Materials engineering, processing, and device application of hydrogel nanocomposites

Hydrogels are widely implemented as key materials in various biomedical applications owing to their soft, flexible, hydrophilic, and quasi-solid nature. Recently, however, new material properties over those of bare hydrogels have been sought for novel applications. Accordingly, hydrogel nanocomposites, i.e., hydrogels converged with nanomaterials, have been proposed for the functional transformation of conventional hydrogels. The incorporation of suitable nanomaterials into the hydrogel matrix allows the hydrogel nanocomposite to exhibit multi-functionality in addition to the biocompatible feature of the original hydrogel. Therefore, various hydrogel composites with nanomaterials, including nanoparticles, nanowires, and nanosheets, have been developed for diverse purposes, such as catalysis, environmental purification, bio-imaging, sensing, and controlled drug delivery. Furthermore, novel technologies for the patterning of such hydrogel nanocomposites into desired shapes have been developed. The combination of such material engineering and processing technologies has enabled the hydrogel nanocomposite to become a key soft component of electronic, electrochemical, and biomedical devices. We herein review the recent research trend in the field of hydrogel nanocomposites, particularly focusing on materials engineering, processing, and device applications. Furthermore, the conclusions are presented with the scope of future research outlook, which also includes the current technical limitations.

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Gi Doo Cha

Gi Doo Cha received his B.S. (2016) from the School of Chemical and Biological Engineering at Seoul National University. Under the supervision of Prof. Dae-Hyeong Kim, he is working on the synthesis and application of bioresorbable electronics and hydrogel nanocomposites.

Wang Hee Lee

Wang Hee Lee received his B.S. (2018) from the School of Chemical and Biological Engineering at Seoul National University. Under the supervision of Prof. Dae-Hyeong Kim, he is working on the application of hydrogel nanocomposites and fabrication of electronics for the cell culture platform.

Moon Kee Choi

Moon Kee Choi received her B.S. (2010) from the School of Chemical and Biological Engineering at Seoul National University. She obtained her Ph.D. (2016) from the Department of Chemical and Biological Engineering at the Seoul National University. Since she joined the faculty of the School of Materials Science and Engineering at Ulsan National Institute of Science and Technology in 2019, she has focused on the synthesis and applications of nanomaterials and soft optoelectronics.

Dae-Hyeong Kim

Dae-Hyeong Kim received his B.S. (2000) and M.S. (2002) degrees from the School of Chemical Engineering at Seoul National University. He obtained his Ph.D. (2009) from the Department of Materials Science and Engineering at the University of Illinois at Urbana-Champaign. Since he joined the faculty of the School of Chemical and Biological Engineering at Seoul National University in 2011, he has focused on stretchable electronics for bio-medical and energy applications.

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1. Introduction

Hydrogels consist of three-dimensional (3D) crosslinked hydrophilic polymer networks with remarkable characteristics such as softness, deformability, and biocompatibility.^1,2 These features allow for the use of hydrogels as key materials in various applications, including tissue engineering,^3,4 contact lenses,⁵ wound dressing,^6,7 drug delivery,⁸ and artificial muscles,⁹ wherein they are directly interfaced with the human body. However, conventional hydrogels have several limitations with respect to material performances, particularly in recent novel device applications such as bioelectronics,^10,11 optoelectronics,^12–14 energy devices,^15,16 and memory devices.^17,18 Therefore, the modification of the backbone polymer has been extensively studied to impart hydrogels with new functions^19,20 and enhance their properties.^21,22 Despite many advances, the challenges for the enhancement of the material performance persist for the chemical alteration of the hydrogel in such an approach. In many cases, attempts to improve a specific property of the hydrogel by modifying the backbone polymer structure cause a trade-off among the other material properties (i.e., reduced performance in other material properties).²³

As an alternative approach to enhance the performance of a hydrogel and to diversify its functions, various nanomaterials have been incorporated into the hydrogel media, i.e., hydrogel nanocomposites (Fig. 1a and 1b).^24–26 This approach can yield hydrogels with improved mechanical/optical/electrical/magnetic/enzymatic properties.^27,28 The nanomaterials encapsulated in the hydrogel matrix hardly affect the native properties of the 3D macromolecular network of the hydrophilic polymer chains due to their nanoscale dimensions. Consequently, the hydrogel nanocomposite can exhibit new material performances and functions stemming from the incorporated nanomaterials, while the intrinsic nature of the pristine hydrogel is still largely maintained.^29–31 In addition, the incorporation of nanomaterials into the hydrogel matrix facilitates the long-term dispersion of the nanomaterials and mitigates potential issues with respect to nanomaterial toxicity.^29,32,33 Therefore, various nanomaterials ranging from zero-dimensional (0D) nanoparticles to two-dimensional (2D) nanosheets³⁴ have been incorporated into hydrogel matrices. This incorporation of nanomaterials results in various novel material properties, such as remarkable mechanical properties, high conductance, stimuli-responsiveness, facile signal detection ability, and catalytic activity (Fig. 1c).

Fig. 1 Schematic illustration of materials engineering, processing, and device application of hydrogel nanocomposites. The incorporation of (a) nanomaterials into (b) the hydrogels leads to (c) the hydrogel nanocomposites, which exhibit various characteristics such as mechanical enhancement, conductance, stimuli-responsiveness, and facile catalysis. Combined with (d) patterning technologies, which are classified as top-down and bottom-up methods, hydrogel nanocomposites can be applied as (e) sensors, actuators, energy devices, and tissue engineering scaffolds, in a mechanically soft form. (c) Mechanical enhancement, reprinted with permission.¹⁶⁵ Copyright 2019, Wiley-VCH. (e) Sensor, reprinted with permission.¹⁴² Copyright 2019, American Chemical Society.

Despite the advantages of the hydrogel nanocomposite, few types of hydrogel nanocomposites have been used for industrial and commercial applications, particularly for device applications, due to the lack of processing technologies. The soft and hydrophilic nature of the hydrogels limits the direct application of conventional photolithography to hydrogel composites. Therefore, novel patterning techniques have been extensively researched. The patterning techniques applicable to hydrogel nanocomposites have several requirements. First, patterning techniques should not involve harsh processing conditions, such as excessive heat and highly reactive chemicals that can cause the failure of the hydrogel network or filler materials. Second, the patterning resolution desired for the device fabrication needs to be accomplished.^35,36 Several patterning technologies, which are classified as top-down (e.g., photolithography,³⁷ laser cutting,²⁵ and viscoelastic lithography³⁸) and bottom-up (e.g., selective gelation³⁹ and 3D printing^40,41) approaches, have been reported for processing the hydrogel nanocomposites into desired shapes (Fig. 1d).^42,43

