Nanocomposite hydrogels for biomedical applications

Abstract Nanomaterials' unique structures at the nanometer level determine their incredible functions, and based on this, they can be widely used in the field of nanomedicine. However, nanomaterials do possess disadvantages that cannot be ignored, such as burst release, rapid elimination, and poor bioadhesion. Hydrogels are scaffolds with three‐dimensional structures, and they exhibit good biocompatibility and drug release capacity. Hydrogels are also associated with disadvantages for biomedical applications such as poor anti‐tumor capability, weak bioimaging capability, limited responsiveness, and so on. Incorporating nanomaterials into the 3D hydrogel network through physical or chemical covalent action may be an effective method to avoid their disadvantages. In nanocomposite hydrogel systems, multifunctional nanomaterials often work as the function core, giving the hydrogels a variety of properties (such as photo‐thermal conversion, magnetothermal conversion, conductivity, targeting tumor, etc.). While, hydrogels can effectively improve the retention effect of nanomaterials and make the nanoparticles have good plasticity to adapt to various biomedical applications (such as various biosensors). Nanocomposite hydrogel systems have broad application prospects in biomedicine. In this review, we comprehensively summarize and discuss the most recent advances of nanomaterials composite hydrogels in biomedicine, including drug and cell delivery, cancer treatment, tissue regeneration, biosensing, and bioimaging, and we also briefly discussed the current situation of their commoditization in biomedicine.

and so on; 2DM can be divided into single layer and multiple layers (Table 1). Nanomaterials possess many excellent functions due to their nanoscale size and rich structures. The 3D sizes of 0DM do not differ too significantly (length: width: height ≈ 1) (Figure 2a). 1 Over the past few decades, various 0DM have been successfully prepared, such as gold nanoparticles (Au NPs), 34 mesoporous silica nanoparticles (MSNs), 34 silver nanoparticles (Ag NPs), 36 and titanium dioxide (TiO 2 ) nanoparticles. 37 Au NPs, as a kind of precious metal nanoparticles, have rich properties due to their nanostructure: good biosafety, phototherapeutic properties, surface modification, bioimaging, and so on. For example, Au NPs have been used as alternative nanoprobes for live cell imaging by dark field microscopy (DFM). 38 F I G U R E 1 Schematic diagram of the main content of this review. Nanomaterials can be divided into zero-dimensional materials (0DM), onedimensional materials (1DM), and two-dimensional materials (2DM) according to their size, length-diameter ratio, and diameter-thickness ratio. Based on the polymer composition, hydrogels can be distributed into the natural polymer, synthetic polymer, and composite polymer hydrogels. According to the macroscopic phenotype of the composite systems, nanomaterials and hydrogels mainly combined into four composite systems, including nanocomposite hydrogel microneedles (MNs), injectable nanocomposite hydrogels, self-healing nanocomposite hydrogels and bioimaging nanocomposite hydrogels. We reviewed the recent advances and future challenges of the composite systems, which almost involve all areas of biomedicine, including drug and cell delivery, cancer treatment, tissue regeneration, biosensing, and bioimaging 1DM refers to materials possessing a relatively large length-todiameter ratio (Figure 2b), such as nanocrystalline cellulose (CNCs), 62 gold nanowires (Au NWs), 63 carbon nanotubes (CNTs), 3 and so on. 1DM often exhibits a high degree of anisotropy and based on this, it simultaneously exhibits many excellent properties such as extremely high tensile strength and specific responding to temperature and 3-Aminophenylboronic acid, aniline, and polyvinyl alcohol Ultramolecular assembly of hydrogels, dynamic bonds (hydrogen bonding and π-π stacking) Self-healing, 3D scaffold, drug loading capability, electric conduction humidity. 64,65 For example, CNTs, as a new carbon-based nanomaterials containing hollow fibrous structure, have properties of high tensile strength, gas adsorption, high conductivity, and thermal conductivity. Thus, it is commonly used for mechanical and conductive enhancement of macroscopic materials, commonly used in the field of biosensing. 66 2DM refer to materials that possess a relatively large diameterthickness ratio ( Figure 2C) such as graphene, 61,67,68 reduced graphene oxide (rGO), 69 graphene oxide (GO), 39,40 phosphorene, 44,70,71 MXene, 48

