Applications of Bioadhesives: A Mini Review

Bioadhesives have demonstrated their superiority in clinical applications as tissue adhesives, hemostats, and tissue sealants. Because of the intrinsic stickiness, the applications have been expanded to various areas, such as functional wound dressing, factor delivery vehicles, and even medical device fixation. While many literature works discussed the mechanism of bioadhesives, few of them specifically summarized the applications of bioadhesives. To fill in the blanks, this review covers recent research articles and focuses precisely on the applications of bioadhesives which can be generally classified as follows: 1) wound closure, 2) sealing leakage, and 3) immobilization, including those already in the clinic and those showing great potential in the clinic. It is expected that this article will provide a whole picture on bioadhesives’ applications and lead to innovations in the application of bioadhesives in new fields.


INTRODUCTION
Bioadhesives have been changing the surgical process with increasing importance and rapid development over the past 30 years (Ge and Chen, 2020;Taboada et al., 2020). The growing interest in producing adhesives and sealants makes them constitute a market share of $38 billion currently (Spotnitz and Burks, 2012;Qu et al., 2018;Liang et al., 2019). Compared with traditional invasive wound closure methods, including sutures, wires, and staples, bioadhesives have less possibility to damage the tissues and can promote wound healing through different mechanisms. For example, the bioadhesives possess antibacterial, anti-inflammatory, and antioxidant properties (Giano et al., 2014;Zhao et al., 2020). Other properties like self-healing and injectability significantly increase bioadhesives' ease of use . Preventing leakage is also an essential role of bioadhesives. Leakage happens easily after the surgical process, which is up to 30% in some challenging situations. The leakage will easily lead to pain, inflammation, infection, and a high mortality rate (Artzi, 2013;Slieker et al., 2013;Pausch et al., 2020). With an aim to prevent those postoperative leakages, different bioadhesives have been developed accordingly. FocalSeal ® was developed to avoid air leakage during lung surgery. DuraSeal ® was designed for the spine and dura sealing. Coseal ® was used as an adjunct of suture to prevent the leakage of blood vessels.
Moreover, they can remain stable on the site of application because of the intrinsic adhesion property. So, another important function of bioadhesives is immobilization. They can immobilize themselves as functional wound dressings to promote wound healing without other fixation methods (Yang et al., 2021). They can also be employed as vehicles to deliver functional items like drugs or cells to realize local delivery (Patel et al., 2014;Hu et al., 2021). With the development of smart biomedical devices, like wearable devices, implantable detectors, or sensors, a question has been raised about how to fix those devices on/in the body through noninvasive methods without damaging the tissues or the medical devices, to which the bioadhesive is also a good solution (Hwang et al., 2018;Deng et al., 2021).
Since bioadhesives are being explored in all sorts of fields, there is a need to summarize these applications, including the existing ones and potential ones. However, till now, most reviews focused on either bioadhesives' adhesion mechanism or their applications on wound closure and leakage prevention; they seldom specifically discussed the overall applications of bioadhesives (Zhu et al., 2018;Bao et al., 2020;Ge and Chen, 2020;Taboada et al., 2020). Hence, in this review, the applications of bioadhesives have been summarized and grouped into three categories ( Figure 1): 1) wound closure, 2) sealing leakage, and 3) immobilization. The examples of each category were demonstrated with the hope of providing a whole picture of the applications of bioadhesives and accelerating the innovation of bioadhesives in new fields. It is worthy to note that some bioadhesives own properties of two or three categories. Here, the bioadhesives are grouped according to their primary functions and the authors' understanding of the bioadhesives.

