Cutting-Edge Progress in Stimuli-Responsive Bioadhesives: From Synthesis to Clinical Applications

With the advent of “intelligent” materials, the design of smart bioadhesives responding to chemical, physical, or biological stimuli has been widely developed in biomedical applications to minimize the risk of wounds reopening, chronic pain, and inflammation. Intelligent bioadhesives are free-flowing liquid solutions passing through a phase shift in the physiological environment due to stimuli such as light, temperature, pH, and electric field. They possess great merits, such as ease to access and the ability to sustained release as well as the spatial transfer of a biomolecule with reduced side effects. Tissue engineering, wound healing, drug delivery, regenerative biomedicine, cancer therapy, and other fields have benefited from smart bioadhesives. Recently, many disciplinary attempts have been performed to promote the functionality of smart bioadhesives and discover innovative compositions. However, according to our knowledge, the development of multifunctional bioadhesives for various biomedical applications has not been adequately explored. This review aims to summarize the most recent cutting-edge strategies (years 2015–2021) developed for stimuli-sensitive bioadhesives responding to external stimuli. We first focus on five primary categories of stimuli-responsive bioadhesive systems (pH, thermal, light, electric field, and biomolecules), their properties, and limitations. Following the introduction of principal criteria for smart bioadhesives, their performances are discussed, and certain smart polymeric materials employed in their creation in 2015 are studied. Finally, advantages, disadvantages, and future directions regarding smart bioadhesives for biomedical applications are surveyed.


Introduction
An increase in the cost of healthcare and the age of the population has resulted in a rising request for bioadhesives and drug delivery systems [1]. The term "bioadhesion" was introduced for the first time in the 1970s. Bioadhesion is defined as the phenomenon in which two materials, one of which should be biological, are attached for a long time by interfacial tailoring [2]. Due to biodegradability, biocompatibility, and large molecular weight, bioadhesives can be applied in many hard-and soft-tissue applications, drug delivery, reinforcing fragile tissues in therapy, and helping with hemostasis [3]. Despite the potential benefits of bioadhesives, the functionality of commercially available bioadhesives is limited [4]. For example, existing adhesives are designedto support the injured tissues mechanically. To further explore the potential of bioadhesives in medicine, scientists have developed multifunctional bioadhesives with antimicrobial ability to limit microbial adherence and growth [5,6]. Additionally, some bioadhesives with self-healing capabilities

Principal Criteria in Bioadhesive
The adhesion term is defined as the potency of the adhesive to flow, wet the entire surface, and develop specific physicochemical intermolecular forces between the substrates and adhesive [25]. The phenomenon that two materials, one of which should be biological in character, are linked for a long time by interface tailoring is known as bioadhesion [3]. A bioadhesive system aims to make tight contact with the biologic substrate for a long time by interfacial forces. Bioadhesion in biological systems can be divided into class one with attachment between two biological phases, such as platelet aggregation and tissue repair; class two, adhesion between two biological phases (e.g., platelet aggregation and wound healing); and class three, adhesion of a biological degree to an artificial substrate (e.g., cell adhesion to culture dishes and biofilm formation on artificial devices), and adhesion of artificial material to a biological substrate (e.g., adhesion of synthetic hydrogels to soft tissues and adhesion of sealants to dental enamel), which are all examples of bioadhesion in biological systems [26,27]. Irrespective of the type and application, three factors are essential in the design of bioadhesives, including the capa-

Principal Criteria in Bioadhesive
The adhesion term is defined as the potency of the adhesive to flow, wet the entire surface, and develop specific physicochemical intermolecular forces between the substrates and adhesive [25]. The phenomenon that two materials, one of which should be biological in character, are linked for a long time by interface tailoring is known as bioadhesion [3]. A bioadhesive system aims to make tight contact with the biologic substrate for a long time by interfacial forces. Bioadhesion in biological systems can be divided into class one with attachment between two biological phases, such as platelet aggregation and tissue repair; class two, adhesion between two biological phases (e.g., platelet aggregation and wound healing); and class three, adhesion of a biological degree to an artificial substrate (e.g., cell adhesion to culture dishes and biofilm formation on artificial devices), and adhesion of artificial material to a biological substrate (e.g., adhesion of synthetic hydrogels to soft tissues and adhesion of sealants to dental enamel), which are all examples of bioadhesion in biological systems [26,27]. Irrespective of the type and application, three factors are essential in the design of bioadhesives, including the capability to create powerful inter-responsive bioadhesive, which can protonate or deprotonate with pH changes. PAA can be swelled through electrostatic repulsion and experience high sorption and release in drug delivery systems [43]. Impressive self-assembly in the liquid state and mass transport in the solid-state can be attained in light-responsive polymers such as azobenzenes that isomerize quickly from one state to another and change size under UV light [44]. Electrochemicalresponsive polymers are another smart adhesive group that responds to electric fields by changing their size or shape [45]. More details on the types of smart bioadhesives and their applications are provided in the following section.

Light-Responsive Bioadhesives
Light-responsive smart adhesives as noninvasive tools to regulate cell adhesion can be applied to tissue engineering, cell diagnostics, and medicine. The physicochemical behaviors of photosensitive molecules are altered or degraded in response to light irradiation with suitable wavelength and intensity [46,47]. Table 1 summarizes light-responsive bioadhesives trouped by stimulus responses and contains information about the inspiration and application. The light-responsiveness of O-nitrobenzyl was first cited by Ciamician and Silber about a century ago [48]. UV radiation activates most photochemical processes, such as acrylate polymerization, thiol-ene reaction, nitrobenzyl, and spiropyran groups. However, UV light-induced injury to biological specimens and live organs may restrict its use in-vitro and in-vivo because of intrinsic cytotoxicity and poor tissue penetration [49]. Photo-activation with near-infrared (NIR) light due to neglectable phototoxicity, easy access, clean, inexpensive, and sufficient penetration into the tissue can be considerable [50]. Li et al. [51] utilized spiropyran (SP) conjugated multi-shell upconversion nanoparticles (UCNPs) for adjusting cell adhesion/detachment reversibly and noninvasively. The UC-NPs are ceramic lattices incorporated with trivalent lanthanide ions that could convert NIR light to UV radiation and activate photochemical processes on request. High-power and low-power NIR treatments were used to activate ring-opening and ring-closing procedures, respectively ( Figure 2A). Such conversions caused the relation between SP and the cellular protein surface to be replaceable, resulting in reversible cell adhesion and detachment. Bian et al. [52] synthesized a reversible visible-light-responsive biofunctional surface by interacting the host-guest of azobenzene derivatized polycation/polyanion on a cyclodextrin (CD)-terminated substrate for switching from antibacterial to bioadhesion. They showed that the polyanions with COO − groups provided bioadhesive properties, while the azobenzene functionalized polycations with quaternary ammonium groups had vigorous antibacterial activity. They could be switched by alternate assembly when exposed to visible light. Light-responsive bio-inspired MnO 2 hybrid (BMH) bioadhesives were employed in a research study for efficient melanoma photo-thermo-chemotherapy and multidrug-resistant (MDR) bacteria-contaminated healing of wounds( Figure 2B) [53]. As one of the "light-responsive" materials, MnO 2 nanosheet was produced to induce spatial and temporal controlled hyperthermia for further photothermal therapy. Furthermore, the two-dimensional nanosheets could be perfect bioactive molecule delivery carriers, allowing potent synergistic treatments for cancer and wound healing due to their high surface area and high binding energy via electrostatic and polar interactions. Based on the results, enhancing the local access to oxygen increased the cellular toxicity of doxorubicin (DOX) versus melanoma. Bioadhesive hydrogels with a positive charge, macropores, and alkyl chains could catch and limit microorganisms. WS 2 nanosheets produced heat when exposed to NIR, and the antibiotic was triggered to release at the wound site.