| RECENT ADVANCES IN HYDROGELS
According to the polymer composition, hydrogels can be distributed into the natural polymer, synthetic polymer, and composite polymer hydrogels (Table 1). Natural polymer hydrogels exhibit good biocompatibility and biodegradability, and hence they possess very promising application potentials in biomedicine. For example, researchers have used chitosan and β-glycerophosphate to prepare an injectable thermosensitive hydrogel (Figure 2d). 52 Dextran and cellulose, as typical nonionic natural polysaccharide hydrogels, usually need to be combined with cells or nano drugs to meet specific requirements. 45,97 Sodium alginate is sensitive to Ca 2+ and has good biocompatibility. It can load cells or nano drugs for human body. 53 Synthetic components also possess excellent properties and are easy to design and modify, and they also play an indispensable part in the construction of hydrogels. For example, researchers have used poly(caprolactone)-poly (ethyleneglycol)-poly(caprolactone) to develop an injectable thermosensitive hydrogel (Figure 2e). 54 Poly(acrylamide-co-maleic anhydride) (P(AM-co-MAH)) hydrogel is self-healing because of rich hydrogen bonds, and polymethyl vinyl ether-salt-maleic acid hydrogel possesses large swelling capacity due to the hydrophilic group ( COOH). 55,56 For practical applications, hydrogels are often required to simultaneously possess many properties such as good biocompatibility, biodegradability, proper hydrophilic, good mechanical properties, and special functional groups. However, many natural polymers or synthetic polymers cannot meet the above requirements alone.  Figure 2f). 57 The designed composite hydrogel can simultaneously possess the excellent properties of natural or synthetic polymers to achieve synergistic complementarity. 98 Hydrogels that are able to intelligently respond to environmental changes (such as heat, pH, light, and ultrasound) can be designed by introducing relevant functional groups to achieve in situ gelation and controlled drug release. 99 For example, groups with double bonds can be grafted onto dextran by transesterification. When exposed to UV light, double bonds can be polymerized to form photo-sensitive hydrogels. 100 It is also possible to design self-healing hydrogels by introducing dynamic cross-linking. 98 For example, the hydrogel that based on 3-aminophenylboronic acid, aniline, and polyvinyl alcohol, has strong self-healing ability because of the dynamic cross-linking (hydrogen bonding and π-π stacking). 101

| RECENT ADVANCES OF NANOCOMPOSITE HYDROGELS IN BIOMEDICAL ENGINEERING
Nanomaterials have successfully demonstrated their huge application potential in nanomedicine by virtue of their various distinctive physical and chemical characteristics. 15,42,45 For example, Au NPs have good catalytic activity, photothermal conversion performance, biological imaging performance, and electrical conductivity. 38 However, they do exhibit some shortcomings that inevitably hinder their application effect and practicality (such as burst release, rapid removal, poor biological adhesion, and irreversible deformation). 19

| Recent advances of nanocomposite hydrogel microneedle patches
MN technology has the advantages of painlessness, low invasiveness, low infectivity, and it is an ideal transdermal method. 102 The length of MNs is usually no more than 1 mm, which is much smaller than the traditional metal injection needles (the length of the traditional metal injection needles is not less than 4 mm). 103

| Recent advances of injectable nanocomposite hydrogels
Injectable nanocomposite hydrogels can be prepared by adding nanomaterials to injectable hydrogels. Nanomaterials can adjust the structures and properties of hydrogels at the nano level and can also expand the functions of the system (such as PTT and PDT). Injectable hydrogels can effectively improve the retention effect of nanomaterials and make the composite systems have good plasticity to adapt to various biomedical application. 113 One of the outstanding advantages of injectable nanocomposite hydrogels is that they can almost adapt and fill any application place (such as various of wounds).
In injectable systems, nanomaterials generally blend with hydrogels through physical action. and gene therapy. 24,114 Tumor PTT based on nanomaterials has become a popular anti-tumor method in recent years. 42,47 According to different light-mass interaction mechanisms in optical radiation, the photothermal conversion mechanism can be divided into two types stemming from nanomaterials, including nano metallic materials based on local plasmon heating and nano semiconductor materials with nonradiation relaxation. 115 Both mechanisms can perform effective light-to-heat conversion. The photothermal mechanism of nano metal materials primarily involves the generation of thermal electrons under light radiation and the final photothermal conversion. Such nanomaterials include classic precious metal nanomaterials (such as Au NPs and Ag NPs) and emerging two-dimensional plasmon materials (such as MXenes). 115 The photothermal mechanism of nanosemiconductor materials primarily involves electron diffusion under light radiation and composite carriers. 116 The 2D BP is an example of these materials. The anti-tumor effect of PTT is related to the photothermal conversion efficiency of nanomaterials. 117  produce a 42 C high temperature and hypertoxic active oxygen in response to magnetic field to achieve anti-tumor ( Figure 5c). 119 Tumor immunotherapy based on injectable nanocomposite hydrogels also exhibits very good potential. 122  Nanoparticles integrate the anticancer drug DOX and arginine-rich molecules to achieve both chemotherapy and immunotherapy. 124 128 Additionally, myocardial infarction can cause myocardial ischemia and based on this, pro-vascularization is necessary during treatment. 129 (Figure 6d).
The 2D BP produces local heat (PTT) and ROS (PDT) under NIR, which cannot only remove hyperplastic synovial tissue but also stimulate the regeneration of cartilage injury. Concurrently, the degradation products of BP can provide sufficient raw materials for osteogenic differentiation. 133

