsive polymer, was coated on gold nanorods. The resulting core-shell nanocomposites were intravenously injected into mice, and the right kidney of each mouse was then exposed to near-IR laser irradiation (Figure 10-A). The organs were subsequently collected and the amount of gold nanorods in these organs was analyzed, as shown in Figure 10-B. Nanogels collapsed and aggregated during the on/off positions of the light source, according to diameter changes shown in Figure 10-C. The gold particles or any kind of encapsulated drug molecules within the nanogel core can be released in a controlled manner [25].

Figure 10

(A) A scheme showing the administration of the gold-hydrogel particle nanocomposites followed by near-IR light irradiation. (B) White and light-gray bars indicate the distribution after 10 and 30 min, respectively, when particle nanocomposites were injected with no irradiation. The black bars indicate the distribution when nanocomposites are injected followed by laser irradiation. The last diagram indicates the injection of polyethylene glycol (PEG)-modified gold nanorods and laser irradiation. (C) The hydrodynamic diameters of PNIPAAm-coated gold nanorods upon irradiation using a near-IR laser with increasing power density. The periods of laser irradiation are indicated by the gray area. Reproduced from Ref. [25] with the permission of The Royal Society of Chemistry.

4.1 Hydroxyapatite

Hydroxyapatite is a mineral found in teeth and bones. It is mainly used as a filler for amputated bone substitution or as a coating for implants for bone ingrowth promotion. However, they have some drawbacks, such as a low bioresorption rate in vivo, a poor stimulating effect on the growth of new bone tissues, low crack resistance and small fatigue durability in the physiological environment. One approach to overcome these drawbacks is to modify the hydroxyapatite structure with uorine or silicon. The biodegradation properties, protein adsorption and adhesion of the coating to the metal substrate can be improved by using uorine [27].

Cell-laden protein-based hydrogels are potentially used in regenerative medicine and soft tissue engineering. Some studies tried to improve the poor mechanical strength of protein-based hydrogels and made them suitable for hard tissue engineering as well. For example, by incorporating nHA into gelatin-based hydrogels, the stiffness of hydrogel significantly improved while the structural integrity and swelling ratio did not change considerably. New minerals with a near-spherical shape also formed homogeneously on the surface of nanocomposites after incubation in simulated body fluid (SBF). Due to the shape of the minerals, they are assumed to be calcium apatite (Figure 11). Moreover, the embedded cells easily extended, proliferated and unified with adjacent cells in the nanocomposite. Thus, it can be said that nHA not only acts as a reinforcing filler, but also stimulates cellular growth and provides a bioactive character for the hydrogel nanocomposite [28].

Figure 11

The SEM cross-sectional micrographs of hydrogel/HA nanocomposites containing different concentrations of HA nanoparticles after 30 days of incubation in SBF at 37°C. Reprinted from Ref. [28], Copyright (2015) with permission from Elsevier.

A recent study demonstrated the fabrication of nanocomposite microspheres based on chitosan, gelatin and nHA. Results indicate that, by changing the nHA/biopolymer (chitosan/gelatin) weight ratio, stirring rate and biopolymer concentration, the particle size and morphology of nanocomposite microspheres would be influenced. Morphological tests indicate that it is possible to fabricate microspheres in wide ranges of particle sizes and different morphologies – from a dense one for drug delivery systems to a porous one for cell delivery applications [29, 30]. NH₂ content and crosslinking density of such composites based on chitosan/gelatin/nHA can also have great impacts on their performance and mechanical stability in aqueous media [31].

4.2 Synthetic silicate nanoparticles (nanoclays)

Mixing linear and branched polymers with nanoclays leads to tissue-adhesive nanocomposite hydrogels with improved mechanical properties [32]. Nanoclay morphology is anisotropic and plate-like with a high aspect-ratio, resulting in high surface interactions. The polymer chains reversibly adsorb and desorb on the silicate surfaces due to the non-covalent interactions between the polymers and the nanoparticles (Figure 12) [33, 34].

Figure 12

The polymer chains crosslinked with the nanosilicate particles. Ref. [34], (© Springer-Verlag 2008) “with permission of Springer”.