Thermo-Responsive Bioadhesives
The temperature is of great interest among external stimuli because of its broad application, effortless control, and capability to use in-vitro and in-vivo states [63]. As a minimally invasive technique, thermo-sensitive bioadhesives show conformational changes in response to temperature stimuli, particularly near-physiological human body temperature, to generate interim polymer chain cross-linking via multiple physical interactions [64]. An ideal thermo-responsive system is a polymer solution with low viscosity at ambient temperature that, after injecting into target sites, changes into a gel at body temperature. Some studies focused on thermo-responsive bioadhesives are listed in Table 2. Light-responsive bioadhesives. (A) An illustration of SP-UCNP usage as a NIR-triggered photo-switch to modulate cell adhesion/detachment in a non-invasive and reversible manner by adjusting the power density of a laser. Reprinted with permission from Ref. [51]. Copyright 2015, ACS Publications. (B) (i) Schematic illustration of BMH hydrogel's composition and structure for simultaneous anti-cancer treatment and MDR bacteria-infected scar tissue. (ii) The nanostructure of BMH hydrogel effectively increased chemotherapy by enhancing O 2 generation via breaking endogenous H 2 O 2 and enhancing intracellular buildup of DOX by PTT Reprinted with permission from Ref. [53]. Copyright 2020, Elsevier.
Although light-responsive bioadhesives possess many advantages, such as minor damage to cells, remote modulation, and high controllability of stimulus, they still have several limitations to being converted into medical products, including the incapacity of light sources to penetrate tissue [59], the use of UV light as a non-biofriendly source [60], and weak mechanical strength [61]. Many light-responsive bioadhesives require complex synthesis techniques that restrict their potential to be developed. Though NIR-triggered agents are more popular than UV-triggered agents, no investigation studied the effect of NIR-triggered agents on deep tissues. Only a few studies have been conducted on superficial disease models. In addition, due to their lower efficiency, these systems require a longer exposure time to have a therapeutic impact [62]. The unwanted extreme warmth may injure the surrounding healthy cells as a result of the unwanted extreme warmth. Furthermore, most of these studies were conducted in-vitro, and it is essential to continue development and confirm results in-vivo.