| Skin tissue engineering
Skin damage is often accompanied by bacterial infections that cause secondary wound deterioration. 40 The shape and depth of the skin wounds are often irregular, and it is difficult to fully fit the wound even after cutting the gels. nanoparticles into a chitosan matrix to develop an injectable temperature-sensitive nanocomposite hydrogel. The gel cannot only promote the regeneration of skin tissue but can also mimic the effects of PTT and PDT to effectively inhibit skin tumors (Table 2). 37

| Recent advances of self-healing nanocomposite hydrogels
Self-healing hydrogel means that the material can repair properties to their original state after being damaged, which could prolong the lifespan of the material and reduce its unreliability. 106 Referring to the self-healing mechanism, the self-healing behavior is mainly induced by the reversible interaction of the hydrogel itself (dynamic chemical bonds and noncovalent interactions). 101,145 There are many dynamic chemical bonds, such as C N bond (acyl hydrazone bond and imide bond), B O bond (phenyl borate), C C/C S bond (reversible radical reaction), Schiff base bond and disulfide bond. There are also many dynamic noncovalent interactions, such as multiple hydrogen bond interaction, π-π stacking, ion interaction (metal coordination), hostguest interaction, and hydrophobic interaction. 58,101,106,145 In recent years, self-healing hydrogels have exhibited great potential to become brittle hydrogel substitutes based on their durability and long-term stability. 106 However, depending on their intended use, self-healing hydrogels also must include a variety of properties such as electrical conductivity, photosensitivity, adhesion, and appropriate mechanical strength. Nanomaterials are small and possess various characteristics such as conductivity, light sensitivity, and pH response. 16,146 Therefore, a promising method is to incorporate nanomaterials into selfhealing hydrogels to develop nanocomposite hydrogels possessing multiple functions and self-healing ability. Due to the interaction of polymer-nanomaterials (such as charge interaction, hydrogen bond and hydrophobic interaction), nanomaterials can also enhance the self-healing ability of hydrogels. 106 Self-healing nanocomposite hydrogels exhibit huge application potential in controlled drugs release, electronic skin, and biosensing. 147

| Controlled drugs release
Self-healing nanocomposite hydrogels can control the release of medicines through dynamic networks on/off. 148  hydrophilic copolymer that can rapidly gel at physiological pH. 150 The hydrogel not only has self-healing ability, but also shows multiresponsiveness to pH, glucose, H 2 O 2 , and temperature. The hydrogel system has huge potential for controlled drugs release.

| Bionic electronic skin
The materials used to prepare the electronic skin must possess good toughness, self-healing properties, and electrical conductivity to allow

| Glucose sensor
Blood glucose monitoring is very necessary for diabetic patients. Then, CeO 2 /MnO 2 nanoparticles loaded with GOx were connected to the gel through covalent action to serve as an electrocatalysis medium ( Figure 9a). 57 An additional covering agent was concurrently applied to the hydrogel to av CeO 2 /MnO 2 NPs run-off. The gel was then covalently bonded to a flexible chip to form a flexible glucose sensor. Since the CeO 2 /MnO 2 NPs act as electrocatalytic medium, the sensor exhibits a rapid and sensitive response to glucose (t < 3 s). Due to the reversible Schiff base bond between quaternized chitosan and oxidized dextran, the hydrogel exhibits strong self-repair properties that allow the sensor to adapt to various deformations and damage. The hydrophilic polymer network and self-healing function greatly improve the sensitivity and service life of the glucose sensor, and the sensor can even work continuously for more than 30 days in vitro. In addition, study has been successfully examining glucose in oral saliva by nanocomposite hydrogel combined with GOx. 154 These studies show that nanocomposite hydrogels combined with GOx has great potential in noninvasive detection of glucose.

