1 s2.0 S0144861722006920 Main

Carbohydrate Polymers 295 (2022) 119787
Contents lists available at ScienceDirect
Carbohydrate Polymers
journal homepage: www.elsevier.com/locate/carbpol
Biomedical engineering of polysaccharide-based tissue adhesives: Recent

advances and future direction
Hanieh Shokrani a, b, Amirhossein Shokrani c, Farzad Seidi a, *, Muhammad Tajammal Munir d,
Navid Rabiee e, i, Yousef Fatahi f, g, Justyna Kucinska-Lipka h, *, Mohammad Reza Saeb h, *
a
Jiangsu Co-Innovation Center for Efficient Processing and Utilization of Forest Resources and International Innovation Center for Forest Chemicals and Materials,
Nanjing Forestry University, 210037 Nanjing, China
b
Department of Chemical Engineering, Sharif University of Technology, Tehran, Iran
c
Department of Mechanical Engineering, Sharif University of Technology, Tehran, Iran
d
College of Engineering and Technology, American University of the Middle East, Kuwait
e
School of Engineering, Macquarie University, Sydney, New South Wales 2109, Australia
f
Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
g
Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
h
Department of Polymer Technology, Faculty of Chemistry, Gdańsk University of Technology, Narutowicza 11/12, 80-233 Gdańsk, Poland
i
Department of Materials Science and Engineering, Pohang University of Science and Technology (POSTECH), 77 Cheongam-ro, Nam-gu, Pohang, Gyeongbuk, 37673,
South Korea
A R T I C L E I N F O A B S T R A C T
Keywords: Tissue adhesives have been widely used for preventing wound leaks, sever bleeding, as well as for enhancing
Tissue adhesives drug delivery and biosensing. However, only a few among suggested platforms cover the circumstances required
Polysaccharides for high-adhesion strength and biocompatibility, without toxicity. Antibacterial properties, controllable degra
Bio-adhesives
dation, encapsulation capacity, detectability by image-guided procedures and affordable price are also centered
Bio-glue
to on-demand tissue adhesives. Herein we overview the history of tissue adhesives, different types of
Biomedical engineering
polysaccharide-based tissue adhesives, their mechanism of gluing, and different applications of polysaccharide-
based tissue adhesives. We also highlight the latest progresses in engineering of tissue adhesives followed by
existing challenges in fabrication processes. We argue that future studies have to place focus on a holistic un
derstanding of biomaterials and tissue surface properties, proper fabrication procedures, and development of
magnetic and conductive responsive adhesives in order to bridge the huge gap between the present studies for
clinical implementation.
1. Introduction 2019; Nam & Mooney, 2021; Shokri et al., 2022; Zhong et al., 2021).
Correspondingly, Table 1 (top) depicts the history of tissue adhesives,
Millions of surgical operations have been carried out around the since 1940 till now. Despite such advancements, the applications of most
world and in almost all cases, surgeons have been willing to close the of the existing adhesives have been challenging because they might
induced wounds preventing from the leaks, severe bleeding, preparing cause further damages to the tissue and increase the level of potent
antibacterial barriers, as well as enhancing the healing process. Classical inflammation and infection. Moreover, these systems have been known
techniques consist clips and staples, which have been forecasted to own to be painful and could leave some unattractive scars on the surface of
a global market value of US$15 billion annually by 2024 (Shagan et al., the patients’ body.
2020; Taboada et al., 2020). Tissue-adhesives as hemostasis agents, Recently, some Food and Drug Administration (FDA) approved glues
sealants, delivery platforms as well as implantable biomedical devices have entered the clinics. In a general view, we can categorize them into
have been widely under investigation in different areas of biomedical the internal and external ones on the ground of their applications.
engineering, especially during the last three decades (Buchaim et al., External bio-adhesives are usually utilized in topical medications,
* Corresponding authors.
E-mail addresses: [email protected] (F. Seidi), [email protected] (N. Rabiee), [email protected] (J. Kucinska-Lipka), [email protected]
(M.R. Saeb).
https://doi.org/10.1016/j.carbpol.2022.119787
Received 29 April 2022; Received in revised form 1 June 2022; Accepted 23 June 2022
Available online 27 June 2022
0144-8617/© 2022 Published by Elsevier Ltd.
H. Shokrani et al. Carbohydrate Polymers 295 (2022) 119787
whereas the internal ones are generally used in intracorporal conditions biodegradable adhesives, potent to strongly bind to the tissue in the wet
(direct contact with body fluid and organs) (Fan et al., 2016; Li, Liu, and dynamic environment in addition to antibacterial properties.
et al., 2022; Yuk et al., 2019). They can bind to the tissue surface not Different categories of glues, powders, nanoparticles, as well as hydro
only in highly dynamic tissues, but also under wet conditions. They also gels are suggested by different groups of scientists (Lu et al., 2020; Pan
pose antimicrobial activity, which is a requirement for efficient healing et al., 2020; Yazdi et al., 2021). In order to increase the biocompatibility
of tissue. However, most of them suffer from limited possibility of of bio adhesives, researchers make good use of inspiration from the
remote controlling over adhesion, low adhesion strength, and to some nature. To the best of our knowledge, polysaccharide-based hydrogels
extent from the relatively high level of toxicity. (especially chitosan and dextran) are top class of adhesive biomaterials,
Considering all the above-mentioned, plenty of investigations are due to their optical properties, hemostasis activities, biocompatibility as
underway in order to find some nontoxic (nontoxic byproducts) and well as inherent antimicrobial features (Pang et al., 2020; Sanandiya
Table 1
(Top) A glimpse at the history and progression of tissue adhesives from early 1940 up to present (Balakrishnan et al., 2017; Chao & Torchiana, 2003; Coover, 1959;
Ennker et al., 1994; Shagan et al., 2020; Spotnitz, 2014; Young & Medawar, 1940); and (bottom) functional groups attached to tissue surface and tissue adhesive
biomaterials.
History of tissue adhesives progression (Balakrishnan et al., 2017; Chao & Torchiana, 2003; Coover, 1959; Ennker et al., 1994; Shagan et al., 2020; Spotnitz, 2014; Young & Medawar,
1940)
Different functional groups on the tissue surface and tissue adhesive biomaterials
Functional groups in Chemical structure Functional Chemical structure Pros and cons Refs.
adhesives groups on
tissues
NHS esters Amine Thiol Pros: High reactivity and spontaneous cross- Bu et al. (2019)
linking
Cons: Susceptibility to hydrolysis, and long-term
storage requires a dry condition
Cyanoacrylates Amine Pros: Rapid polymerization process Korde and Kandasubramanian