Thermo-Responsive Bioadhesives
The temperature is of great interest among external stimuli because of its broad application, effortless control, and capability to use in-vitro and in-vivo states [63]. As a minimally invasive technique, thermo-sensitive bioadhesives show conformational changes in response to temperature stimuli, particularly near-physiological human body temperature, to generate interim polymer chain cross-linking via multiple physical interactions [64]. An ideal thermo-responsive system is a polymer solution with low viscosity at ambient temperature that, after injecting into target sites, changes into a gel at body temperature. Some studies focused on thermo-responsive bioadhesives are listed in Table 2.  The addition of collagen to the system resulted in larger pore size and enough interconnectivity, making it suitable for use as biomaterials for bone tissue engineering.
Gelation temperature at 37 • C. [75] Polymers are classified into two categories [68]. The first case is LCST, which is insoluble above its critical temperature. The second case is the upper critical solution temperature (UCST), which precipitated and underwent a phase shift in its critical temperature, the temperature at which the polymers keep miscible in solution. At the same time, phase separation occurs when the temperature rises over the critical value, which is called "negative temperature-sensitive polymers" in LCST materials (e.g., PNIPAM, gelatin, and carrageenan) [76]. In contrast, UCST materials are known as "positive temperature-sensitive polymers". They are miscible at room temperature, while their solubility diminishes when the temperature drops below the critical value, causing phase separation. Examples include (acrylamide-co-butyl methacrylate), PAA, and polyacrylamide (PAAm) [77]. The thermosensitive microstructure changes of a supramolecular hydrogel bioadhesive containing ureidopyrimidinone (UPy) and PNIPAM ( Figure 3A) were investigated by scanning electron microscope (SEM) images ( Figure 3B) [78]. This bioadhesive displayed large pores at the 25 • C (approximately 3.4 µm) while the size of the pores decreased to around 0.82 µm at 37 • C. Interestingly, the pores could regain their primary size (about 4.0 µm) by turning back the temperature to 25 • C. This suggested that the macromolecule chains became hydrophilic at a lower temperature than the LCST and may generate bigger pores during the lyophilization process. In contrast, the polymer chains were dehydrated and collapsed at a temperature higher than LCST, and the size of pores became smaller. This bioadhesive was a good candidate for drug delivery application. Zheng et al. [70] designed a bioadhesive based on quaternized chitosan (QCS-C) embedded into poly(d,l lactide)-poly(ethylene glycol)-poly(d,l-lactide) (PLEL) for wound healing. In the below LCST, the PLEL polymer was a random coil unimer ( Figure 3C). With the increase in temperature above LCST, the PLEL structure changed to a micelle because of the hydrophilic poly(ethylene glycol) chain (outer shell) and the hydrophobic poly(d,l-lactide) chain (inner core). The presence of QCS-C could be effective in decreasing sol-gel transition temperature. In addition, the rheological property of the bioadhesive indicated that it could flow freely below the gel point and was fully suitable for in situ injection. As the temperature increased from 33 to 40 • C, the storage modulus approached the loss modulus, indicating a semisolid property. As a result, the human body's temperature may be ideal for therapeutic wound management. Zhang et al. [71] prepared a thermos-responsive bioadhesive by simply combining galactose modified xyloglucan (mXG) and hydroxybutyl chitosan (HBC). The obtained bioadhesive as a cytocompatible and hemocompatible hydrogel prevented repeated adhesion after adhesiolysis, enhanced wound healing, and reduced tissue injury.  Comprehensive studies have focused on applying thermo-sensitive bioadhesives for tissue engineering and in vitro transplantable tissues. In tissue engineering and regener- Comprehensive studies have focused on applying thermo-sensitive bioadhesives for tissue engineering and in vitro transplantable tissues. In tissue engineering and regenerative medicine, intelligent bioadhesives can be employed as injection systems to transfer growth factors and cell stimuli-responsive surfaces to regulate cell adherence or penetration [79]. For instance, Moreira et al. created a bioactive thermogelling chitosan-based injection of bioadhesive hydrogel for bone regeneration. Recently, regenerative medicines with the ability for cell culture to remedy the lost functions of organs and tissue have been becoming promising treatments. To form transplantable tissues invitro, selecting a cell separation method with enough purity and function after dissociation is interesting. In this regard, the separated cells using the thermo-responsive adhesive brush have shown high function [80]. Even though this process requires a relatively long time, cell purification is not needed for constructing tissues. Moreover, separated cells using this polymer show good function without correction of the cell surface, which is significant for manufactured tissue transplantation.Furthermore, the separation can be accomplished simply by changing the external temperature of the adhesive brush surfaces that have been created [81]. Polymer brushes are unique macromolecular structures with a dense array of polymer chains immobilized on a surface or interface by one of their end chains. These structures have promising applications for stimuli-responsive and cell adhesive surfaces [82]. In the study by Nagase et al. [72], thermo-responsive copolymer bioadhesives were developed by copolymerizing butyl methacrylate (BMA) into PIPAAm. The adhesion characteristics of copolymer brush surfaces at 37 • C and detachment at 20 or 10 • C were confirmed for human umbilical vein endothelial cells (HUVECs) and normal human dermal fibroblasts (NHDFs), respectively ( Figure 4A,B).
Polymers 2022, 14, x FOR PEER REVIEW 11 of 32 using this polymer show good function without correction of the cell surface, which is significant for manufactured tissue transplantation.Furthermore, the separation can be accomplished simply by changing the external temperature of the adhesive brush surfaces that have been created [81]. Polymer brushes are unique macromolecular structures with a dense array of polymer chains immobilized on a surface or interface by one of their end chains. These structures have promising applications for stimuli-responsive and cell adhesive surfaces [82]. In the study by Nagase et al. [72], thermo-responsive copolymer bioadhesives were developed by copolymerizing butyl methacrylate (BMA) into PIPAAm. The adhesion characteristics of copolymer brush surfaces at 37 °C and detachment at 20 or 10 °C were confirmed for human umbilical vein endothelial cells (HUVECs) and normal human dermal fibroblasts (NHDFs), respectively ( Figure 4A,B). To investigate bone tissue repair, Saravanan et al. [83] developed a thermosensitive chitosan/glycerophosphate adhesive hydrogel containing graphene oxide (GO) with the applicability of injectable. They found that the inclusion of GO into the matrix significantly improved swelling and protein adsorption ability. They further concluded that a GO-containing chitosan/GP hydrogel possessed the ability to produce osteogenic differentiation of mesenchymal stem cells (MSCs), making it appropriate for bone tissue engineering.
The induction of antibacterial properties is another promising application of ther- To investigate bone tissue repair, Saravanan et al. [83] developed a thermosensitive chitosan/glycerophosphate adhesive hydrogel containing graphene oxide (GO) with the applicability of injectable. They found that the inclusion of GO into the matrix significantly improved swelling and protein adsorption ability. They further concluded that a GO-containing chitosan/GP hydrogel possessed the ability to produce osteogenic differentiation of mesenchymal stem cells (MSCs), making it appropriate for bone tissue engineering.
The induction of antibacterial properties is another promising application of thermalresponsive adhesives. The mechanism of antibacterial surfaces depending on bactericidal agents is classified into releasing-based and contacting-based bactericidal agents [84]. In the first case, biocides are usually incorporated or preloaded into a matrix and then released into the surroundings to kill the bacteria (e.g., releasing drugs to decrease infection in sores). Bioadhesives containing quaternary ammonium are extensively utilized for contactingbased mechanisms for the second group. It is related to the low toxicity, excellent cell membrane infiltration character, extended residence time, environmental constancy, and biological activity of ammonium [85]. For example, dopamine (DA) as an anchoring site was loaded into the polyethersulfone (PES) membrane surface to develop an adhesive layer, then the adhesive was stuck onto the membrane by using photoinduced crosslinking copolymerization of methacryloxyethyltrimethyl ammonium chloride (DMC) and NIPAAm ( Figure 5A) [84]. The results showed that the quaternary ammonium salts in the hydrogel film could lead to the destruction of the adhering bacteria. On the other hand, the dead bacteria detached from the surface by decreasing the temperature below the LCST of PNIPAM. In addition, the clotting test revealed that the changed surfaces improved blood compatibility and prevented hemolysis. In other work, 3D printable thermo-responsive PNIPAM/cellulose nanofibrils (CNFs) were developed to provide a new platform for regulating LCST properties and tuning bioadhesive behaviors [86]. In response to temperature, the hydrogel system containing 2% CNF had exchangeable bioadhesion. Above the LCST, the adhesion of the PNIPAm/CNF hydrogels to bacteria was stronger. It could be related to the wholly extended CNF, which made a semi-interpenetrating polymer with PNIPAm. The bioadhesive was severely weakened at 40 • C. The CNF chains were divided into small separate sections, considerably reducing the bacteria-CNF contact area. Therefore, temperature control might be utilized to keep or release bacteria that have developed on the hydrogel surface ( Figure 5B).
Despite advantages such as easy accessibility, low side effects, stability of drugs, etc., thermo-responsive materials have disadvantages such as poor mechanical strength, limitation in drug loading ability [87,88], and uncontrollable on/off state of actuation [89], which need more studies.