WOUND CLOSURE
Wound closure is one of the most widely used applications of bioadhesives (Table 1). Sutures, wires, and staples have been the routine practice of wound closure for many years (Mehdizadeh and Yang, 2013). However, concerns about the scar tissues, secondary injury, foreign body reaction, wicking-induced infection, impaired wound healing process, and complex postoperative care are still waiting to be addressed (Harsha and Vasudha, 2018). As a good alternative, bioadhesives can adhere two wounds together through a noninvasive behavior. Typically, bioadhesives close the wounds by three methods： bringing the two sides of an injury together from the wound surface (Figure 2A), bringing the tissues beneath the surface together ( Figure 2B), or closing wounds in both ways ( Figure 2C). Firm adhesion is the property needed for all the three types. Moreover, the bioadhesives applied to wounds (Figures 2A,C) should be biodegradable and biocompatible and should not hinder the healing process . The bioadhesives used on the surface are generally tape-like ones with strong cohesion strength (Bae et al., 2013;Yang et al., 2013). Cohesion, which is defined as the internal strength of an adhesive, together with adhesion creates a strong bond; few people conducted in-depth research on cohesion strength alone. However, it is reported that the photo-crosslinking strategy is commonly used to develop tapelike bioadhesives with high cohesion strength. Besides, the double network strategy has also been used to develop bioadhesive tapes with good wound closure efficacy by increasing the cohesion strength Pausch et al., 2020). Cyanoacrylate-based bioadhesives are the most widely used tissue adhesives for wound closure in the market, initially synthesized in 1949 (Harsha and Vasudha, 2018). Although they are not tapelike, they play roles mainly according to the second type because of their strong adhesion strength. However, their applications on wet tissues were limited because of their water-initiated curing. They also raise security concerns for exothermic polymerization, cytotoxic degradation products, and long degradation time (Bu et al., 2017;Harsha and Vasudha, 2018). So, special attention should be paid to avoid pushing cyanoacrylate-based bioadhesives into the wound, which can cause irritation and foreign body reaction. There are indications of holding wound edges together for at least 30 s before releasing. Because of the brittle property of the barriers formed by cyanoacrylate, it is suggested that cyanoacrylates are not suitable for wounds over joints, like the knees, groins, or hands, where adhesion easily fails because of the skin torsion (Harsha and Vasudha., 2018).

Skin Closure
Skin closure is one of the main goals for wound closure-targeting bioadhesives which is in high demand because of the increasing workload of general surgery (Lu et al., 2020). This application has expanded popularity also because people pay more attention to their physical appearance. Dermal surgeons prefer using bioadhesives to improve their work efficiency. Patients tend to use noninvasive methods because there is usually less pain and a better cosmetic outcome (Ge and Chen, 2020). Luo et al. developed a new bioadhesive from the skin secretion of Chinese giant salamander. Later, the ability to close the wound was tested on the back of the rats with four incisions (2 cm). At the 5th day of postoperation, the bioadhesive-treated group showed the best healing effect among all groups, with no scar formation, infection, and inflammation (Deng et al., 2019). Du et al. fabricated an adhesive patch with poly-(ethylene glycol) diacrylate/quaternized chitosan/tannic acid based on musselinspired chemistry. The efficacy of the wound closure was FIGURE 1 | The applications of bioadhesives in human bodies and their categories. Bioadhesives have been explored in human bodies in different organs, including the brain, eyes, heart, liver, and skin. Their applications can be grouped into three categories. (A) Wound closure, which has been used in topical skin, and brittle/hard tissues. (B) Sealing leakage, including most explored blood leakage and other fluids or gas leakage. (C) Immobilization for wound dressing, drug/cell delivery, and fixation of devices.
tested on a full-thickness incision model. It was proved that at day 7 postsurgery, the patch-closed skin incisions exhibited more complete epidermis and dermis structures, and higher collagen deposition levels than the untreated tissues (Du et al., 2019).