Owing to the recent advances in patterning technologies customized for hydrogels, the hydrogel nanocomposites can be patterned into desired shapes and be applied to various applications requiring high-resolution patterns of complex geometries.²⁸ Consequently, patterned hydrogel nanocomposites have been spotlighted for their potential as active layers of the electronic, electrochemical, and biomedical devices, including sensors,⁴⁴ actuators,⁴⁵ energy devices,²⁵ and tissue engineering scaffolds^46–48 (Fig. 1e). In particular, the soft, physically transformable, and biocompatible characteristics of the patterned hydrogel nanocomposites, which are not exhibited by conventional electronic materials, allow for the development of next-generation flexible and stretchable electrical/electrochemical devices with unconventional functions and performance.⁴⁹

This article reviews the recent research trend of the hydrogel nanocomposites, particularly focusing on materials engineering and properties (Fig. 1a–c), processing (Fig. 1d), and device applications (Fig. 1e). First, novel material designs and the resulting unconventional performances of the hydrogel nanocomposites (e.g., excellent mechanical properties, high conductance, stimuli-responsiveness, and facile catalysis) are presented with respect to the dimensions of the filler nanomaterials. Representative top-down and bottom-up technologies for the patterning of hydrogel nanocomposites are then briefly summarized. After that, recent research achievements regarding advanced device applications of the patterned hydrogel nanocomposites are presented. Thereafter, the conclusions are presented, including the current challenges and the future outlook.

2. Materials engineering of hydrogel nanocomposites

There have been many attempts towards the incorporation of diverse nanomaterials into hydrogel networks for increased hydrogel functionality while maintaining the intrinsic material properties such as softness and deformability. The selection of the appropriately-shaped and functionalized filler nanomaterials (e.g., dots, rods, wires, fibers, and sheets) is a key factor in achieving the target performance and function of the hydrogel nanocomposite for the desired application. Hence, representative materials engineering approaches for the fabrication of hydrogel nanocomposites are proposed, which are classified according to the dimensions of the nanofillers, i.e., 0D, one-dimension (1D), or 2D.

2.1. Hydrogel nanocomposites based on 0D nanomaterials

Hydrogel nanocomposites that incorporate 0D nanoparticles (NPs) have received more attention than hydrogel nanocomposites based on nanomaterials with other shapes and dimensions. NPs have features of small size but large surface area simultaneously, making them suitable for the formation of stable and highly functional nanocomposites without significant structural breakdown of the hydrogel polymer networks.²⁹ In addition, NPs, in comparison with nanomaterials of other dimensions, have an advantage in terms of the diverse material choices such as metal, semiconductor, oxide, and polymeric NPs, due to their relatively facile synthesis.^50–52 Thanks to these diverse types of NP-based filler materials,^53,54 the functional hydrogel nanocomposites based on 0D nanomaterials have exhibited rapid developments with regard to various unconventional material properties and performances.

One representative research direction is the improvement of the mechanical properties of the original hydrogel using the nanoparticle fillers.^55,56 Based on the non-covalent interaction between the NPs and the backbone polymer chains (hydroxypropylmethylcellulose derivatives, HPMC-x; Fig. 2a left), for example, hydrogel nanocomposites can exhibit shear-thinning and self-healing properties (Fig. 2a right).²⁶ Due to the dynamic and reversible features of the interaction, the nanocomposites can be easily deformed under the external strain and be restored to their original state after the release of the applied force. Based on a similar principle, the composite that consists of Ag-lignin NPs, a polyacrylic acid/pectin hydrogel, and an ammonium persulfate additive achieved tough, stretchable, and adhesive properties (Fig. 2b).⁵³ In particular, the interactions between the hydrogel network and NPs resulted in remarkable mechanical properties, whereas the dynamic catechol redox conditions caused by the Ag-lignin NPs were found to sustain the long-term adhesion properties of the nanocomposites (Fig. 2c).

Fig. 2 Hydrogel composites based on 0D nanomaterials. (a) Material design of the composite (left) and its rheological response to the external strain (right). (b) Material design, molecular interaction mechanism of the composite and (c) changes in adhesion strength during the cyclic adhesion test. (d) Material design of the light-responsive composite and (e) its drug release behavior in response to NIR irradiation. (f) Schematic illustration (top), optical image (bottom), and (g) change in the curvature of the composite-film bilayer device in response to NIR irradiation. (h) Material design of the catalytic composite and (i) its ultrasound sensing activity of tumors on the rabbit liver versus the time after intravenous injection. (j) Material design of the composite and (k) and catalytic activity measured through the absorbance change at 400 nm. (a) Reprinted with permission.²⁶ Copyright 2015, Nature Publishing Group. (b and c) Reprinted with permission.⁵³ Copyright 2019, Nature Publishing Group. (d and e) Reprinted with permission.⁶⁰ Copyright 2017, American Chemical Society. (f and g) Reprinted with permission.⁶¹ Copyright 2017, Wiley-VCH. (h and i) Reprinted with permission.⁶⁴ Copyright 2015, American Chemical Society. (j and k) Reprinted with permission.⁶⁵ Copyright 2015, The Royal Society of Chemistry.

In addition to their application for mechanical reinforcement, the hydrogel nanocomposites have been studied as potential reservoirs for hydrophobic materials. The hydrogel facilitates the sustained drug release by physically incorporating the drugs into the hydrogel network, but it cannot store a high concentration of hydrophobic drugs.⁸ Hydrogel nanocomposites have been proposed as a feasible solution for this issue because hydrophobic drugs can be loaded within filler NPs.^57,58 Furthermore, depending on the type of incorporated NP, the hydrogel NP composite can exhibit targetability and stimuli-responsiveness, which are useful for drug delivery.^59,60 For example, Wang et al. reported a NIR-responsive hydrogel nanocomposite, which consists of a polyethylene glycol hydrogel cross-linked with polydopamine NPs (PDANPs), for the on-demand drug delivery (Fig. 2d).⁶⁰ The PDANPs retain the drugs through the molecular interaction between NPs and drugs in the normal state. The PDANPs generate heat under NIR irradiation, and the loaded drugs (SN38, anticancer agent) can be released in proportion to NIR irradiation with excellent on–off controllability (Fig. 2e).

The stimuli-responsive hydrogel nanocomposites can also be applied to soft robotics.^61–63 For example, Shi et al. proposed a bilayer of the composite film, poly(n-isopropylacrylamide) (PNIPAM) hydrogel/Au NPs and a polyacrylamide film, for soft robotics (Fig. 2f).⁶¹ The Au NPs in the composite film generate heat in response to NIR irradiation, which results in the shrinkage of the PNIPAM hydrogel layer, whereas the polyacrylamide layer is inert to NIR irradiation. This mismatch of the thermal expansion between two adjacent layers results in bending of the entire film (Fig. 2h and 2g), whose properties can be employed as soft actuators in combination with a customized patterning technique.