pH-Responsive Bioadhesives
Ionic polymers are commonly used in pH-responsive adhesives. Protonation or deprotonation of ionic side chains in these polymers can cause swelling of polymer backbones due to electrostatic repulsion [90]. pH-responsive materials can be divided into anionic and cationic bioadhesives based on the pendant group in the polymer chains [91]. When the adhesive's acid dissociation constant (pK a ) is lower than the pH of the surrounding aqueous solution, the swelling/deswelling behavior of anionic materials is triggered by osmotic pressure. In contrast, the cationic materials that contain donor electron groups such as amine become protonated and swelled in an aqueous solution with a lower pH (<pK a ) [14]. For a better understanding, some polymers' swelling and shrinking behavior, such as chitosan, is referred to as external and environmental pH [92]. At lower pH, the protonation of the amine group of chitosan generated electrostatic repulsion, allowing polymer chains to extend and interact with water molecules more efficiently, thereby enabling water solubility. The amine group is deprotonated when the pH rises, implying no net charge [93]. Further, the amine groups destroy the chitosan structure and decrease the water solubility. As a result, the pK a value is effective in the water solubility of some pH-responsive polymers. Pores are typically produced in other polymers with pH-dependent solubility for more specialized pH-sensitive uses. The waterinsolubility of these polymers at low pH (e.g., in the stomach) and their solubility at higher pH (e.g., in the small and large intestines) causes materials to leach out and form a porous and permeable film. In bioadhesives, synthetic polymers such as PAA, proteins, and polysaccharides are commonly classified as pH-sensitive polymers [5,94]. According to studies, diseasedcaries in people's mouths fluctuate between 4.5 and 6. Therefore, dual adhesive membranes and oral drugs can be applied to protect from oral infections and oral tissue regeneration. Table 3 summarizes different types of pH-responsive bioadhesives and their applications.
Polymers 2022, 14, x FOR PEER REVIEW 12 of 3 the changed surfaces improved blood compatibility and prevented hemolysis. In othe work, 3D printable thermo-responsive PNIPAM/cellulose nanofibrils (CNFs) were de veloped to provide a new platform for regulating LCST properties and tuning bioad hesive behaviors [86]. In response to temperature, the hydrogel system containing 2% CNF had exchangeable bioadhesion. Above the LCST, the adhesion of the PNIPAm/CNF hydrogels to bacteria was stronger. It could be related to the wholly extended CNF which made a semi-interpenetrating polymer with PNIPAm. The bioadhesive was se verely weakened at 40 °C. The CNF chains were divided into small separate sections considerably reducing the bacteria-CNF contact area. Therefore, temperature contro might be utilized to keep or release bacteria that have developed on the hydrogel surfac ( Figure 5B). Despite advantages such as easy accessibility, low side effects, stability of drugs, etc thermo-responsive materials have disadvantages such as poor mechanical strength, lim itation in drug loading ability [87,88], and uncontrollable on/off state of actuation [89] which need more studies.

pH-Responsive Bioadhesives
Ionic polymers are commonly used in pH-responsive adhesives. Protonation o deprotonation of ionic side chains in these polymers can cause swelling of polyme backbones due to electrostatic repulsion [90]. pH-responsive materials can be divided into anionic and cationic bioadhesives based on the pendant group in the polyme chains [91]. When the adhesive's acid dissociation constant (pKa) is lower than the pH o the surrounding aqueous solution, the swelling/deswelling behavior of anionic material is triggered by osmotic pressure. In contrast, the cationic materials that contain dono   Controlled release from a pH-dependent peptidic coating. [96]
At acidic conditions, the hydrogels had a larger swelling ratio and pore size than at pH 7.4. [97] D-α-tocopheryl PEG 1000 succinate conjugated chitosan.

Chitosan Drug delivery
Invivo pharmacokinetic results demonstrated the relative bioavailability of bioadhesive micelles was effective beneficial for brain cancer therapies with the prolonged release.
A pH decrease triggered the drug release. [98]

Dopamine Drug Delivery
In vivo studies confirmed the injection of bioadhesives could achieve high therapeutic efficiency against tumor growth while avoiding significant damage to healthy organs.
The faster release rate of the drug at pH 5.0 than at pH 7.4. [99]

Collagen and PEG
Collagen Diabetic wound repair Bioadhesive loaded stem cell factor as an anti-inflammatory and biocompatibility dressing was used for tissue regeneration.
Effective in drug release rate.
[100]  For pH-controlled delivery of antimicrobial peptides (AMP) into the oral cavity, Boda and coworkers [101] prepared bioadhesive membranes combined with chitosan and pectin derivatives with dual adherence to soft and hard tissue surfaces ( Figure 6A). Pure chitosan membranes indicated suitable adhesion to enamel tissue/hard, whereas the presence of oxidized pectin can be an effective way to increase mucoadhesion. One of the drawbacks of this work was that the effect of pH on the adhesive qualities of membranes was not studied. Yadav et al. [103] developed pH-sensitive adhesive for antibacterial applications. They learned how to brush dispersity and thickness affected the initial attachment and future detachment of Staphylococcus epidermidis bacteria to a pH-responsive PAA brush system. With increasing pH value, the instinct properties of PAA changed from neutral, hydrophobic, and dried up to negatively charged, hydrophilic, and swollen. Switching from pH=4 to 9 also removed microorganisms from the brush surface. Based on the results, an optimal thickness of 13 up to 18 nm was recognized for maximizing microorganism detachment on the PAA brushes at pH 4. The brush dispersion did not affect bacterial adhesion. Recently, a series of injectable pH-responsive self-healing bioadhesives have been produced by radical polymerization of acryloyl-6-aminocaproic acid (AA) and AA-g-Nhydroxysuccinimide (AA-NHS) for wound healing applications [104]. The good hemostatic performance, histomorphological evaluations, and wound healing results demonstrated the therapeutic efficacy of the AA/AA-NHS hydrogel in a swine gastric hemorrhage/wound model ( Figure 6B).

Chitosan and pectin
Despite the reality that pH-responsive bioadhesives have demonstrated wide applications in medicine, there are still issues with the evolution of a bioadhesive, which can behave in favorable procedures under basic and acidic situations. The swelling property is necessary for bioadhesives because liquid absorption is critical during tissue regeneration [105]. However, some adhesives lose their mechanical strength due to solution uptake. On the other hand, the pH value of the media pH may differ depending on the intensity of the complaint or the type of damaged tissues, making it difficult to maintain the bioadhesive's adhesion capabilities during the therapy process [106]. Furthermore, the actions of pH-sensitive bioadhesives might be initiated during administration or use, rendering these systems susceptible to off-target distribution.

