Applications of Highly Stretchable and Tough Hydrogels

Stretchable and tough hydrogels have drawn a lot of attention recently. Due to their unique properties, they have great potential in the application in areas such as mechanical sensing, wound healing, and drug delivery. In this review, we will summarize recent developments of stretchable and tough hydrogels in these areas.


Introduction
Due to the high water content and excellent biocompatibilities, hydrogels have been used for wound healing, tissue culture, tissue/cartilage replacement [1], scaffolds for cell growth [2], etc. When combined with electronics, hydrogels have been used to develop a variety of biomedical devices, including sensors [3][4][5][6][7][8][9][10][11][12][13], switchable micro patterns [14], self-oscillators [15], etc. Most hydrogels have relatively low tensile strength and low elasticity, which limits their application capacity in the biomedical field. In order to improve the mechanical properties of hydrogels, highly stretchable and tough hydrogels have been invented recently [16]. These highly stretchable and tough hydrogels generally consist of one or more gel networks of two or more polymer chains crosslinked both chemically (typically via covalent bond) and physically (typically via intermolecular interactions) [17,18]. Recently, we wrote a review on the synthesis and fundamental properties of highly stretchable and tough hydrogels [19]. In this review, we will summarize the applications of the most up-to-date highly stretchable and tough hydrogels for mechanical sensing, drug delivery, and wound dressing. This review is a part II, with a focus on the applications.

Highly Stretchable and Tough Hydrogels for Mechanical Sensing
Mechanical sensors are a class of sensors used to measure the mechanical properties of an object. One major approach of measurement is through piezoresistivity, which is the effect exhibited when there is a change in resistance due to applied pressure. Many of these piezoresistive sensors, also known as strain gauges, were made from a polyester base with wire or metallic foil. These sensors generally have a low stress limit and cannot be readily repaired when damaged. Highly stretchable, tough hydrogels have high stress limits and can self-heal over time. Mechanical hydrogel sensors are wearable, due to the high stress limit that they possess, i.e., their reasonable stretchability. When appraising the use of hydrogels in sensors, one must consider the gauge factor of the gel, the healing time and efficiency, and the mechanical property of hydrogels. 1 2 / , where ε is the strain, L is the change in length, L is the original length, ν is the Poisson's ratio, ρ is the resistivity, R is the change in strain resistance, L is the unstrained resistance.
In 2015, Frutiger et al. [20] developed a soft strain sensor, by modifying a commercially available silicone, that exhibited a high stretchability (up to 700%), however, this elastomer tended to have low gauge factors (0.348 ± 0.11). In 2016, Cai et al. [21] developed a polyvinylalcohol (PVA)-based hydrogel with a single wall carbon nanotube (SWCNT) conductor in an attempt to create a highly stretchable gel with high gauge factor ( Figure 1). The hydrogel exhibited a gauge factor of 0.24 at 100% strain and 1.51 at 1000% strain. The gauge factor was shown to have improved due to the addition of the SWCNT conductor, based on the gauge factors that were recorded of the gel without the SWCNT conductor (0.09 at 100% and 0.53 at 1000%). Wang et al. [22] determined that the gauge factor can be improved with a synthesized hydrogel with polyaniline (PANI) and polyacrylic acid (PAA) in 2018 ( Figure 2). After cutting and healing (a), the hydrogel can hold a ~500 g mass (b). Strain percentage vs. stress over multiple healing cycles showed the gel had a gauge factor of 11.6 for up to 100% strain and 4.7 for strains above 100% (c). The gel showed the combination of PANI and PAA attributes to the high stretchability and conductivity of the gel. Electrical conductivity test showed that the hydrogel healed with a green LED bulb could stretched more than 400% before breaking (d), and the gel can be healed multiple times without losing the conductivity (e). The hydrogel healing process was also discussed (f). Wang et al. [22] determined that the gauge factor can be improved with a synthesized hydrogel with polyaniline (PANI) and polyacrylic acid (PAA) in 2018 ( Figure 2). After cutting and healing (a), the hydrogel can hold a~500 g mass (b). Strain percentage vs. stress over multiple healing cycles showed the gel had a gauge factor of 11.6 for up to 100% strain and 4.7 for strains above 100% (c). The gel showed the combination of PANI and PAA attributes to the high stretchability and conductivity of the gel. Electrical conductivity test showed that the hydrogel healed with a green LED bulb could stretched more than 400% before breaking (d), and the gel can be healed multiple times without losing the conductivity (e). The hydrogel healing process was also discussed (f). At a similar time in 2018, Zhang et al. [23] proposed the use of MXenes in hydrogels to improve the sensor performances ( Figure 3). The PVA/MXene hydrogel demonstrated high stretchability and a high gauge factor. The recorded gauge factor was 25 at 40% strain. The conductive MXene filler increased strain sensitivity and mechanical properties of the PVA gel, due to MXene nanosheets having an abundance of surface functional groups. These functional groups can alter the surfaces to become negatively charged and hydrophilic. At a similar time in 2018, Zhang et al. [23] proposed the use of MXenes in hydrogels to improve the sensor performances ( Figure 3). The PVA/MXene hydrogel demonstrated high stretchability and a high gauge factor. The recorded gauge factor was 25 at 40% strain. The conductive MXene filler increased strain sensitivity and mechanical properties of the PVA gel, due to MXene nanosheets having an abundance of surface functional groups. These functional groups can alter the surfaces to become negatively charged and hydrophilic.