Moreover, the hydrogel–NP composites have been widely implemented in imaging⁶⁴ and catalysis.^65,66 The dual-enzyme-loaded hybrid composite, which is composed of two types of enzymes (catalase and superoxide dismutase), iron-oxide NPs, and a backbone hydrogel polymer, was reported for ultrasound and magnetic resonance imaging applications (Fig. 2h).⁶⁴ Such a composite amplifies the signal intensity of ultrasound imaging due to the oxygen bubble generation originating from the enzymatic reaction of the dual enzymes within the hydrogel composite (Fig. 2i). In addition, the iron oxide NPs conjugated to the backbone polymers of the hydrogel increase the T₂ signal contrast significantly in comparison to the control group. This demonstrates the potential of the hydrogel composite for use as the soft contrast agent in ultrasound and magnetic resonance imaging applications.

The catalytic activity of NPs can be enhanced when they are incorporated into the hydrogel matrix, given that the porous structure of the hydrogel facilitates the dispersion of catalytic NPs and the diffusion of reactants, which allows for facile catalytic reactions and enables various reaction pathways.⁶⁶ The Ag NPs embedded in polyacrylamide/than in acid hydrogel were investigated for application as a soft catalytic nanocomposite (Fig. 2j).⁶⁵ The charged hydrogel backbone polymer, namely, poly(aspartic acid), facilitates the homogeneous diffusion of Ag⁺ into the hydrogel matrix due to the electrostatic interactions between the hydrogel chains and ions (Fig. 2j). Thereafter, the synthesis of the nanocomposites is carried out through the in situ reduction reaction that transforms Ag⁺ into Ag NPs. The hydrogel nanocomposite exhibits efficient catalytic reduction of 4-nitrophenol, which was confirmed by the absorbance peak change of the reactant (Fig. 2k).

In addition to the examples introduced above, hydrogel nanoparticle composites have been developed to serve other functions, such as antibacterial activity,⁶⁷ tissue repair,⁶⁸ and cell adhesion.⁶⁹ This versatility of hydrogel nanoparticle composites is due largely to the diversity of incorporated NPs. However, for some functions, e.g., conductivity, hydrogel nanoparticle composites exhibit limited performance;⁷⁰ therefore, hydrogel nanocomposites that incorporate nanomaterials of other dimensions have been studied.

2.2. Hydrogel nanocomposites based on 1D nanomaterials

Nanomaterials grown with one orientation such as nanotubes (NTs),^71,72 nanowires (NWs),⁷³ and nanofibers (NFs)⁷⁴ are regarded as 1D nanomaterials. The percolated networks of 1D nanomaterials generally exhibit superior carrier transport capability (i.e., high electrical conductivity) in comparison to those of nanomaterials with other dimensions (i.e., 0D or 2D nanomaterials).^75,76 Moreover, they can maintain high conductivity even under mechanical deformations, given that the contact between 1D nanomaterials can be appropriately sustained under such conditions.^77–79 The unique properties of the percolation networks of 1D nanomaterials significantly increase their applicability to flexible and stretchable electrodes for electronic and electrochemical devices.^80–82

For example, Lim et al. fabricated a stretchable conductive hydrogel nanocomposite using a mixture of an alginate hydrogel and Ag NWs (Fig. 3a).²⁵ The Ca²⁺ treatment allows for the physical cross-linking between alginate hydrogel backbones during the swelling process of the dry hydrogel components while containing the high concentration of the conductive Ag NW fillers. The developed hydrogel nanocomposite is highly conductive, due to the incorporation of the high content of Ag NWs, but also much softer than the conventional rubber materials and/or their composites, due to the lower intrinsic modulus of the hydrogel media than rubbers. With high concentrations of Ag NWs (0.3–0.5 wt%), the hydrogel nanocomposite exhibits stable conducting properties (0.01–0.1 S), even when stretched up to 30% (Fig. 3b).

Fig. 3 Hydrogel composites based on 1D nanomaterials. (a) Material design of the conductive composite and (b) change in resistance at applied strain with respect to incorporated nanowire concentration. (c) Material design, molecular interaction mechanism, exploded view of the composite and (d) changes in resistance versus alternating current frequency. (e) Compressive stress of the composite versus strain and schematic illustration (inset) of its deformation under compression. (f) Schematic illustration for the synthetic process and (g) current response versus compressive strain. The inset shows the optical image of a brighter bulb under pressure. (h) Schematic illustration of the composite integrated with a potentiometric sensor and (i) changes in pH versus glucose concentration. The inset shows the scanning electron microscopy images of hydrogel nanofibers. (j) Encapsulation ratio of enzymes in the composite and (k) relative activity compared with those of free enzymes. (a and b) Reprinted with permission.²⁵ Copyright 2019, AIP Publishing LLC. (c and d) Reprinted with permission.⁸³ Copyright 2018, The Royal Society of Chemistry. (e–g) Reprinted with permission.⁸⁴ Copyright 2017, Wiley-VCH. (h and i) Reprinted with permission.⁴⁴ Copyright 2017, American Chemical Society. (j and k) Reprinted with permission.⁸⁸ Copyright 2016, The Royal Society of Chemistry.

Dai et al. reported a self-healing, conductive, and stretchable hydrogel nanocomposite composed of a conducting Au-CNT film sandwiched between hydrogel layers.⁸³ The hydrogel layers consist of a double network polymer (poly(γ-glutamic) acid and polyacrylic acid) and the iron cation (Fig. 3c top). The electrostatic interaction between the polymer chains and ions (Fig. 3c bottom) allowed for the hydrogel to be stretchable and self-healing. Moreover, when integrated with the Au-CNT film (Fig. 3c top right), the hydrogel nanocomposite exhibits self-healing, stretchable, and conductive properties (Fig. 3d).

Another approach that combines the NFs and the hydrogel has allowed for the fabrication of nanocomposites with shape-memorable and super-elastic properties (Fig. 3e).^84,85 The lyophilization of the uniform mixture of the alginate and SiO₂ NFs forms a cellular-like structure (Fig. 3e inset), which leads to remarkable mechanical properties. After the ionic cross-linking of the alginate (Fig. 3f), the nanocomposite exhibits variable conductivity that is sensitive to external pressures, which confirms its suitability for pressure sensor applications (Fig. 3g).

The hydrogel nanocomposite based on 1D nanomaterials was applied to sensing^86,87 and catalysis.^88,89 For example, a pH-sensitive hydrogel–NF composite was applied to the monitoring of the metabolic activity of the cancer cell.⁴⁴ The hydrogel–NF film was immobilized on the potentiometric sensor, which enhanced the sensitivity by increasing the surface area for the electrochemical reaction (Fig. 3h). The in vitro experimental results of the sensor with tumor cells confirm its detection capacity by the measurement of the pH in accordance with an increase in the glucose concentration, which is due to the increased metabolism of the cancer cells (Fig. 3i).

The application of nanocomposites to catalysis was reported in another study.^88,89 The enzymes encapsulated in the hydrogel–NF composite are more stable with respect to external environmental changes (i.e., changes in pH and temperature) than the free-standing enzymes.⁸⁸ Based on the self-assembly of the hydrogel backbone materials such as zinc ions and adenosine 5′-monophosphate, many negatively charged enzymes can be electrostatically confined into the hydrogel network during the gelation process (Fig. 3j). Therefore, the hydrogel nanocomposite can minimize protein denaturation and maintain the long-term stability of enzymes by the prevention of their exposure to external environments, which is applicable to biological catalyst systems (Fig. 3k).