Depending on the clay type, the individual layers could be composed of two, three or four sheets of either SiO₄⁴⁻ tetrahedra or [AlO₃(OH)₃]⁶ octahedra. These layers can organize themselves over one another like pages of a book, with a regular Van der Waals gap between them, called an “interlayer”. This interlayer possesses net negative charge, which is due to the ionic substitutions in the sheets of clay minerals. The layer charge is neutralized by cations occupying the inter-lamellar and can be easily replaced by other required cations or molecules [35].

Montmorillonite nanolayers have been exfoliated in the chitosan sulfate (SMMT) matrix, presenting a nanohybrid membrane for wounds with low to moderate exudates. These novel wound dressings showed improved physicochemical properties than conventional nanocomposite films. They did not show any cytotoxicity against fibroblast cells and a better cell attachment was observed on Chitosan/SMMT [36].

A type of bio-modified clay, chitosan-intercalated montmorillonite (chitoMMT), has been incorporated into novel hydrogels and compared with the clay-free ones. An electroresponsive polymer served as the hydrogel base and ChitoMMT is embedded within the network to achieve super-swelling nanocomposite. ChitoMMT exhibited no cytotoxicity and enhanced the gel strength and thermal stability at the optimized content of 6% [37].

Highly charged nanoparticles can localize clotting factors. By concentrating clotting factors, blood coagulation could be induced. Nanoclays are positive along the edge and negative on the top and bottom surfaces. Hence, these charged disks can form self-assembled structures that can dynamically form and break. According to shear-thinning specifications of such systems in aqueous media, they could be used for minimally invasive therapies (Figure 13) [2, 38].

Figure 13

The scheme showing the preparation of the nanocomposite gels and injection of nanocomposite hydrogel through a surgical needle. The TEM image shows the size of the silicate nanoparticle. This is an unofficial adaptation of Ref. [38] that appeared in an ACS publication. ACS has not endorsed the content of this adaptation or the context of its use.

One approach for hemorrhage treatment is to engineer into a wound site some injectable biomaterials, which flow with minimal applied pressure during injection, thus avoiding additional patient trauma. The material should solidify quickly and remain at the wound site. To avoid biomaterial loss or flow to unwanted areas, it should be thermally stable. One way to achieve this is to add nanoclays into the gelatin, which would significantly improve the physiological stability, injectability, hemostatic performance and nanocomposite-clot strength. The human blood initiates coagulation in 5–6 min in normal conditions. The incorporation of nanoclays into gelatin leads to a decrease in the observed clotting time in vitro (Figure 14) [38].

Figure 14

The clot formation as a function of time and nanocomposite composition. xNCy (“x” represents the total solid weight percent and “y” is percent of the total solid weight percent that is nanoplatelet). This is an unofficial adaptation of Ref. [38] that appeared in an ACS publication. ACS has not endorsed the content of this adaptation or the context of its use.

Recent studies have shown that nanoclay can induce the osteogenic differentiation of human mesenchymal stem cells (hMSCs) without the use of exogenous growth factors [39]. For example, poly(glycerol sebacate) (PGS), a widely used material in tissue engineering applications because of its tough elastomeric mechanical properties, biocompatibility and controllable degradation, lacks enough bioactivity and has limited utilization for musculoskeletal tissue engineering. By covalently reinforcing the PGS network with 2D nanoclays, a bioactive highly elastomeric and mechanically stiff nanocomposite is obtained, while also significantly enhancing cell adhesion and proliferation (Figures 15 and 16). The in vitro stability of nanocomposites is also better with the higher amount of nanosilicates [40]. However, the long-term cytotoxicity of silicate nanoparticles must be investigated through further in vivo experiments.

Figure 15

(A) Chemical structure of PGS. (B) Interactions between PGS chains and nanosilicates. Reprinted from Ref. [40], Copyright (2015), with permission from Elsevier.

Figure 16

(A) PGS (B) PGS-Nanosilicate. Reprinted from Ref. [40], Copyright (2015), with permission from Elsevier.

4.3 Glass ceramics

Glass is an inorganic, amorphous material with a randomly arranged atomic structure [41]. It is possible to rearrange the random structure of glass to an ordered structure

of a ceramic, which is more stable than others (Figure 17). The result is called a glass-ceramic.