Electromagnetic-Responsive Bioadhesives
Field-responsive polymers can be exploited in applying sonic, magnetic, electric, and electromagnetic fields. An electric field's changing geometrical shapes and sizes can be depicted as a synergy of coulombic, electrophoretic, and electroosmotic interactions [47]. Electro-responsive polymers are classified into two groups: ionic and dielectric [108]. Various types of electro-responsive bioadhesives and their applications are given in Table 4. The first group is known as conducting polymers, in which response to an electric field leads to the mobility of free ions and a change in the local concentration of ions in solution or within the material [109]. The migration of ions in an electric field can cause the asymmetric distribution of charged ions, the formation of a concentration gradient of ions, the generation of an osmotic pressure difference, and finally, the production of a swollen hydrogel. On the other hand, the second group includes dielectric elastomers and electrostrictive polymers created by electrostatic (coulombic) forces [110].

Electromagnetic-Responsive Bioadhesives
Field-responsive polymers can be exploited in applying sonic, magnetic, electric, and electromagnetic fields. An electric field's changing geometrical shapes and sizes can be depicted as a synergy of coulombic, electrophoretic, and electroosmotic interactions [47]. Electro-responsive polymers are classified into two groups: ionic and dielectric [108]. Various types of electro-responsive bioadhesives and their applications are given in Table 4. The first group is known as conducting polymers, in which response to an electric field leads to the mobility of free ions and a change in the local concentration of ions in solution or within the material [109]. The migration of ions in an electric field can cause the asymmetric distribution of charged ions, the formation of a concentration gradient of ions, the generation of an osmotic pressure difference, and finally, the production of a swollen hydrogel. On the other hand, the second group includes dielectric elastomers and electrostrictive polymers created by electrostatic (coulombic) forces [110]. Polydopaminepolypyrrolemicrocapsules (PDA-PPyMCs), as electro-responsive and conductive polymers, have been synthesized on titanium electrodes that can release medications locally and accurately [107]. The preparation steps of the electro-responsive system are described in Figure 6C. Based on the results, the adhesion strength of the PDA-PPy for reacting with various substrates was enhanced by increasing the PDA amount. Also, PDA-PPyMCs presented an excellent ability to attach to cells and drug-loading due to strong cell affinity, porous form, electro-responsivity, and good conductivity. Thismeans they could be used as a conductive substrate to transfer electrical impulses to stimulate cell action. However, precise control over the magnitude and duration of electric current provided a unique advantage to electro-responsive bioadhesives. Moreover, their applications have drawbacks, such as wired and bulky instruments [111]. Furthermore, they need to implant electrodes in the bioadhesive matrix, which determines their applications for topical or subdermal implants.

Biomolecule-Responsive Bioadhesive
Sensitive bioadhesives to biomolecule amounts can activate the localized therapeutic drug release to mimic the short-and long-term molecular regulatory processes seen in tissues at the cellular level. Biomolecule responsive bioadhesives have been highly regarded for their structural transition in response to the main target biomolecule [119]. For instance, glucose-responsive adhesives can indicate structural changes in reaction to the glucose amount in diabetes disease. Insulin injections may possess various problems, such as a long treatment period and diet restrictions, which present an alternative therapy way with the capability of immediate responses to blood glucose levels; safe and continual administration seems essential [17]. Types of electro-responsive bioadhesives and their applications are listed in Table 5. Zhou et al. [120] developed a stimulus-sensitive turnover method using a bioadhesive oral delivery nanoparticle system coupled with glucose oxidase (GOx) and insulin as an intelligent glucose-responsive switch. The L-cysteine-alginate in glucoseresponsive nanoparticles with a suitable weight ratio of 2:1 showed good encapsulation efficiency, bioadhesion, and pH stability, which are favorable for oral delivery. In-vitro studies revealed that glucose-responsive nanoparticles switch insulin release behavior "ON" in response to a hyperglycemic condition by catalysis of GOx and "OFF" in response to normal blood glucose levels. Despite promising features, obstacles such as poor stability in various environmental conditions, unfavorable behavior at physiological pH, poor glucose selectivity, and slow response rate raise concerns about the clinical usage of glucoseresponsive bioadhesives [121]. Detect early biomarkers in complex body fluid. [122]

Modified PEG Drug delivery
The injectable, self-healing and adhesive hydrogel could have applications in 3D cell culture substrates for tissue engineering and controlled macromolecule release.
Size-dependent controlled release of proteins encapsulated within the network and the glucoseresponsive release of larger proteins. [123] Hyaluronic acid cross-linked with divinyl sulfone.

Hyaluronic acid Diabetic patients
The released insulin from glucose-responsive nanocarriers displayed a practical hypoglycemic effect for a longer time after oral administration to diabetic rats than insulin-loaded nanocarriers.

2-nitroimidazole-lcysteine-alginate 2-nitroimidazole Diabetic patients
Invivo experiments on type I diabetic rats showed that the hyperglycemia risk was reduced following oral administration, and a standard glucose range was maintained for a long time.

Multi-Responsive Bioadhesives
Multi-responsive bioadhesives have been created to develop multifunctional bioadhesives for different biomedical applications [125]. These bioadhesives are specifically attractive for drug delivery applications. Recent advances in intelligent drug delivery adhesive carriers have great promise. They provide a way to promote formulations tailored to drug delivery systems and the release of drug control based on stimuli responses [126]. An intelligent drug delivery system can release an active chemical at the proper place and at a rate that adjusts in response to disease progression [127].Some of the multi-responsive bioadhesives and their applications are provided in Table 6. Le et al. [128] synthesized pH and temperature-sensitive injectable bioadhesives of poly (sulfamethazine-ester-urethane) (PSMEU) and poly(ethylene glycol) (PEG) by in-situ developing injectable hydrogelators ( Figure 7A). Although PEG-PSMEU bioadhesive was free-flowing at ambient temperature, it quickly became a gel when exposed to body physiological conditions (pH 7.4 and 37 • C). These bioadhesives could promote skin wound repair due to their superior adhesive, bioresorbable, and mechanical characteristics. In addition, hypodermic implantation of PEG-PSMEU repaired the damaged skin and led to wound healing without an inflammatory response. In their research, Lee et al. [129] indicated that alginate-boronic acid hydrogel could be orally administrated in drug delivery systems because of its tolerance to high acidic conditions in the stomach ( Figure 7B). In addition, the adhesive nature of alginate-BA could increase the residual time in the body. For the first 30 min, a clear fluorescent signal was observed in the esophagus region for alginate-BA ( Figure 7C, right panel, yellow circle). It was related to alginate-BA's gelation in the esophagus region (pH upshifts to 7.4). On the other hand, alginate was wiped off, and no fluorescence was noticed when administered orally (top, left panel). The alginate-BA hydrogel led to strong fluorescent signals (e.g., red spots) in the colon after 24 h. However, alginate alone had weak dispersive signals of residual fluorescence (bottom, left panel). Abebe et al. [130] synthesized a self-adhesive hydrogel based on modified alginate with gallic acid (GA) and in-situ polymerization of polyacrylic acid for pH and strain-responsive transdermal delivery. According to the findings, stretching led to an increase in the release rate, but strain percentage had the opposite impact. As demonstrated in Figure 7D, strain percentage of 100% resulted in increased release within the first 10 min, but the releasing pattern reversed after 20 min at pH = 5.5. In 2019, a triple stimuli-responsive hydrogel with self-adhesive, self-healing capabilities was developed using N, N-diethylacrylamide (as a thermo-sensitive part), PDA (as a NIR light-sensitive part), and acrylic acid (as a pH-sensitive part) [131]. The resulting bioadhesive was extensively employed in wound dressings and wearable technology. Furthermore, the hydrogel with an optimum mass fraction of 0.4 wt.% of PDA was for the removal of methylene blue, with a maximum adsorption capacity of 305.4 mg/g. The disintegration rate of hydrogel increased by decreasing pH value from 9 to 3. [132]