2.3. Hydrogel nanocomposites based on 2D nanomaterials

Hydrogel nanocomposites based on 2D nanomaterials, e.g., nanosheets (NSs),^90–92 are suitable for applications that exploit their high mechanical deformability, in addition to the other remarkable properties of the original 2D nanomaterials. Therefore, research studies on hydrogel-2D nanomaterial composites were focused on the improvement of the mechanical properties of the composites^93,94 or the exploitation of their deformability for novel applications^24,95 while utilizing the remarkable functions of the 2D materials.

For example, Jing et al. reported that the hydrogel nanocomposite based on hydroxylated boron nitride NSs (OH-BNNS) and the polyvinyl alcohol hydrogel exhibits enhanced mechanical and thermal properties due to the hydrogen bonding between NSs and the hydrogel (Fig. 4a).⁹⁶ The boron nitride NSs are functionalized with the hydroxyl group through the oxidation process (Fig. 4a top), and the strong hydrogen bonding is achieved between OH-BNNS and polyvinyl alcohol chains during the gelation process. Moreover, such characteristics (i.e., enhanced mechanical and thermal properties) are controllable by changing the concentration of NSs (Fig. 4b), which can be optimized depending on the desired applications.

Fig. 4 Hydrogel composites based on 2D nanomaterials. (a) Material design, synthetic process of the composite and (b) its thermal response with respect to nanosheet concentration. (c) Material design, molecular interaction mechanism of the composite, and (d) differences in conductivity difference depending on its components. (e) Synthetic process of the composite and (f) schematic illustration of its thermoresponsive deformation. (g) Optical image of the NIR-responsive bent structure of the actuator (top) and changes in curvature/temperature versus NIR irradiation time (bottom). (h) Schematic illustration of the composite deformation in response to phenol, and (i) volume-change response to various materials. (j) Synthetic process of the doped nanosheet, and (k) Tafel plot of various composites. (a and b) Reprinted with permission.⁹⁶ Copyright 2017, American Chemical Society. (c and d) Reprinted with permission.⁹⁷ Copyright 2016, Wiley-VCH. (e and f) Reprinted with permission.²⁴ Copyright 2015, Nature Publishing Group. (g) Reprinted with permission.⁴⁵ Copyright 2016, The Royal Society of Chemistry. (h and i) Reprinted with permission.¹⁰¹ Copyright 2019, Wiley-VCH. (j and k) Reprinted with permission.¹⁰² Copyright 2017, Elsevier Ltd.

In another study, a hydrogel nanocomposite that exhibits conductive, adhesive, and tough properties was reported,⁹⁷ which is composed of a polydopamine-polyacrylamide hydrogel and graphene oxide NSs (Fig. 4c). The molecular interactions between polydopamine, polyacrylamide, and graphene oxide NSs induce tough mechanical features, whereas the interactions between the catechol groups in the polydopamine chains provide the composite with adhesive and self-healing properties. Due to the trade-off between the mechanical and conductive properties of the composite depending on the degree of reduction of the graphene oxide NSs, the graphene oxide NSs are partially reduced to optimize the conductivity and mechanical strength, with a slightly lower conductivity (0.08 S cm⁻¹) than that in the fully reduced state (0.1 S cm⁻¹, Fig. 4d).

Hydrogel nanocomposites based on 2D nanomaterials have been researched in the field of soft robotics.^40,45,98 For example, a thermo-responsive anisotropic actuator was introduced by incorporating titanate NSs into a hydrogel network.²⁴ During the polymerization of the hydrogel backbone, titanate NSs are arranged in parallel in response to an applied magnetic field (Fig. 4e). When the temperature exceeds the critical temperature, water molecules are released from the hydrogel network, thereby enhancing the electrostatic permittivity (Fig. 4f). This results in an increased repulsion force between the parallel titanate NSs, which causes the anisotropic thermal expansion of the hydrogel nanocomposite. With respect to the photothermal-responsive actuator, the MoS₂ NSs, which can convert light into heat, are incorporated into the hydrogel network (Fig. 4g top).⁴⁵ For the homogeneous dispersion of MoS₂ NSs, they are functionalized with chitosan for the enhancement of the electrostatic interaction between the hydrogel network and NSs. The cruciform actuator composed of the hydrogel and the MoS₂ NSs can, therefore, be successfully fabricated, by demonstrating their deformability in response to the changes in the temperature concomitant of external NIR irradiation (Fig. 4g bottom).

Hydrogel–NS composites have also been researched for the chemical/electrochemical device applications.^99,100 For example, a hydrogel nanocomposite composed of the PNIPAM hydrogel and MoS₂ NSs was proposed for a volumetric phenol detector.¹⁰¹ When the phenol molecules are introduced into the hydrogel nanocomposite, the molecules interact with the functional group of MoS₂ and simultaneously form hydrogen bonds with the backbone polymer. Due to the simultaneous reactions of phenol with the hydrogel backbone polymer and MoS₂ NSs, the volume of the hydrogel decreases (Fig. 4h), and the hydrogel nanocomposite demonstrates a high phenolic-sensitivity (Fig. 4i).

As mentioned in section 2.1, the catalytic activity of nanomaterials can be increased when they are incorporated into a hydrogel network. This can be applied to the case of the hydrogel–NS composites. For example, the hydrogel–nanosheet composites, which are composed of MoS₂ NSs conjugated onto the graphene hydrogel, exhibit excellent electrochemical hydrogen evolution performances.¹⁰² The fillers in the hydrogel nanocomposite are manufactured at the nanometer scale for increased catalytic efficiency (Fig. 4j). In the synthetic process, several carbons in graphene are doped using ammonium hydroxide. Such protonated carbons react with the precursor anions of MoS₂ and serve as the nucleation sites for the MoS₂ crystals. Hence, vertically-aligned MoS₂ NSs with more exposed active edge sites can be synthesized, which results in enhanced electrocatalytic activity by far compared to unmodified ones (Fig. 4k).

3. Patterning techniques for hydrogel nanocomposites

Hydrogel nanocomposites exhibit remarkable material properties and versatile functionalities, however, the development of facile high-resolution patterning techniques is required for advanced device applications. Due to their high water-absorption capacity and permeability, hydrogel nanocomposites are susceptible to severe conditions in the conventional patterning processes¹⁰³ that involve excessive heating, light, and/or harsh chemical conditions.^25,104 To prevent the destruction of the hydrogel network during the patterning process,¹⁰⁵ conventional patterning techniques are modified to realize the desired shapes of the hydrogel nanocomposites while maintaining their original performances. Given that the bottleneck of patterning is the cutting of the polymeric matrix, not filler materials, the patterning technologies can be similarly applied to hydrogels and hydrogel nanocomposites. This section presents a discussion on the recent developments in micro/nano-technologies used for the patterning of hydrogels, which are classified as top-down and bottom-up approaches.