Wound Closure of Hard or Brittle Tissues
Other kinds of wound closure, in which bioadhesives show super advantages, are closing wounds of hard and extremely brittle tissues. In hard tissues like bones, bioadhesives provide a quick and straightforward method to fix the broken pieces, especially for small bone fragments (Farrar, 2012). For example, comminuted bone fracture is a severe orthopedic condition. The difficulty in fixation of the small bone pieces often leads to bone reduction, further resulting in bone displacement, bone union deformation, and nonunion. Based on citrate, Xie et al. developed an injectable bioadhesive to fix small bone pieces in comminuted bone fractures (Xie et al., 2015). Hydroxyapatite was added to the system to improve the healing efficacy. It was demonstrated that the bioadhesive increased bone formation with markedly enhanced three-point bending strength compared with the negative control. In extremely brittle or sensitive tissues like nerves, traditional sutures can cause irreversible damage. Besides, skilled surgeons are required for suturing those tissues, which entails prolonged surgical time and surgical skills. In our previous work, the octa-PEG-based bioadhesives have been used to close the nerve transection. After adding lithium chloride, the adhesive-reconnected nerves showed a low level of fibrosis, inflammation, and myoatrophy, as well as robust axonal regeneration and functional recovery . Corneal is another brittle tissue in which closure can  Osteotomy was performed at two sites with a surgical electric saw to produce a 10-mm length bone block. The bone blocks were cut into several segments (usually 3-4 fragments) using a bone rongeur Male New Zealand Rabbits Xie et al. (2015) Chitosan, glycerol, glutaraldehyde Bone sheets were cut into rectangular cuboids with a constant transversal section of 13 mm × 7.0 mm. Along 30 mm in the cuboid center, the transversal section was reduced to 6.5 mm × 6.5 mm. Subsequently, 4-mm diameter holes were drilled at both ends of the cuboid. Finally, the drilled cuboid was cut in half at the center of its longitudinal axis with a diamond wheel Cancellous bones extracted from bovine humerus head Cedano Serrano et al. (2017) Nerve injury closure Octa-arm poly (ethylene glycol), octa-arm PEGamine, LiCl The sciatic nerve in the right leg was subjected to a transection at 0.5 cm distal to the sciatic notch, then octa-PEG-SS and LiCl-octa-PEG-NH2 were injected into the interface of the proximal stump and distal stump of the transected nerve SD rats Bu et al. (2020) Vascular anastomosis Poloxamer, 2-octylcyanoacrylate adhesive (Syneture) The left common iliac artery of the rat was divided and ligated at the bifurcation and anastomosed to the right common iliac artery in an end-to-side fashion. Then 2-octylcyanoacrylate was applied in a circumferential manner to complete the anastomosis Male Fisher rats Chang et al. (2011) Frontiers in Bioengineering and Biotechnology | www.frontiersin.org September 2021 | Volume 9 | Article 716035 be achieved by the bioadhesives. Shirzaei Sani et al. had engineered a gelatin-based adhesive biomaterial GelCORE to close the eye incision in an ex vivo model. It was found that the mean leak pressure of glue was more significant than that of commercial control groups (Shirzaei Sani et al., 2019).

SEALING LEAKAGE
Leakage is a common complication of surgeries and injuries. After lung resections, the incidence of air leakage was reported to be around 50% (Mueller and Marzluf, 2014). Cerebrospinal fluid leakage, caused by injuries or brain and sinus surgery, can lead to headaches, meningitis, and seizures. Gastric fluid leakage can cause severe tissue damage and infection, which happens easily after surgical procedures. So leakage prevention is vital in reducing operative risks, and decreasing the complications and the cost. Bioadhesives for leakage prevention are also called tissue sealants, which attracted the attention of researchers and have shown great potential in the clinic (Ryu et al., 2011;Nie et al., 2013;Behrens et al., 2014;Chan Choi et al., 2014;Chen et al., 2017;Yan et al., 2018;Kim et al., 2020). Some examples of the tissue sealants are summarized in table 2.