| Strain sensor
Any hydrogel used as a skin strain sensor must possess good toughness, conductivity, and self-repair ability to allow for long service life and good electrical signal transmission ability under external stress. 155  various motions in real-time. 153 Moreover, the hydrogel system can also promote angiogenesis, accelerate collagen deposition, anti-infection, so as to repair diabetic wounds. The developed nanocomposite hydrogel combines the functions of tissue regeneration and biosensing, and it can likely achieve dynamic monitoring of human movement while repairing diabetic wounds.

| Recent advances in bioimaging nanocomposite hydrogels
Common imaging methods in the biomedical field include magnetic resonance (MRI), photoacoustic (PAI), and fluorescence imaging (FLI).
Combining nanomaterials with imaging functions and hydrogels with good biocompatibility to obtain bioimaging nanocomposite hydrogels. 14  quickly. 170 The safety of nanomaterials is mainly related to the material itself (such as element composition, nano size, surface charge).
Among them, the size of nanomaterials is a factor affecting their biosafety and properties. For example, 10 nm Au NPs absorb green light and thus appear red. The melting temperature decreases dramatically as the size goes down. Moreover, 2-3 nm Au NPs are excellent catalysts, which also exhibit considerable magnetism. At this size, they are still metallic, but smaller ones turn into insulators. Their equilibrium structure changes to icosahedral symmetry, or they are even hollow or planar, depending on size. 171 Therefore, in commercialization, it is also very important to select the appropriate size and ensure good size uniformity of nanomaterials. In addition, deep application in vivo usually requires higher safety than superficial application. The deeper the application depth of the product, the easier it is to contact the human blood circulation system and central nervous system, the higher the safety requirements of the product. 172 Nanocomposite hydrogels also tend to be complex systems even when applied to shallow surfaces, which require high safety.
Biomedical products mainly contain medical devices and new drugs. Medical devices can be divided into Class I, II, and III according to the use risk of products from small to large. 173  and high cost of R&D, production, and approval, but also comes from the difficulties in the production and material design of nanomaterials and hydrogels themselves.
Compared with in vivo applications, in vitro biomedical applications (biosensors, artificial skin, and biological actuators) pay more attention to the functionality and stability of the composite systems.
This puts forward higher requirements for the material design and manufacture of nanomaterials and hydrogels. For in vitro applications, nanomaterials act more as the sensing core, endowing the composite system with electrical conductivity, being able to sense various small changes in the surrounding environment (temperature, stress, light, and substance concentration) and convert them into electrical signals. 57,156 Nanomaterials need to perform signal conversion repeatedly in this process, which puts forward higher requirements on the functionality and stability of nanomaterials. Therefore, in material designs, nanomaterials need to consider the good homogeneity, appropriate size, micromorphology, and surface chemical modification.
In vitro applications also place extremely high requirements on the environmental tolerance of hydrogels. The hydrogels mainly determine the macroscopic phenotype of the composite systems. In vitro applications require hydrogels to withstand extreme temperatures, maintain humidity, wear resistance, strong flexibility, viscosity, degradation resistance, and appropriate swelling rate. In addition, the hydrogels must also have good retention of nanomaterials. 49,57 In designing, hydrogels often consider suitable polymer molecular weight, directional chemical modification, multicomponent combination, and so on. Manufacturing is also very important for product transformation. In the manufacturing process, it is necessary to control the cost of products, such as production capacity, input/output ratio, qualified product ratio, automation degree, and so on. At present, a trend is to expand the in vivo functions of in vitro products, such as integrating skin repair functions on biosensors. 153 However, this puts forward higher safety requirements for the composite system and brings difficulties to the design and preparation of materials.

DATA AVAILABILITY STATEMENT
Data sharing not applicable to this article as no datasets were generated or analysed during the current study.