3.1. Top-down approaches for hydrogel patterning

A patterning process that eliminates undesired portions from the original bulk material to achieve micro-/nano-scale structures is considered as a top-down approach, whereas the construction of complex structures from simple and small components is considered as a bottom-up approach.¹⁰⁶ The top-down patterning technique generally includes conventional microfabrication methods such as cutting and milling.^25,107 Representative top-down patterning approaches employed for hydrogel patterning include methods such as photolithography,³⁷ laser-cutting,²⁵ soft-lithography,¹⁰⁸ and viscoelastic lithography.³⁸

Ultraviolet (UV) light based photolithography has been known to be a rapid and high-throughput processing technique among hydrogel patterning techniques.¹⁰⁹ Huang et al. proposed a practical method for the construction of a soft micro-robot by the photolithographic patterning of multiple hydrogel layers. This micro-robot consists of magnetic nanoparticles and a UV-patternable non-swelling hydrogel layer composed of poly(ethylene glycol)diacrylate on a swelling thermo-responsive N-isopropylacrylamide hydrogel layer (Fig. 5a).³⁷ During photolithography, the alignment of the incorporated magnetic nanoparticles within the hydrogel can be controlled by the orientation of the external magnetic field. The shape and deformability of the hydrogel nanocomposite are determined by the differences in the swelling behavior of the multiple patterned hydrogel layers and the changes in the alignment of the incorporated magnetic nanoparticles, respectively. This multi-layered patterning provides the micro-robot with precise and independently controllable deformation, which can serve as a basis for the manufacture of micromachines with desired complex 3D shapes and movement.

Fig. 5 Top-down approaches for hydrogel patterning. (a) Schematic illustration of the photolithography process. (b) Schematic illustration of the laser-cutting method. (c) Schematic illustration of the patterning process including X-ray lithography and soft-lithography. (d) Hepatocytes cultured on nanotopography (top) and confocal microscopy image of its albumin expression (green) on the PEG gel microstructure (bottom left) and heparin gel microstructure with fibroblasts (bottom right). (e) Schematic illustration of a high-aspect-ratio honeycomb structure and (f) its fabrication process from viscoelastic materials on hole patterns (top) and honeycomb array formation after application of vacuum pressure (bottom). (a) Reprinted with permission.³⁷ Copyright 2016, Nature Publishing Group. (b) Reprinted with permission.²⁵ Copyright 2019, AIP Publishing LLC. (c and d) Reprinted with permission.¹⁰⁸ Copyright 2015, American Chemical Society. (e and f) Reprinted with permission.³⁸ Copyright 2016, Nature Publishing Group.

Photolithography is difficult to be applied for the patterning of hydrogels whose composing materials exhibit weak chemical resistance to the solvent used in the photolithography process.¹⁰⁹ As a solution to this issue, a laser-cutting method was introduced.²⁵ The patterning of hydrogels using a well-focused laser light allows for the rapid, simple, and large-scale cutting of hydrogel nanocomposites into desired shapes without altering their electrical and mechanical properties under wet conditions.¹¹⁰ For example, Lim et al. developed electronic and energy devices composed of stretchable and conductive hydrogel nanocomposites that were patterned by laser-cutting (Fig. 5b).²⁵ The laser-cutting method simplifies the processability of highly conductive alginate hydrogel–Ag NW composites into desired shapes, which can be potentially employed in various applications ranging from wearable electronic devices¹¹¹ to energy storage devices.⁸⁰

Although laser-cutting is a simple and practical process, it cannot be used to shape the hydrogels at the nanometer scale.¹¹² X-ray lithography is an effective technique for the nano-scale patterning of various materials, however, the high-energy X-ray can damage the hydrogel network. To overcome this issue, the integration of two complementary patterning methods was proposed for the high-resolution patterning of hydrogels.¹⁰⁸ As shown in Fig. 5c, molds with suitable nano-topographies were fabricated using X-ray lithography, for the high-resolution cell culture platforms. Thereafter, soft lithography was employed for the development of hydrogel cell culture scaffolds to prevent the direct exposure of the hydrogel to the X-rays.¹¹³ As a result, the cell function of the hepatocytes on the hydrogel microstructure was more significant than that achieved using a flat hydrogel, as observed (Fig. 5d).

As mentioned above, the mild processing conditions of soft lithography allow for the preservation of the original properties of the hydrogel network after the patterning process.¹¹⁴ Therefore, the integration of multiple patterning methods, including soft lithography, has been actively investigated for patterning hydrogels into complex structures. For example, an integration strategy was proposed for the fabrication of a hydrogel with a honeycomb structure of the hydrogel with a high aspect ratio (Fig. 5e).³⁸ Jeong et al. proposed viscoelastic lithography integrated with soft lithography for the fabrication of a honeycomb mold that can accommodate numerous cells and drugs. The procedure for viscoelastic lithography is illustrated in Fig. 5f. First, a highly viscous polydimethylsiloxane (HV-PDMS) solution is placed on a mold patterned with holes. It should be noted that the HV-PDMS solution does not seep into the holes due to its high viscosity. Thereafter, spherical bubbles are formed in the HV-PDMS solution under vacuum conditions (Fig. 5f top), and the interaction due to the proximity of the bubbles results in the formation of walls between bubbles with increasing sizes, thus leading to the formation of a compact honeycomb structure (Fig. 5f bottom). The shape and size of the high aspect-ratio honeycomb structures can be simply regulated by changing the applied vacuum pressure and the base mold pattern. Due to the adjustable shapes and sizes of the molds, the hydrogel scaffold patterned by soft lithography can be implemented as a drug delivery reservoir, and for the facilitation of uniform cell spheroid formations without cell loss.

3.2. Bottom-up approaches for hydrogel patterning

Bottom-up patterning approaches such as selective polymerization,¹¹⁵ 3D printing,⁴ and four-dimensional (4D) printing¹¹⁶ have been widely utilized to pattern hydrogel nanocomposites into complex shapes, due to the remarkable advantages such as minimized material loss, low cost, and high production yield which cannot be achieved in the top-down patterning technologies.^117,118 In addition, the hydrogel nanocomposites are not subjected to severe conditions during the bottom-up patterning process; thus, their original mechanical/electrical/optical properties remain unaltered after the patterning process.

Stencil patterning is a simple, rapid, and low-cost bottom-up patterning method for the construction of a large number of identical patterns in a single printing process.¹¹⁵ For example, stencil-mask-aided selective polymerization was employed to obtain complex conductive patterns of a polyion complex/polyaniline hybrid hydrogel (Fig. 6a).³⁹ During the patterning process, the reaction initiator was selectively exposed to aniline monomers in the as-prepared hydrogels through the stencil mask (Fig. 6b), thus inducing the gelation of the precursors into desired shapes. This method is employed in the low-cost high-throughput construction of multi-channel arrays of tough hydrogel-based bioelectronics.