Bleeding
In this review, bleeding is considered as the leakage of the blood, resulting from trauma, surgical process, diseases, and even some medicines. It is one of the most frequent complications in patients.  (Cui et al., 2019). In our previous work, the concept of fabricating sealants with strong cohesion strength has been used (Bu et al., 2016;Bu et al., 2019). Tough sealants based on ammonolysis-based Tetra-PEG hydrogels were fabricated, which showed promising efficacy in pigskin massive bleeding and rabbit femoral artery section models (Bu et al., 2016). Hemostasis is another critical situation for patients with coagulation disorders, such as hemophilia, Von Willebrand disease, and aged patients taking anticoagulation drugs. Shin et al. presented a hemostatic hypodermic needle that will be able to prevent bleeding following tissue puncture. The surface of the needle was coated with catechol-functionalized chitosan that would be transformed from the solid to the gel phase in situ to seal punctured tissues . Later, Kim et al. used the catechol-conjugated chitosan to fabricate a hemostatic sponge (Kim et al., 2021). They used preclinical models to evaluate the hemostatic efficacy, including the heparinized rabbit model of femoral artery bleeding, the pig model of traumatic blunt liver injury with hemodilutional and hypothermic coagulopathy, and the anticoagulant-treated rabbit model of liver resection bleeding. A further clinical study performed on 15 patients showed that this sponge demonstrated an excellent hemostatic effect compared with the commercialized controls.  Liver bleeding was triggered by puncture with a 20-G needle SD rats; C57BL/6 mice; Kunming mice (Lih et al. 2012, Zhu et al. 2017, and Qu et al. 2018 Tannic acid, poly (ethylene glycol); chitosan/pluronic composite hydrogel; chitosan/poly-lysine hydrogel; poly (γ-glutamic acid), dopamine hydrochloride (DA); N-(3-aminopropyl) methacrylamide (APM); DOPAmodified gelatin; hydrazide-modified poly (L-glutamic acid) (PLGA-ADH), dual-functionalized alginate; epigallocatechin gallates (EGCGs), tyramine, hyaluronic acids, tyrosinase Liver bleeding was triggered by puncture with an 18-G needle Normal ICR mice; SD rats; Female balb-c mouse (Ryu et al. 2011, Nie et al. 2013, Behrens et al. 2014, Chan Choi et al. 2014, Chen et al. 2017, and Kim et al. 2020 DNA from salmon testes, tannic acid Liver bleeding was triggered by puncture with a 23-G needle ICR mice  Glycol chitosan (GC), 3-(4-hydroxyphenyl) propionic acid

Other Leakages
Except for blood leakage, there are also some other leakage types. In lung surgery, prolonged air leakage is the most common complication after surgical dissection and resection. The criteria of an ideal sealant for lung leakage include the following: 1. The sealant can stand higher burst pressure than that generated during physiological breathing; 2. the sealant should be elastic with a proper elastic modulus to support the inflation and deflation of lung tissue. Annabi et al. used methacryloyl-substituted tropoelastin (MeTro) to engineer a highly flexible sealant . After applying MeTro to a porcine model, it was found that the sealant completely sealed the severely leaking lung tissue in the absence of sutures or staples. Urinary fistulas have been considered a severe socioeconomic problem, which occurs most commonly as a result of prolonged obstructed labor, which causes pelvic floor ischemia and, at times, substantial tissue loss (Margules and Rovner, 2019). Kim et al. developed water-immiscible mussel protein-based bioadhesive, which successfully sealed ex vivo urinary fistulas and provided good durability and high compliance . Liu et al. developed gelatin methacrylate-based double-network hydrogel to manage the leakage of gastric contents without sutures successfully .

IMMOBILIZATION
The last category for bioadhesives includes those for immobilization ( Table 3). Because of the intrinsic adhesion property, they can immobilize themselves as functional wound dressing or delivery vehicles. By adhering items together, they even can fix other medical devices.

Functional Wound Dressings
Advanced fixation methods are still in need because traditional wound dressing methods lack the ability of adhesion to wounds, which increases the operative difficulty index for both the patients and doctors. Compared with these methods, bioadhesives can easily fix themselves on the wound area, contributing to the increasing popularity of bioadhesives to be used as a functional wound dressing (Liang et      bioadhesives with rapid self-healing, extensibility, and compressibility for joints and skin wound healing (Qu et al., 2018). They loaded curcumin into the bioadhesive and found that it significantly accelerated wound healing with a higher granulation tissue thickness in a full-thickness skin defect model. Inspired by embryonic wound closure, Blacklow et al. fabricated mechanically active dressings to accelerate wound healing (Blacklow et al., 2019). The bioadhesive dressing will contract at body temperature, which further applies force to draw the wound edges together in a pursestring-like manner. Adhesive dressings are beneficial in places where the fixation is difficult, like brittle tissues. Lin et al. developed a viscoelastic adhesive patch that accommodates the cyclic deformation of the myocardium. It was found that the patch outperformed most existing acellular epicardial patches in reversing left ventricular remodeling and restoring heart function after both acute and subacute myocardial infarctions in rats (Lin et al., 2019). In addition to the heart, defects from the corneal, cartilage, and calvarial were explored to be treated with bioadhesives with good outcomes (Feng et al., 2016;Han et al., 2018;Lin et al., 2019;Shirzaei Sani et al., 2019).