Healing Time and Efficiency
Hydrogel sensors are able to heal from any deformations that occur. This includes the selfhealing of the gel's appearance, electrical recovery, and mechanical recovery. The inability to heal in any of those ways would negatively impact the use of the hydrogel as a sensor.
The PVA/SWCNT hydrogel was able to heal its appearance partially in 30 s and completely within 60 s at room temperature, with no scarring left on the gel. While the gel may have only partially healed, the PVA/SWCNT gel manages an electrical healing time of 3.2 s [21].
Liu et al. [24,25] prepared a PVA-based hydrogel that is self-healing and self-adhesive. They used polydopamine (PDA) to assist in self-healing and adhesiveness, and achieved complete selfhealing in 250 milliseconds under ambient temperature. Similarly, Zhang et al. [26] utilized MXenes to increase the sensitivity of PVA-based hydrogel. The PVA/MXene hydrogel showed an 'instantaneous' healing time. MXenes, having numerous surface functional groups, contributes to the hydrogen bonding found in PVA, which explains the incredible healing time.

Stretchability
If a sensor is to be wearable, it should generally be highly stretchable to ensure comfort for the wearer. Shao et al. [25] formulated an ionic hydrogel based on polyacrylic acid (PAA) and aluminum ions. The gel achieved a fracture strain of 2952%, showing that the gel is ultra-stretchable. The abovementioned PVA/MXenes hydrogels was able to achieve a stretchability of 3400%. Most recently, in 2019, Yang et al. developed a PVA/Borax gel. The biocompatible hydrogel has the ability to stretch up to a strain of 5000%. Table 1 summarizes other hydrogel-based mechanical sensors that have been developed from a variety of groups.

Healing Time and Efficiency
Hydrogel sensors are able to heal from any deformations that occur. This includes the self-healing of the gel's appearance, electrical recovery, and mechanical recovery. The inability to heal in any of those ways would negatively impact the use of the hydrogel as a sensor.
The PVA/SWCNT hydrogel was able to heal its appearance partially in 30 s and completely within 60 s at room temperature, with no scarring left on the gel. While the gel may have only partially healed, the PVA/SWCNT gel manages an electrical healing time of 3.2 s [21].
Liu et al. [24,25] prepared a PVA-based hydrogel that is self-healing and self-adhesive. They used polydopamine (PDA) to assist in self-healing and adhesiveness, and achieved complete self-healing in 250 milliseconds under ambient temperature. Similarly, Zhang et al. [26] utilized MXenes to increase the sensitivity of PVA-based hydrogel. The PVA/MXene hydrogel showed an 'instantaneous' healing time. MXenes, having numerous surface functional groups, contributes to the hydrogen bonding found in PVA, which explains the incredible healing time.