Fig. 6 Bottom-up approaches for hydrogel patterning. (a) Optical image of the patterned hydrogel (b) using a stencil mask for the selective polymerization. (c) Shear-induced alignment of nanofibers (left) and swelling behavior of the hydrogel nanocomposite (right) and (d) flower-like morphological changes during swelling. (e) Schematic illustration of the 4D printing process with ferromagnetic domain input in the hydrogel nanocomposite and (f) simulation/experimental results of 3D architecture transformation response to the external magnetic field. (g) Schematic illustration of the 3D printing process with double nozzles and (h) printed hydrogel nanocomposites with a 2D circular pattern (left) and 60° alternating fan-shaped circular pattern (right). (a and b) Reprinted with permission.³⁹ Copyright 2018, American Chemical Society. (c and d) Reprinted with permission.⁴⁰ Copyright 2016, Nature Publishing Group. (e and f) Reprinted with permission.⁴¹ Copyright 2018, Nature Publishing Group. (g and h) Reprinted with permission.¹²⁸ Copyright 2018, American Chemical Society.

Although selective gelation is a simple method for the formation of multiple hydrogels, it can only be applied to the shaping of simple 2D structures. Hence, hydrogel patterning requires advanced technologies such as 3D printing for the construction of complex structures required in the fields of soft robotics,^119,120 flexible electronics,^121,122 and biomedicine.¹²³ Gladman et al. proposed a biomimetic 3D printing method that accomplishes mesoscale structures with controllable anisotropy through a shear-induced alignment at the nozzle (Fig. 6c).⁴⁰ By harnessing anisotropic swelling, accurate and detailed control can be achieved over the curvature in bilayered structures. This strategy integrated with a biocompatible and flexible hydrogel composite ink achieves the plant-inspired complex 3D structural morphology transformable during swelling (Fig. 6d), which can be applied to biomedical devices,¹²⁴ soft robotics,¹²⁵ and tissue engineering.⁴

To meet the demands for hydrogel patterning technologies that require higher levels of precision and complexity than that of the general 3D printing method, Kim et al. presented a 4D printing technology with programmed ferromagnetic domains in the hydrogel, wherein the iron oxide NP is injected in the desired spatial direction (Fig. 6e).^41,126 The direction of the ferromagnetic domain can be designed differently as per compartment by switching the applied magnetic field during the printing process; thus, the patterned hydrogel composite can be rapidly and reversibly transformed through external magnetic actuation (Fig. 6f). This precise formation of a complex hydrogel structure is useful in various applications with respect to reconfigurable soft electronics and soft robots that require delicate movements.¹²⁷

In addition to the strategies focused on the change in morphologies of the hydrogel, variations in printing hardware have also been proposed for the enhancement of the performance of existing 3D printing techniques.¹²⁸ When two composites with different mechanical properties/responsiveness are injected through different nozzles (Fig. 6g), complex 3D structures can be successfully obtained with high multi-responsiveness characteristics that are sufficient for the material to change its shape as intended under external stimuli (Fig. 6h). Moreover, multiple nozzles can enhance the printing feasibility of complex structures in comparison with that of single nozzles, thus demonstrating their potential use in future applications.¹²⁹

4. Advanced device applications of hydrogel nanocomposites

By virtue of the recent progress in patterning techniques, hydrogel nanocomposite-based devices with complex structures have been developed and utilized in various fields, such as electronic,¹³⁰ electrochemical,¹³¹ and biomedical applications.²⁶ The attainment of the elaborate 3D structures of functional hydrogel nanocomposites while maintaining their original characteristics, such as softness, deformability, and biocompatibility^132,133 enables them to be applied to more extensive applications.¹³⁴ Herein, we present the recent advanced device applications of hydrogel nanocomposites in sensors,¹³⁵ actuators,¹³⁶ energy devices,¹³⁷ and tissue engineering scaffolds.^87,138

4.1. Sensors

Conductive hydrogel nanocomposites have been extensively explored as sensing electrodes in physical,¹³⁹ chemical,¹⁴⁰ electrochemical,¹⁴¹ and electrophysiological¹⁴² sensors. In particular, the softness of the hydrogel nanocomposites has been exploited in biomedical applications, as they can facilitate the correction of mechanical mismatches at the interface between the tissue and sensing electrodes.¹⁴³ In addition, the sensors based on patterned hydrogel nanocomposites can make a more seamless contact to the target tissue, dramatically improving the quality of sensing such as the signal-to-noise ratio of the sensor.² These sensors with an elaborately-patterned structure exhibit higher sensitivity than the unpatterned ones. In this subsection, recent studies on hydrogel nanocomposite-based sensors for biomedical applications are presented.

The most extensively used hydrogel-based sensors are physical sensors for the monitoring of human motion. Fig. 7a presents a motion sensor based on a 3D-printed conductive hydrogel nanocomposite. The nanocomposite consists of a nanostructure of conductive polymers (polypyrroles) inside a tough hydrogel network. The nano-network of polypyrroles confers bulk-state conductivity on the tough hydrogel, thereby the hydrogel nanocomposite exhibits superior mechanical and electrical performance in addition to the electrically self-healing properties. In addition, once a good balance is established between the chemical and physical crosslinking networks, the hydrogel nanocomposite achieves 3D printability without severe degradation of performances. Therefore, the sensor based on the hydrogel nanocomposite shows a highly accurate motion sensing capability, which was demonstrated by the detection of repetitive finger motions with bending angles of 20°, 45°, and 90° (Fig. 7b).¹⁴⁴

Fig. 7 Sensor and actuator applications of hydrogel nanocomposites. (a) Schematic illustration of the 3D-printable hydrogel nanocomposite (top) and optical image of a 3D printed flexible sensor (bottom). (b) Resistance variation of the sensor depending on the bending degree of a finger. (c) Fabrication process of the hydrogel nanocomposite based E-skin (left) and electrocardiogram signals recorded by the commercial electrode and the hydrogel nanocomposite electrode (right). (d) Material design of the hydrogel nanocomposite lens. (e) Electroretinogram signal of the dark-adapted state (top) and light-adapted state (bottom) recorded by the hydrogel nanocomposite lens. (f) Transformation of the hand-shaped actuator in response to NIR irradiation. (g) Temperature-responsive transformation of actuators. (h) Optical time-lapse images of micromachines under magnetic field and (i) their 3D structure change according to the programmed alignment of magnetic nanoparticles. (a and b) Reprinted with permission.¹⁴⁴ Copyright 2017, Wiley-VCH. (c) Reprinted with permission.¹⁴⁵ Copyright 2018, American Chemical Society. (d and e) Reprinted with permission.⁵ Copyright 2019, American Chemical Society. (f) Reprinted with permission.⁶¹ Copyright 2017, Wiley-VCH. (g) Reprinted with permission.¹⁵⁰ Copyright 2016, Wiley-VCH. (h and i) Reprinted with permission.³⁷ Copyright 2016, Nature Publishing Group.