Electronic skin
In vitro cytotoxicity results indicated that hydrogel with high adhesiveness and biocompatibility suggested good cell affinity and biocompatibility.
Locally controllable deformation of the hydrogel by remote NIR irradiation.
[133] Cross-linking in alkaline pH or reduction of disulfide bonds changed mechanical and surface properties and cell function. [134]

Light and thermal/PNIPAM and GO
Wound healing, wearable electronic devices, and sensors.
Phase change occurs shortly after touches the human body. [135]

Drug delivery
In vitro cytotoxicity studies confirmed that hydrogels had excellent cell compatibility, with 5-Fu-loaded hydrogels having a lower cell growth inhibition efficiency for normal LO2 cells but a higher cell growth inhibition efficiency for cancer HepG2 cells than pure 5-Fu at the same drug concentration.
The value of medication released was low in an acidic environment (pH 1.2) but high in a neutral environment. [136]

Strain and electric
Utilized in clothing to monitor various body movements Membranes possessed washable, comfortable, good mechanical properties and satisfactory moisture proof sensing performance.

Strain and thermoresponsive
Electronic skin, human-machine interface, and remote medical healthcare Hydrogel showed high stretchability, excellent toughness, and impressive stress loading-unloading cyclic stability.
Motion capture and gesture identification by the hydrogel strain sensor. [138]
Drug release occurred at intracellular acidic pH. [139]
Detection of physical motion and physiological signals of human body. [140] Cetylpyridinium salicylate/cetpylpyridinium chloride pH and temperature Drug delivery The preparation of hybrid pharmaceutical ionogels through encapsulation of the chemotherapeutic drug imatinib mesylate within the ionogel matrix.
The maximum release drug was conducted at an acidic pH at 37 • C. [141]

Dual-cross-linked ionohydrogel
Temperature and strain

Wearable ionotronic devices
The bioadhesives possessed excellent mechanical properties, transparency, high ionic conductivity, and robust adhesion, along with the advantages of superior antifreezing and long-term antidehydration properties. [142]
pH-responsive branched nanocarrier for co-delivery of DOX and MTX. [143] Ionic liquids (ILs) are a type of organic salt that is made up of cation-anion pairs of an organic ion and an inorganic counterion, in which the cationic or anionic part is a relatively large organic moiety [144]. These cations and anions affect their properties in these compositions, including polarity, electroconductivity, viscosity, and volume. Consequently, ILs are ionresponsive making them attractive for various applications, including multi-responsive adhesives [145]. For example, dual-cross-linked ionohydrogelhas been developed using IL binary solvent system [142]. The IL incorporated adhesive hydrogel revealed admirable mechanical characteristics, transparency, high ionic conductivity making it promising for flexible ionotronic adhesive devices. Kuddushi et al. [141] also developed a stimuli-responsive and self-healable bioadhesive based on an ester-functionalized IL. Results demonstrated that the hydrogel was responsive to intracellular biological stimuli, including acidic pH of cancerous cells and temperature, making it promising for the controlled release of anticancer drugs. In addition, the morphology of hydrogel was changed by changing the shape and size of the gelator. In another interesting study, microwaveresponsive adhesives were developed using simple mixing of acrylic adhesives with ionic liquids [146]. Fast response to microwave irradiation was reported via local heating of the IL. This response resulted in adhesive failure in less than 30 s. One of the main applications of ILs based adhesives is sensing [140]. In a recent study, a self-healable and ultrastrong adhesive ionogel was developed for multifunctional strain sensors. Li et al. [147] prepared a polysiloxane-supported ionogel by locking ionic 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([EMIM][Tf2N]), into poly(aminopropylmethylsiloxane) (PAPMS) grafted with [2-(methacryloyloxy)ethyl] trimethylammonium chloride (METAC). Due to its adhesive behavior and high ionic conductivity, the obtained ionogelwas promising for flexible electronic devices such as sensors. In addition, Yu et al. [148] fabricated an adhesive hydrogel by multiple cross-linking between a PIL and k-carrageenan. The results indicate that the addition of PIL has a great influence on the adhesion strength of hydrogels. It can be due to interactions with charged groups or polar groups through ion-dipole and dipole-dipole interactions. Due to having suitable electrochemical performance, high mechanical stability, and strain sensitivity, these conductive adhesives can be appropriate for wearable strain sensors and the monitoring of human health [149].
However, alginate alone had weak dispersive signals of residual fluorescence (bottom, left panel). Abebe et al. [130] synthesized a self-adhesive hydrogel based on modified alginate with gallic acid (GA) and in-situ polymerization of polyacrylic acid for pH and strain-responsive transdermal delivery. According to the findings, stretching led to an increase in the release rate, but strain percentage had the opposite impact. As demonstrated in Figure 7D, strain percentage of 100% resulted in increased release within the first 10 min, but the releasing pattern reversed after 20 min at pH = 5.5. In 2019, a triple stimuli-responsive hydrogel with self-adhesive, self-healing capabilities was developed using N, N-diethylacrylamide (as a thermo-sensitive part), PDA (as a NIR light-sensitive part), and acrylic acid (as a pH-sensitive part) [131]. The resulting bioadhesive was extensively employed in wound dressings and wearable technology. Furthermore, the hydrogel with an optimum mass fraction of 0.4 wt.% of PDA was for the removal of methylene blue, with a maximum adsorption capacity of 305.4 mg/g.