Stretchability
If a sensor is to be wearable, it should generally be highly stretchable to ensure comfort for the wearer. Shao et al. [25] formulated an ionic hydrogel based on polyacrylic acid (PAA) and aluminum ions. The gel achieved a fracture strain of 2952%, showing that the gel is ultra-stretchable. The above-mentioned PVA/MXenes hydrogels was able to achieve a stretchability of 3400%. Most recently, in 2019, Yang et al. developed a PVA/Borax gel. The biocompatible hydrogel has the ability to stretch up to a strain of 5000%. Table 1 summarizes other hydrogel-based mechanical sensors that have been developed from a variety of groups.

Highly Stretchable and Tough Hydrogels for Wound Healing
Although hydrogels are already being utilized for wound healing, many of these commercial hydrogels have flaws. For instance, commonly used in surgery to create a fibrin clot, fibrin glue has issues with weak adhesion strength and the risk of transfer of blood diseases [52,53]. Fibrin glue TISSEEL [54] is vulnerable to debonding. Polyethylene glycol-based adhesives like COSEAL, although it has good adhesion properties and effectively prevents leaking of blood from vessels, carries poor mechanical properties and induces swelling [55]. Similarly, cyanoacrylate-based adhesives, super glues, are hampered by their poor biomechanical compatibility [56]. Despite being the strongest class of tissue adhesives, these adhesives are cytotoxic and poor with wet surfaces, making it difficult to be applicable to wound healing [57]. In terms of self-healing, a commercial carboxymethyl hydrogel only healed 27% in a week and 70% in 10 days [58]. With these flaws, researchers have looked for alternative solutions and methods to create hydrogels better suited for wound healing with efficient healing time and effective adhesion strength.

Healing Properties
When hydrogels are examined for their uses in wound healing, the healing time is a critical factor. Healing time is the necessary time needed for a wound to heal. In 2013, Sakai et al. developed a simple yet effective method that allows a highly stretchable gel to in situ gelate when a solution is poured onto a wound [58]. This solution, containing a PVA derivative with phenolic hydroxyl properties (PVA-Ph), glucose oxidase (GOx), and horseradish peroxidase (HRP), allows the hydrogelation to occur as quickly as five seconds. This PVA-Ph hydrogel was able to heal 77% of the initial wounds in seven days and 96% within 10 days, which is more effective than the previously mentioned commercial carboxymethyl hydrogel. Le et al. combined dopamine-modified four-armed poly (ethylene glycol) (PEG) and poly (sulfamethazine ester urethane) (PSMEU) to better control physical and mechanical properties [59]. The PEG-PSMEU hydrogel was tested on longitudinal cuts to measure healing time. These wounds completely closed after a week. These developed hydrogels also had other healing characteristics. Consequently, Qu et al. reported that loading the quaternized chitosan/Pluronic ® F127 (QCS/PF) gel with curcumin results a tunable antioxidant ability [60]. Ballance et al. reported that the addition of cyclodextrin in a polyacrylamide gel increases mechanical strength [61]. More importantly, this hydrogel demonstrated antibacterial properties when treated with quinine. The gel's improved stretchability resulted in a greater release of quinine, leading to successfully inhibit the growth of E. Coli. Liu et al. reported the combination of PEG-D4 with Laponite forms an injectable gel that degrades nontoxically [53]. In fact, many of the developed hydrogels are applicable on tissue skin unlike the previously mentioned commercial adhesives.

Adhesion Strength
To be applicable to wound healing, gels must have great adhesion strength. Adhesion strength is how a polymer sticks and bonds to surfaces. When adhesion strength is measured, multiple tests are usually done on a variety of surfaces. To compare with human skin, porcine skin was commonly used. Qu et al. increased the adhesion strength of 4.4 kPa to 6.1 kPa on porcine skin with the increase of Pluronic ® F127 (PF127-CHO) [60]. This strength was comparable to that of a fibrin glue adhesive. Li et al. developed tough adhesives, the toughest of which had an adhesion strength of 83 kPa on porcine skin [62]. The adhesion occurred in a few minutes, lending itself to more uses, unlike cyanoacrylate, which hardens upon contact with tissue skin. Han et al. added polydopamine (PDA)-intercalated clay nanosheets to a PAM hydrogel to make it more adhesive [63]. While the hydrogel only has an adhesion strength of 28.5 kPa on porcine skin, it showed 120 kPa when measured on glass. When adhered to the glass slides, this hydrogel could support a load of 500 g. Most recently, Wang et al. made a tyrosine hydrochloride gel with the adhesion strength of 453 kPa on pigskin [64]. As time progressed, the adhesion strength has rapidly improved in hydrogels.