In addition to the physical motion sensor, Jo et al. developed wearable electronic skin (E-skin) that consists of a metallic NW–silk protein hydrogel composite, which is capable of sensing electrochemical and electrophysiological activities.¹⁴⁵ The patterned NW network incorporated into the stretchable silk hydrogel (Fig. 7c left) enhances the sensitivity of the hydrogel nanocomposite to serve as an electrode in biomedical sensors. The ECG measurement of the E-skin shows that its sensing performance is comparable to that of the commercial ECG sensors (Fig. 7c right). Such a soft E-skin device can be widely employed for the monitoring of human health and prevention of diseases.

Hydrogel nanocomposite devices can considerably reduce the mechanical mismatch between biological systems and themselves, thus minimizing the scope of physical damage to tissues and organs.² However, there are several limitations in the application of hydrogel nanocomposite sensors to highly sensitive organs, which include the eye and brain. In a related study, Wei et al. prepared an electronic smart lens by the deposition of a metal-coated nanofiber (NF) and in situ electrochemical deposition of poly(3,4-ethylenedioxythiophene)/poly(styrene sulfonate) (PEDOT/PSS) onto a commercial hydrogel lens (Fig. 7d).⁵ The porosity of the integrated electronic smart lens is sustained by the mesh structure of the NF-based conductor and the selective deposition of PEDOT/PSS employed as an adhesive layer, which is patterned through photolithography. Consequently, the device exhibits suitable characteristics as a lens, such as gas permeability, wettability, and optical transparency, in addition to mechanical compliance and robustness.^5,146 To demonstrate the performance of the device in vivo, the full-field electroretinogram (ERG) measurement was conducted on a rabbit model (Fig. 7e). The experimental results revealed that the ERG response under the dark-adapted conditions (Fig. 7e top) was significantly different from the ERG response under the light-adapted conditions (Fig. 7e bottom). This integration of the hydrogel nanocomposite with a commercial device demonstrates its potential for application in implantable sensors with advanced functionalities and biocompatibility.

4.2. Actuators

Based on the stimuli-responsiveness of nanomaterials and the deformability of hydrogels, hydrogel nanocomposite actuators that reversibly respond to external stimuli have attracted significant attention in the field of soft robotics.^147,148 In particular, using the patterning technologies, the resolution and shape-complexity of hydrogel nanocomposite actuators can be enhanced to the level of commercial products, which is important for the delicate control of the movements of soft robots. Herein, we present a review of representative hydrogel nanocomposite actuators that can respond to diverse external stimuli such as light,¹⁴⁹ heat,¹⁵⁰ and magnetic field.¹⁵¹

In general, photo-responsive hydrogel nanocomposite actuators exhibit high-speed response rates and accurate controllability. For example, a soft actuator is fabricated with a light-controllable hydrogel nanocomposite that comprises N-isopropylacrylamide (NIPAm), AuNPs, and acrylamide. It exhibits rapid and tunable movements, such as finger-like flexing and crawling, which can be regulated by the position, path, and intensity of light irradiation (Fig. 7f).⁶¹ Such a photo-responsive actuator provides a precise spatial transformability, which can be applied to light-controlled drug delivery,¹⁵² cell culturing,¹⁵³ and soft robotics.

Moreover, temperature-responsive hydrogel nanocomposite actuators can be designed in larger and more complex forms, given that heat transfer is not limited by the hydrogel medium and target depth. Thus, size-adjustable actuators with various structures can be fabricated in different forms such as helices, tubes, and coils, which can reversibly change their sizes and shapes in response to changes in temperature (Fig. 7g).¹⁵⁰ As a similar type of stimulus-responsive actuator, a magnetically-controllable micro-machine with a highly complex shape was realized, which can perform multifarious movements reminiscent of swimming (Fig. 7h).³⁷ Huang et al. invented an organism-inspired micromachine with motional characteristics that can be controlled by a programmed magnetic field. Moreover, the final 3D shape of the micromachine can be modulated during the folding process by the alignment of the magnetic NPs embedded in the micromachine (Fig. 7i). This magnetically controllable micromachine can navigate through complex environments, and it is expected to facilitate minimally invasive biomedical/environmental operations.

4.3. Energy devices

Hydrogel nanocomposite-based soft energy devices have the advantage of safety in comparison with conventional lithium-based energy storage devices.¹⁵⁴ With the introduction of patterning technologies, they can exhibit a larger surface area for the electrochemical reactions. We herein present recent research studies on applications of patterned hydrogel nanocomposites to the energy devices including batteries¹⁵⁵ and antennas¹⁵⁶ for wireless power transfer to the battery.

Hydrogel nanocomposites have been spotlighted as a promising material candidate for the electrode of the lithium-ion batteries (LIBs) due to their large active surface area, strain endurance, and internal pathways that facilitate the electron and ion transport.¹⁵⁷ Sun et al. presented a high performance cathode material for LIBs, which is composed of an interconnected structure of Ag NWs, Li₄Ti₅O₁₂ (LTO), and graphene oxide hydrogel (Fig. 8a).¹⁵⁸ The layer-by-layer printing process reduces the portion of electrochemically inactive components in stacked LIBs, thus leading to the enhancement of the areal capacity. Consequently, in cyclic voltammetry analysis, the redox peaks of the rGO-Ag NW-LTO electrodes are less polarized and become sharper than those of the rGO-LTO electrodes (Fig. 8b). This implies that the rGO-Ag NW-LTO electrodes have faster reaction kinetics due to the incorporation of Ag NWs.

Fig. 8 Energy device and tissue engineering scaffold applications of hydrogel nanocomposites. (a) Schematic illustration of the fabrication process for the 3D-printed electrode (top) and charge transfer in the battery (bottom). (b) Cyclic voltammetry for LIBs with rGO-Ag NWs-LTO and rGO-LTO electrodes. (c) Coil-shaped hydrogel nanocomposite antenna and optical image (inset) of its attachment on the skin. (d) S₁₁ peak analysis data under the applied strain of up to 30%. (e) Fabrication process of nanofiber yarn network (NFY-NET)/hydrogel 3D scaffold and confocal microscopy image (bottom right). (f) Percentage of the cells aligned within ± 10° on 3D NFY-NET scaffolds with respect to various aspect-ratios, when compared with that of the 2D scaffold. (g) Schematic illustration for the injection of the cell-laden hydrogel nanocomposite (left) and optical image of the injection process into a star-shaped mold (right). (h) Quantification of the cell area of the hMSCs encapsulated in the hydrogel nanocomposite depending on the culture time before hydrogel stiffening; **p < 0.01. (a and b) Reprinted with permission.¹⁵⁸ Copyright 2020, Elsevier Ltd. (c and d) Reprinted with permission.²⁵ Copyright 2019, AIP Publishing LLC. (e and f) Reprinted with permission.⁴⁶ Copyright 2017, American Chemical Society. (g and h) Reprinted with permission.¹⁷³ Copyright 2017, Wiley-VCH.