Clinical Applications of Stimuli-Responsive Bioadhesives
Intelligent adhesives have been widely applied in biomedical applications, including tissue engineering, drug delivery, epidermal sensors, tissue sealants, and wound healing. The stimuli-responsive bioadhesives can be developed to regulate their adhesiveness based on applied stimulations. After the wound is healed, the bioadhesive must be removed from the wound closure process [150,151]. However, there is a risk of injuring tissue and triggering pain for patients during the removal process. The ability to modulate adhesiveness on-demand with stimuli-responsive bioadhesives allows the bioadhesive to be removed from the wound site without causing any damage or pain [13]. When the intelligent bioadhesive is used to adhere to dynamic tissues, it is subjected to periodic external stresses. The bioadhesive may suffer irreversible physical damage as a result. Selfhealing functionality is used as an efficient technique to assure the stability of bioadhesives in dynamic tissue settings. After the physical injury, self-healing bioadhesives repair their mechanical structure while keeping their original characteristics [152]. The stimuliresponsive bioadhesive can be programmed to deliver therapeutic medicines on demand. Due to the dynamic nature of the tissue healing process, temporal management of tissue is required for more effective tissue repair with fewer adverse outcomes. The stimuli-responsive bioadhesives allow for control by releasing antibiotics and therapeutic medicines at the right time to promote cellular differentiation, tissue-specific gene expression, and native tissue healing [153].
Internal body tissues, including bone, heart, nerve, kidney, nerve, and muscle, can also benefit from stimuli-responsive bioadhesives [34]. These interior tissues are moister and rougher compared to the skin tissue environment. The internal tissue environment is intricate and dynamic according to numerous biochemical parameters. As a result, implementing controlled responsiveness can be difficult. Another critical problem is creating stimuli-responsive bioadhesives that are stable in vivo for an extended time [154]. Furthermore, because internal tissue procedures inevitably necessitate incisions, a protracted adhesion process increases the risk of bacterial infection, inflammatory reactions, and tissue damage. Biocompatible bioadhesives with low cytotoxicity have demonstrated an essential role in this field.
Contact between electrodes and tissues is required to obtain electrical biosignals from the body. The touched electrode will experience dynamic motions in epidermal and interior tissues [155]. This might result in mechanical deformations such as stretching, compression, and bending during contact. Internal tissues have a stricter environment for electrode-tissue contact due to muscle contractions from gastrointestinal peristalsis, pulmonary cycles, and heart muscles. The electrodes may now be strongly retained on the tissue surface due to the invention of conductive smart bioadhesives. Furthermore, flexible bioadhesives provide for conformal contact between the electrode and the tissue, allowing direct electrical signal delivery [156]. The clinical applications of smart bioadhesives can be summarized and grouped in Table 7 as follows.  [162]

Light-responsive Hemostasis
The produced bioadhesive with injectability and immediate hemostatic effect can be used as a fast cross-linkable hemostatic agent for irregular wounds in oral/dental surgical procedures. [163] Hemocoagulase/GelMA Visible light-responsive Hemostasis The bioadhesives resulted in fast hemostasis and tissue sealing through the activation and aggregation of platelets as well as the effective transformation of fibrinogen into fibrin. [164] GO/poly(vinylalcohol)/PAA grafted with N-hydroxysuccinimide ester

Electro-responsive Bioelectronic
The obtained bioadhesive with biocompatibility, applicability, mechanical and electrical stability, and recording and stimulation functionalities can be used to improve tissue-device integration and enhance the performance of biointegrated electronic devices. [155] Gelatin/PAAm/Clay hydrogel Salt ions, pH, and stress BioSensor A capacitive pressure sensor with ability of high conductivity, high self-healing efficiency, and robust adhesion has been designed for monitoring human motions. [165]

Wound Healing of Soft and Hard Tissues
One of the most common uses of smart bioadhesives is wound healing. For many years, wound closure has been carried out with wires, sutures, and staples [166]. Nevertheless, concerns about the sign of scar, secondary damage, wicking-induced infection, slowed wound healing, and complicated postoperative care has limited their applications. Smart bioadhesives have become more popular because people are more concerned with their physical appearance [167]. Zhao et al. [157] created a new stimulus-responsive bioadhesive made up of a prepolymer of poly(glycerol sebacate)-co-poly(ethylene glycol)-g-catechol. Three incisions (2 cm) were made on the rats' backs to evaluate their capacity to close wounds. The smart bioadhesive-treated group had higher fibroblast recruitment and proliferation, as well as less inflammatory infiltration, on the seventh day after surgery. Liang et al. [158] fabricated a smart bioadhesive through dual-dynamic bond cross-linking between Fe, protocatechualdehyde containing catechol and aldehyde groups and quaternized chitosan. A full-thickness incision model was used to examine the wound closure's efficacy. On day 7 post-surgery, the sealed incision treated with the bioadhesive exhibited complete epidermis and dermis structures and higher collagen deposition levels than the control group, and the incision closed with surgical sutures. Treatment for wounds of brittle and hard tissues is another type of wound healing where smart bioadhesives are beneficial [168]. Bioadhesives, especially for small fragments of bone, are a quick and easy way to repair damaged portions of hard tissues. The lack of fixation of the small fragments of bone typically results in bone resorption, which can lead to deformation of the bone union, bone movement, and nonunion [169]. Accordingly, Yan et al. [112] developed an electrically conducting bioadhesive to attach tiny bone fragments in comminuted bone fractures. Aniline tetramer and dopamine were added to the system to enhance the cell adhesion, proliferation, and osteogenic differentiation of MC3T3-E1 cells.

Drug Delivery
The recent innovations in smart drug carrier systems seem promising, as they supply a means to promote formulations of targeted drug delivery systems, and drug release control based on stimuli response [170]. Smart bioadhesives in delivery have an advantage over typical hydrogel delivery systems in that they can fix delivered objects on the site. Mucoadhesion is effective in enhancing the bioavailability of poorly absorbed drugs by lengthening their residence time in the gastrointestinal tract, resulting in lower doses and dosage frequency [159,171]. Yan et al. [160] prepared adhesive hydrogel with pH, temperature, and NIR light-responsive behavior for use in controlled release systems. Zhu et al. fabricated a stimuli-responsive bioadhesive by incorporating graphene aerogel into a PNIPAM network with incorporated PDA nanoparticles. The NIR controllability of the bioadhesive for the DOX release was excellent. When the hydrogels were exposed to a NIR laser for one minute, DOX was released, and the amount released rose dramatically. After the laser was turned off, no more drug release was recorded. Smart bioadhesives can also be an important topic in both agricultural and environmental chemistry. For example, the Ca-alginate/PNIPAm-based photothermal adhesive was designed to control the release of imidacloprid (IMI) by sunlight [172]. Researchers showed that the accumulative release percentage of IMI was about 29.8% at 15 • C and increased to about 60.4% at 40 • C. Smart bioadhesives can also be loaded with cells and growth factors. Using a suitable scaffold biomaterial as a cell transport vehicle can create a favorable microenvironment for extending cell survival [173,174].