Delivery Systems
Compared with the traditional hydrogel delivery system, the advantage of bioadhesives in delivery is that they can fix delivered items on the site. Mucoadhesion is very useful in increasing the bioavailability of poorly absorbed drugs by prolonging the residence time in the gastrointestinal tract, leading to reduced dose and dosing frequency (Han et al., 2012;Gong et al., 2017). A lot of mucoadhesive-based delivery systems were developed with some well-summarized reviews (Reddy et al., 2011;Zhang et al., 2016;Zhang et al., 2020;Pathak and Malviya, 2020). Hu et al. encapsulated camptothecin into poly(lactic acid)-hyperbranched polyglycerol-based nano-bioadhesive particles (NPs). Because of the strong bonding of these NPs to squamous cell carcinoma tumor cells, the system significantly reduced the tumor burden and enhanced survival (Hu et al., 2021). Except for the nano/micro scale mucoadhesion, macro-bioadhesives have also been developed to load drugs to achieve better healing efficacy Bu et al., 2020). Cells can also be loaded into the bioadhesives. The use of an appropriate scaffold biomaterial as a cell delivery vehicle can provide a suitable microenvironment to prolong cell viability and present essential factors to direct cell differentiation toward the desired lineages (Khademhosseini and Langer, 2016). Currently, however, a major drawback of the reported cellladen hydrogels is the weak adhesion to the host tissue at the defective site. Hasani-Sadrabadi et al. used alginate-based photocrosslinkable bioadhesives to load mesenchymal stem cells. It was found that the cell-loaded adhesive system leads to complete bone regeneration around the ailing dental implants with peri-implant bone loss (Hasani-Sadrabadi et al., 2020).

Materials used Type of the model Animal species References
Tetra-PEG/agar hydrogel (PA) The drug containing hydrogel was formed in situ on the surface of the rats' skin SD rats Zhang et al. (2019) Tannic acid, poly (ethylene glycol) Each mouse was fed on 0.02 cc of the ICGencapsulated TAPE-OH for the adhesion to the esophagus without any anesthesia BALBc nude mice  Wheat germ agglutinin ( The heart was exposed via a thoratomy, bioadhesive electrodes were used to record epicardial ECG.

Fixation of Other Medical Devices
Nowadays, a growing interest is centered on implantable and wearable medical devices with excellent translational potential in the clinic, like tissue scaffolds, biosensors, and biodetectors. However, it is crucial to establish conformal and stable contact between those devices and the target tissue (Schiavone and Lacour, 2019;. Wires and sutures are required for this fixation, which raises concerns of infection, secondary tissue injury, and scaffold damage. As a noninvasive adhesion method, bioadhesives have the potential to replace these invasive fixation methods. Based on a thin layer of a graphene nanocomposite, Deng et al. developed an electrical bioadhesive that can provide rapid, robust, and on-demand detachable integration of bioelectronic devices on diverse wet dynamic tissues (Deng et al., 2021). Later, they successfully used the e-bioadhesive to record an in situ epicardial electrocardiogram and electrically stimulated a sciatic nerve on a rat model. This technique offers a promising solution for addressing the long-standing challenges in tissue-device integration.
Another good aspect of bioadhesives to be used in these situations is that different functions can be added into the bioadhesives to improve the outcome of the medical devices or reduce the potential complications. For example, the antibacterial property can be introduced to reduce the chance of medical devices' infection (Hwang et al., 2018). In fact, there is still a vast area of bioadhesives in medical device fixation waiting to be explored. However, one should be careful because the bioadhesives may also adversely influence the medical devices. Macnab et al. showed that Tisseel ® significantly attenuated NIR light of a near-infrared spectroscopy during in vitro transmittance and critically compromised photo transmission in vivo (Macnab et al., 2018). Another fixation method is also required when there is a need for tissue transplantation. Islet transplantation is used to treat type I diabetes by replacing the lost beta cell function. Brubaker et al. directly immobilized islets onto intra-abdominal tissue surfaces using a thin layer of a mussel-inspired bioadhesive (Brubaker et al., 2010). On the one hand, the fixation approach offers the potential advantages for convenient, rapid, and minimally invasive islet transplantation by direct apposition of the islet bolus onto tissue surfaces. On the other hand, the technique avoids the intravascular engraftment site, eliminating adverse effects of first-pass blood exposure in the liver while maintaining the capability of rapid islet revascularization and the benefits of direct insulin secretion into the portal circulation.