Figure 17

The structural difference between a glass and a ceramic; (A) Silica glass random structure (B) Quartz (crystallized silica) ordered structure. Image available at Ref. [41].

Bioactive glasses are a group of surface reactive glass-ceramic biomaterials. These can be integrated in polymeric hydrogels as reinforcing bone growth induction agents in order to obtain nanocomposite hydrogels.A commercially available family of bioactive glasses, called bio-glass, comprises SiO₂, Na₂O, CaO and P₂O₅ in specific proportions. The formation of apatite crystals is due to the high ratio of calcium to phosphorus. Meanwhile, calcium and silica ions act as crystallization core. These biocompatible glasses are extensively used as implant materials to repair and replace damaged bone (Figure 18) [42]. Recent studies focused on the modification of bioactive glass surface. The surface morphology is a key component in defining the bioactive response [43].

Figure 18

The bioactive glass coating on a Ti6Al4V (6% Aluminium, 4% Vanadium, 0.25% (maximum) Iron, 0.2% (maximum) Oxygen and the remainder Titanium) implant screw. Image available at Ref. [42].

A bioactive glass transforms to hydroxyapatite crystals and immerses in a physiological environment in five stages. First, Na⁺ cations in the glass network exchange with hydronium ions in the external solution (ion exchange stage). Second, the Si-O-Si molecules breaks into Si-OH silanol groups and the glass network is disrupted (hydrolysis stage). The silanol groups of previous stage condensate and form a gel-like layer (condensation stage); then, an amorphous calcium phosphate layer is deposited on this gel layer (precipitation stage). Finally, the calcium phosphate layer gradually transforms into crystalline hydroxyapatite (mineralization stage) [43].

4.4 Calcium phosphate

Several different forms of calcium phosphate can fulfill different jobs. One type of calcium phosphate is hydroxyapatite, which exists in bones and teeth. Other forms of calcium phosphate are used in food products. However, the use of hydroxyapatite as a food supplement is discouraged [44].

If your diet does not provide a steady supply of calcium, your body can not continuously remove or replace the old or damaged bone with new bone. Calcium phosphate contains a smaller amount of calcium than other types of common and economical supplementations for calcium, like calcium carbonate and calcium citrate. However, dicalcium and tricalcium phosphates have higher amounts of calcium. Tricalcium phosphate has about the same amount of calcium per dose as calcium carbonate, and it is used as a nutritional supplement naturally found in cow milk [44, 45]. Hence, the nanoparticles of calcium phosphate embedded within hydrogels can be a good choice for stimulating bone growth.

4.5 Wollastonite

Wollastonite (CaSiO₃) is a calcium silicate that has been used as a filler to improve the mechanical properties of different composites. It has good bioactivity and biocompatibility, which makes it a potential material for artificial bones and dental roots [46]. In vitro experiments show that a hyroxyapatite surface layer with pH, temperature and ion concentration of human blood plasma is formed upon the exposure of wollastonite to SBF. This finding opens up a wide field for applications of wollastonite as an artificial material that can be used as bioactive bone substitute. Reinforced nanocomposite hydrogels can be obtained by combining these inorganic bioactive nanoparticles with natural or synthetic polymeric hydrogels [47].

5.1 Anti-microbial effect of metallic nanoparticles

Metals like copper and silver can be used as antimicrobial agents, because they are toxic to bacteria and are also stable under physiological conditions. Polymer/metal nanocomposites can also be made by several routes, such as the in situ synthesis of the nanoparticle within a hydrogel or the direct addition of the metal nanofiller into a hydrogel matrix. This can extend the antimicrobial application of these metals.

The antimicrobial mechanism of these nanocomposites is based on the steps explaining how bacteria disappear in the physiological environment. As shown in Figure 19, the bacteria absorbed on the polymer surface and water with dissolved oxygen diffuse to the polymer matrix from the surrounding medium. Oxygen molecules reach the surface and the corrosion process with the embedded metal nanoparticles occurs. Metal ions are released and reach the composite surface, thus causing damage to the bacteria membrane and are eventually diffused into the bacteria [49].

Figure 19

The antimicrobial mechanism of polymer/metal nanocomposites. Adapted from Ref. [49], Copyright (2015), distributed under the terms of the Creative Commons Attribution license.