Leak Sealants in Medical
A common complication of surgeries and injuries is leakage. Headaches, meningitis, and seizures can result from cerebrospinal fluid leaks caused by traumas or brain and sinus surgery [175]. Gastric fluid leakage, common during surgical operations, can result in infection and significant tissue destruction [176]. As a result, leakage control is critical in lowering operation risks, complications, and costs. Tissue sealants, also known as smart bioadhesives for leakage prevention, have piqued the interest of researchers and have showed tremendous promise in the clinic. Blacklow et al. created a thermo-responsive bioadhesive to speed wound healing, contracted at body temperature. Bioadhesive dressings could help heal wounds in other epithelial tissues such as the gut, lung, and liver. Bleeding is one of the most common side effects caused by surgical procedures, injury, diseases, and medications [177]. Hemostasis sealants are widely accessible on the market. However, they have separate limits. Chang et al. presented a hemostatic photo-responsive bioadhesive based on gelatin methacryloyl that was able to prevent bleeding following oral/dental surgical procedures. According to the findings, the bioadhesive could be immediately extruded into the bleeding site and shortened blood clotting time by 45%. Furthermore, it may be easily removed from the bleeding site after clotting and prevent subsequent wound harm. Guo et al. [164] prepared a hemostatic smart bioadhesive composed of hemocoagulase (the same as reptilase) and GelMA, inspired by the coagulation function of snake venom. Blood clotting time with visible light-responsive bioadhesive was about 45 s compared with 5 to 6 min without bioadhesive. Hemostatic bioadhesives achieved hemostasis in 45 s on a liver incision and 34 s on a cut rat tail, reducing blood loss by 79 and 78%, respectively.

Wearable Medical Devices
Nowadays, implantable and wearable medical devices such as tissue scaffolds, biodetectors, and biosensors are attracting a substantial amount of attention . However, conformal and stable contact between such devices and the target tissue needs to be established. This fixation requires the use of sutures and wires, raising the risk of infection, scaffold deterioration, and subsequent injury. Smart bioadhesives have the potential to replace invasive fixing procedures with a noninvasive adhesion method. Deng et al. designed an electrical bioadhesive based on a thin layer of graphene nanocomposite that can provide rapid and on-demand detachable integration of bioelectronic devices onto a variety of wet tissues. They then successfully recorded an epicardial electrocardiogram using the synthesized bioadhesive on-site and electrically stimulated a sciatic nerve in a rat model. Zhu et al. prepared a smart ionic gelatin/PAAm/clay bioadhesive with high conductivity and high self-healing efficiency, which can be used as a capacitive pressure sensor for human motion monitoring.

Conclusions and Future Perspectives
Smart bioadhesives have become a subject of interest recently, not only because they increase the environmental sustainability and the bioadhesive's mechanical and biological features but also the reliability of adhesion when compared with synthetic adhesives. Smart bioadhesives are stimuli-responsive materials that undergo phase and morphology variations in response to environmental stimuli (e.g., temperature, pH, electricity, light, and magnetic fields) and establish a link between therapeutic aims and drug delivery. Wound cover, tissue engineering, skin sensors, and medication delivery systems are just some applications for smart bioadhesives. Once assessing recently established smart bioadhesives, we motivated the creation, ideologies, and applications to accomplish an organized review and offer broad support for outlook materials design that show great potential in treatment areas. Though noteworthy advancement has been achieved in developing smart bioadhesives, several unsolved issues and significant obstacles in materials manufacturing and efficiency evaluation impede their useful application and industrialization. In detail: (i) the first and foremost difficulty is finding low-cost and straightforward approaches to manufacture bioinspired adhesive structures or integrating stimuli-responsive materials into adhesive; due their time-consuming nature or severe conditions, many present synthetic processes are challenging to scale up, limiting these advancements for use only in laboratories. (ii) On the other hand, one inherent problem of smart bioadhesive hydrogels is the dependence on an aqueous system, as the stimulation event is carried out by the transfer of water between the environment and the adhesive [179]. Although some studies have confirmed that a smart bioadhesive can be agitated by moisture in the air, the stimulation performance in the open air will be less than in the water environment [180]. For example, this obstacle may prevent the reconstruction of injured muscles with artificial tissue. (iii) Another challenge is the compromise between degradation and structural and functional stability of the bioadhesive after a long period for different applications. For example, we require bioadhesives that self-destruct after drug delivery to the target tissue [181]. (iv) Another difficulty that must be addressed before smart bioadhesives can be used commercially is drug delivery monitoring [182]. (v) Recently, smart bioadhesives have been utilized for several disease treatments using the transdermal drug method. However, TDD's fundamental problems, such as the differences in drug dosing amounts between humans, parts of the skin, and gender, remain unresolved. The severe problem is that TDD does not accurately control dose absorption through injured and irritated skins, which have unpredictable drug permeability. Therefore, these groups of bioadhesives need more evaluation [183][184][185][186][187][188][189][190][191][192][193][194][195][196][197]. (vi) In contrast to various stimuli (temperature, pH, light, etc.) that have been introduced for drug delivery, a mechanical stimulus (e.g., compressive, tensile, and shear stress) can be created by the skin itself during body movement without the requirement for any external ambient stimulus. It thus makes mechanical stimulus an inexpensive drug delivery monitoring design [130]. (vii) Eventually, despite the progress in bioengineering methods for innovative bioadhesive preparation, numerous factors, such as reaction time, degradability, inflammatory, and immunological response of these materials, must be carefully evaluated to fabricate more cytocompatible bioadhesives for tissue engineering and drug delivery.
In the end, stimuli-responsive materials have broadened the scope of smart bioadhesives by boosting the accuracy in modifying therapeutic molecules' efficacy and decreasing their off-target toxicity. Nevertheless, it is challenging to develop intelligent systems for responding to several physiological signals or external stimuli at nanoscale level. Furthermore, efforts to maintain the payload in place until desired stimulation, the ability to reach deeper layers of tissue, and minimizing unwanted tissue injury are important issues that require further progress. We hope that this study will appeal to increasing notice from research groups performing interdisciplinary research in medical science, polymer science, and engineering and which more collaborative endeavors will be devoted to the progress of intelligent bioadhesives.