Additional Mechanical Properties
He et al. reported that the introduction of a microgel to enhance adhesiveness and improve mechanical strength in its poly (N-isopropylacrylamide) microgel/polyacrylic acid-polyacrylamidepolydopamine (MR/PAAc-PAM-PDA) hydrogel [65]. Fukao et al. combined bioceramic hydroxyapatite (HAp) with double network hydrogels to increase mechanical strength and create a structure similar to bone tissue [66]. Guvendiren et al. reported the integration of 3,4-dihydroxy-l-phenylalanine (DOPA) to the gel increases cohesive and adhesive properties [67]. Unlike healing time, self-healing time refers to the time needed for the hydrogel to recover. In 2018, Chen et al. crosslinked oxidized sodium alginate-dopamine (OSA-DA) and polyacrylamide (PAM) to withstand large deformations and efficiently self-heal [68]. OSA-DA-PAM hydrogel was able to recover 80% within only six hours. Using the dynamic coupling reaction of tyrosine hydrochloride catalyzed by enzymes, Wang et al. developed a gel that completely self-healed within a day in 2019 [64]. The hydrogel was 25% healed in four hours and 68% in 12 h, showing much progress. Table 2 summarizes other hydrogel-based wound dressings that have been developed from a variety of groups.

Highly Stretchable and Tough Hydrogels for Drug Delivery
Highly stretchable, wearable hydrogels have a high potential in use for delivering drugs. In 2013, Zhang et al. formulated an enzyme-incorporated hydrogel made from PAAm and alginate [69]. This gel maintained homogenous throughout, even after being stretched 6.67 times its original size. The gel was put through a 48-h intensive straining and washing process that concluded with no leakage of proteins in the gel. Over a week of time, enzymes in the hydrogel maintained most of their initial activity when stored at room temperature. Any loose, free counterparts in solution, however, lost activity significantly. Park et al. created a hydrogel made from poly (methacrylic acid/ethylene glycol dimethacrylate) and Fe 3 O 4 in 2015 [70]. The composite microcapsules in the gel are biocompatible, responsive to pH, and magnetic, which makes it appropriate for drug delivery. The amount of drug, in this case doxorubicin chloride (DOX), released was 43.8% at pH 2 compared to 9.5% at pH 7. In the same year, Di et al. [71] worked on a tensile strain-triggered drug delivery device. The gel was made of poly (lactic-co-glycolic acid) nanoparticles and Dragon Skin 30, which is a soft, strong, stretchy silicone rubber. The nanoparticles serve as drug delivery depots, while the Dragon Skin works for loading tensile strain. The amount of insulin release saturated after 10 testing cycles at 50% strain with two second intervals. With an interval of four hours, the same amount of insulin was released across several stretching events. Lin [35] demonstrated that when stretched, a polyacrylamide-based gel with alginate and titanium wire accommodates drug diffusion without any breakages or leaking, with a drug diffusion coefficient of 3 × 10 −10 m 2 s −1 . A biocompatible, stretchable, and robust material was fabricated by Liu et al. [48]. The hydrogel is a polyacrylamide-based gel with alginate and polydimethylsiloxane. The design that Liu put forward could be programmed with desirable functionalities by designing the circuits in the cells and structures and patterns of the hydrogel.

Conclusions
Highly stretchable and tough hydrogels can be implemented in multiple different fields, such as mechanical sensors. Properties important to making a good mechanical sensor, such as gauge factor, self-healing, and having strong mechanical properties, can be seen within these hydrogels. Highly stretchable and tough hydrogels, with great adhesion strength and healing times, can be utilized for wound healing. The mechanical properties of tough, highly stretchable hydrogels can be used for drug delivery.