Silver nanoparticles are non-toxic antibacterial agents with a poor binding affinity with surfaces. The nucleation and growth of these nanoparticles can occur in free spaces between the crosslinked networks of hydrogels in the swollen position. In fact, these spaces act as a nanoreactor. Recent advances aim to obtain silver nanoparticles in gel networks (Figure 20). Silver nanoparticle size can also influence the antibacterial activity of the hydrogel nanocomposite. The results of the antibacterial activity test towards E. Coli shows that the lower size nanoparticles have better antibacterial activity, because they could come out of the hydrogel network easily and interact with E. Coli (Figure 21). Even if the silver nanoparticles can leave the hydrogel network, they do not show a high antibacterial activity, especially if the size is large [50].

Figure 20

The SEM of (A) Pure hydrogel and (B) silver nanoparticle grown in crosslinked hydrogel network. Reprinted from Ref. [50], Copyright (2006), with permission from Elsevier.

Figure 21

The antibacterial results of the hydrogel/silver nanoparticles; (A–D) dead bacteria zone increases by silver nanoparticle size decrease. Reprinted from Ref. [50], Copyright (2006), with permission from Elsevier.

5.2 Magnetic nanoparticles

The magnetic nanoparticles embedded within a hydrogel network generate heat when subjected to external magnetic fields. Therefore, the temperature of the surrounding matrix reaches above the lower critical solution temperature (LCST) of the polymer and results in a coil-to-globule transition of the polymer chains (Figure 22). Hence, the therapeutic agents or cells embedded within the hydrogel network are released [25]. The magnetic-based nanocomposite hydrogels can remotely interact with the exterior magnetic fields and can thus be used for biosensing, diagnostic and bioactuation applications [2, 51].

Figure 22

The remote controlled pulsatile drug release from a magnetic hydrogel nanocomposite. A schematic of AMF-induced heating, collapse and squeezing effects. Reproduced from Ref. [25] with the permission of The Royal Society of Chemistry.

For the fabrication of monodispersed core-shell hybrid particles with a magnetic core and a biocompatible polymeric shell, the magnetic nanoparticles are fabricated through the co-precipitation technique. Particle surface iss modified with the amine functional groups of (3-aminopropyl) trimethoxysilane (APTMS). Finally, the hydroxypropyle cellulose (HPC), a thermoresponsive polymer, is covalently joined to the amine groups. This is a unique combination between paramagnetic nature of the particles and the thermoresponsive behavior of the cellulose. Such a hybrid system would be a good remote-controlled drug carrier [51].

By seeding the heart cells within 3D porous scaffolds made from biological or synthetic polymers like alginate or poly lactic acid (PLA), the engineered cardiac patches are produced. Thus, the cells inside the scaffold gradually organize into functioning tissues. However, the patch cannot act strongly as a unit due to the poor conductivity of these materials [52].

In an interesting application, gold nanowires are incorporated within alginate scaffolds for treating damaged heart tissues. Alginate is selected because of its extensive use in myocardial regeneration. The electrically resistant pore walls of alginate can be connected through gold nanowires acting as a bridge between cardiac cells. In order to connect with cells on both sides, nanowires must be longer than the average thickness of the alginate pore wall (Figure 23). Compared to pristine alginate, tissues grown on these matrices are thicker and better unified. In addition, the cells contract synchronously when stimulated electrically. Moreover, the resulting nanocomposites have improved the mechanical properties because the nanowires can act as reinforcing agents [52].

Figure 23

(A) The isolated cardiomyocytes are cultured in either pristine alginate or alginate–nanowire composites; cardiac cells (red), alginate pore walls (blue) and gold nanowires (yellow). (B) and (C) Vertical and horizontal cross-sectional images of incorporated nanowires within alginate scaffolds, respectively. The assembled wires were distributed homogeneously within the matrix. Reprinted with the permission of Macmillan Publishers Ltd: [Nature Nanotechnology] Ref. [52], Copyright (2011).

Table 1 shows some important recent works in the field of nanocomposite hydrogels considering the carbonic, polymeric, inorganic and metallic nanoparticle categorization made in this review.