PERSPECTIVE
Bioadhesives are believed to revolutionize the surgical process (Mehdizadeh and Yang, 2013;Taboada et al., 2020). They have already been widely used as adhesives and sealants in the clinic to reduce complications and improve outcomes. However, those commercialized products are still far from satisfactory. Fibrin-based, PEG-based, and cyanoacrylate-based bioadhesives are the most commonly used ones. Fibrin-based and PEG-based bioadhesives have good biocompatibility but weak adhesion strength. So, most of them are only used as adjunctions for traditional wound closure or sealing methods. Cyanoacrylate-based bioadhesives have strong adhesion strength, but their potential safety concerns limit their wide applications, especially internal applications. Thus, more powerful and commercially transformable bioadhesives for wound closure and sealing leakage are still needed. Compared with traditional wound dressings, bioadhesives get easily attached to the parts where they are applied because of their intrinsic adhesion property (Li and Mooney., 2016). So, there is a growing interest in using bioadhesives as a functional wound dressing. This application is beneficial for tissues where the fixation of traditional wound dressing fails to work, like a beating heart and brittle brain (Lin et al., 2019). However, the absence of removability makes it hard for further wound care or dressing change, resulting in more potential troubles when mechanical debridement is involved. So controllably removable property is also explored for bioadhesives Bu et al., 2019;Villa-Camacho et al., 2015;Konieczynska et al., 2016).
Using bioadhesives for the local delivery of functional items like drugs or cells is also a promising way to realize specialized and prolonged effectiveness. Compared with conventional hydrogel vehicles, bioadhesives can adhere to tissues, making them more stable in special tissues like the beating heart and esophagus (Lin et al., 2019). By mixing Tannic and PEG, Lee et al. developed a new medical glue called TAPE, which had been applied to the esophagus and demonstrated the ability to detect gastroesophageal reflux diseases because it maintained wet-adhesive properties . Bioadhesives are also used to fix medical devices or tissues, of which the importance is increasing with an increasing number of implantable medical devices and tissue transplantation. The fixation using bioadhesives will not damage either medical devices or the tissues. Although very promising, there is a difficulty in avoiding the interference between the functions of medical devices and bioadhesives. Besides, for tissue transplantation, the adhesion strength of bioadhesives available might not be sufficient for large pieces of tissues.
Although massive efforts have been spent on developing bioadhesives, there are only a handful of products available in the market (Taboada et al., 2020). First, the researcher might care too much about the adhesion mechanism, while cohesion is ignored. Cohesion dramatically influences how the bioadhesives would be used, which is particularly important for clinical translation. In the market, ease of use has a positive influence on people's choices. Second, one bioadhesive never fits all the applications. The requirement of bioadhesives for wound closure differs from those for sealing leakage. So, it is suggested to choose the unmet clinical target first and then the relative characterization methods to fabricate bioadhesives for translation.

AUTHOR CONTRIBUTIONS
WD did the literature search and paper writing. XB did the literature research and helped revise the paper. YB was responsible for the whole paper design and manuscript organization.

ACKNOWLEDGMENTS
We sincerely thank Abhay Pandit for offering inspiration and practical advice, as well as writing support for this publication. The study was funded by 'Young Talent Support Plan' of Xi'an Jiaotong University.