To date, various wearable/implantable sensors have been miniaturized^159–162 and integrated with other electronics,^163,164 however, most of the energy devices employed as power supply units in sensors are still composed of large and rigid components.¹⁶⁵ Therefore, significant research attention has been directed toward the manufacture of small and stretchable antennas. The wearable antenna was developed from a patternable nanocomposite combined with a soft stretchable polyacrylamide hydrogel substrate (Fig. 8c).²⁵ The resonance frequency of the developed antenna can be successfully maintained, even when stretched up to 30% due to the high conductivity of the Ag NWs incorporated into the alginate hydrogel and the stress release feature of the soft polyacrylamide substrate. Furthermore, the resonance frequency can be tuned according to the shape of the antenna. The tunable resonance frequency and its stable performance and even mechanical deformations demonstrate its applicability to soft, stretchable, and conductive wearable devices.^137,166

4.4. Tissue engineering scaffolds

Owing to their softness and biocompatibility, hydrogel nanocomposites are excellent candidates as tissue engineering scaffolds.^26,167 The elaborate structure of hydrogel nanocomposites enables the effective control of 3D cellular alignment and elongation.¹⁶⁸ Such advances pave the way for various biomedical applications of hydrogel nanocomposites, including regenerative medicine, drug-screening platforms, and cell culture platforms.^113,169,170 Here, we present the recent research outcomes on the patterned hydrogel nanocomposites for tissue engineering.

Several conductive hydrogel nanocomposites serve as a basis for the development of biomedical scaffolds, especially for neural¹⁷¹ and cardiac¹⁷² cell cultures. For example, networks of conductive nanofiber yarns (NFY-NET) composed of polycaprolactone, silk fibroin, and carbon nanotubes within a methacrylated gelatin hydrogel were reported as 3D hybrid cardiac scaffolds.⁴⁶ The interwoven structure of the conductive NFY-NET mimics the natural cardiac tissue and enables aligned tissue growth, while the hydrogel provides an appropriate environment for cell proliferation (Fig. 8g). Moreover, the scaffold exhibits remarkable biocompatibility due to its soft tissue-friendly interfaces and material composition. Furthermore, the cell growth in the 3D scaffold is accelerated as the shape of the scaffold gets closer to being isotropic, especially even superior to that observed on a 2D scaffold (Fig. 8h). This cardiac-mimic 3D hydrogel scaffold successfully demonstrates the formation of cardiovascular organoids and verifies the potential of the hydrogel nanocomposite in tissue engineering.

In addition to their use in the cell culture scaffolds, the hydrogel nanocomposites can also serve as implantable cell reservoirs. Zhang et al. presented an injectable hydrogel nanocomposite based on bisphosphonate-Mg²⁺ NPs and a hyaluronic acid/polyacrylate hydrogel.¹⁷³ This hydrogel nanocomposite is polymerized via an in situ self-assembly process after UV exposure, and the cells can be effectively encapsulated within the hydrogel network during the gelation process. The hydrogel nanocomposite has injectability, so it can be molded into various desired shapes (Fig. 8 g). This injectable and patternable cell-laden platform shows potential for a customized therapy by providing tailored shapes of the reservoir that fits well onto the morphologies of the target organs. The spread of cells from this 3D scaffold is improved as the culture time before hydrogel stiffening increases, which differs from the trend observed in conventional 2D scaffolds (Fig. 8 h).¹⁷⁴ This indicates a distinct difference between the microenvironments of 2D and 3D cell culture scaffolds, and also implies that the hydrogel nanocomposites can be an effective tool to investigate 3D cellular behavior and biological processes.

5. Conclusions

Hydrogels have been spotlighted as promising materials for various applications due to their softness and biocompatibility, especially in biomedical fields where the conventional rigid materials can cause an unexpected risk and performance deterioration. In addition, the unique deformability and 3D porous network of hydrogels enable their versatile feature when integrated with other materials. However, novel strategies should be developed for the integration of hydrogels with filler materials, considering that the original hydrogel network may be damaged or destroyed upon the incorporation of external materials. Therefore, many approaches have been proposed for the incorporation of nanoscale materials into hydrogels, which have a minimal influence on the original 3D structures of the hydrogels due to their extremely small size. The incorporated nanomaterials can provide the hydrogel nanocomposites with various novel material properties such as mechanical, optical, electrical, and enzymatic properties. Hence, the advanced device applications of the hydrogel nanocomposites have been actively explored with the progress of innovative patterning technologies customized to the hydrogels.

However, owing to many obstacles impeding the realization of hydrogel nanocomposite-based devices without the change in the properties of the hydrogel, very few devices based on hydrogel nanocomposites with substantial levels of performance have been reported. For instance, when nanomaterials and hydrogel polymers are selected for the desired application, a new material engineering method should be developed for the synthesis of homogeneous hydrogel nanocomposites without the deterioration of the properties of the pristine hydrogel. The application of a reported material engineering method to a new combination of hydrogel nanocomposites may not be appropriate because the alteration of a single component results in dynamic changes in the characteristics of the composite, thus the modification in processing technologies is required in detail. Among them, in particular, patterning techniques should be optimized with respect to the pattern resolution and processing conditions.

Even in the case of the reported hydrogel nanocomposite devices, there are many challenges to be addressed to reach the industry level. From a practical point of view, there are potential handling issues due to the intrinsic nature of the hydrogels such as softness and deformability. The long-term stability of the hydrogel nanocomposite is guaranteed, because the nanomaterials can be diffused through the hydrophilic and porous hydrogel network. Moreover, for the clinical applications, the hydrogel nanocomposites require further analyses in a large animal model, whose microenvironment is similar to that of the human body. Such large-scale in vivo experiments may reveal unexpected issues with respect to the performance and biocompatibility of the hydrogel nanocomposites, thus precluding their applicability to humans.

Therefore, the scope of future studies should be focused on the practical advances in the proposed hydrogel nanocomposite-based devices, as well as the development of new hydrogel nanocomposites that can be used to overcome various environmental/biomedical challenges. Despite the hurdles associated with the realization of hydrogel nanocomposite-based devices mentioned above, clear benefits of hydrogel nanocomposites that differentiate them from other conventional types of rigid devices will provide solutions to many current challenges in various fields.

Conflicts of interest

The authors declare no conflicts of interest.

Acknowledgements

G. D. Cha. and W. H. Lee. contributed equally to this work. This work was supported by grants IBS-R006-A1. We acknowledge the support from the Institute of Engineering Research at Seoul National University. The authors acknowledge the 2019 Research Fund (1.190094.01) of UNIST. We acknowledge the support from the National Research Foundation of Korea (NRF) through a grant funded by the Korean government (Grant No. 2019R1F1A1060003).

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Footnote

† These authors contributed equally to this work.

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