Cons: Toxicity issues for monomers, degradation (2018); Leiro et al. (2018)
products, including cyanoacetate and
formaldehyde, and exothermal reaction
Aldehydes Amine Thiol 1,2 Pros: High reactivity and spontaneous cross- Zhang et al. (2018)
aminothiol linking
Cons: Toxicity issues for glutaraldehyde and
formaldehyde
Isocyanates Amine Pros: High reactivity and spontaneous cross- Spring (2018)
linking
Cons: Possible side reactions compromise the
reaction with amines on tissues
Catechol Amine Thiol Pros: Versatile chemistry with a multitude of Hofman et al. (2018); Thi et al.
Imidazole functionalities (2019)
Cons: Oxidization process required to activate
catechol
Aryl azides Amine Pros: High reactivity and spontaneous cross- Ishihara et al. (2006)
linking
Cons: Possible side reactions compromise the
reaction with tissue amines
Transglutaminases Glutamine and Pros: Biocompatibility McDermott et al. (2004)

lysine Cons: Slow reaction process
2
et al., 2019; Seidi et al., 2021; Xu et al., 2018). These polysaccharide- concerns are remained (Chevallier et al., 2021). Bluestar silicone is
based systems can provide a warm, moist and self-healing microenvi another commercial product usable as wound and scar care, transdermal
ronment with desired natural biological properties, providing support patches and wearable devices. According to the reliable reports, it owns
for strong binding to the targeted tissue, particularly when combined acceptable adhesion strength as well as exceptionally high tear strength
with the other biomaterials or nano-materials (Shamekhi et al., 2018; and elongation, in addition to being very flexible and durable. Since this
Yazdi et al., 2020). product is utilized for external applications, its degradation issues are
In this review article, we comprehensively overviewed the chemistry not challenging. However, further studies need to be conducted to
of tissue adhesives, along with mechanisms underlying the adhesiveness investigate the possibility of internal uses in parallel with the potential
of polysaccharide-based adhesives, and applications of polysaccharide- loading capability (Yildiz et al., 2022).
based adhesives, i.e., wound dressing, hemostasis agent adhesives,
antibacterial closures, drug delivery adhesives, cartilage treatment ap 3. Chemistry of polysaccharide-based tissue adhesives
plications of adhesives, as well as implantable adhesives. The most
recent or most innovative developments of polysaccharide-based adhe The wet adhesion of catechol group (C6H4(OH)2) is clear and well-
sives are particularly highlighted. Although there exist some fantastic known. Typically, catechol group can enter Michael reaction with
reviews about synthetic bio-adhesives (Nam & Mooney, 2021), methods thiol (R-SH) and amine (R-NH2) groups, which are abundantly present in
of bio-adhesives preparation (Ryu et al., 2015), primitive tissue adhe the surface of tissue. This is the reason why biopolymers (natural or
sives (Bhagat & Becker, 2017), their mechanism of action (Sánchez- synthetic) conjugated with catechol groups are candidate tissue adhe
Fernández et al., 2019; Zhu et al., 2018), their design strategies (Bao sives (Kim, Lee, & Ryu, 2020; Zheng et al., 2020). In this regard,
et al., 2020), and their origins (Bal-Ozturk et al., 2021), there is no catechol-modified biomaterials have been extensively studied. Addi
article summarizing the most state of the art platforms and applications, tionally, scientists utilize some specific biomaterials like poly-L-lysine
especially polysaccharide-based ones, the most recent improvements, (PLL) as bridging molecules in order to increase the interfacial adhesion
and the existing challenges in addition to the outstanding mechanisms. between the catechol groups and cells or tissues. For instance, a group of
The results indicate that the main requirement of successful bio- scientists chose hyaluronic acid (HA) as a platform for the functionali
adhesive development is pursuing interdisciplinary studies, which zation with catechol groups where PLL was used as a bridging agent.
integrate the biological, chemical and mechanical interactions of tissue Their results indicated that HA could sufficiently enhance the biocom
adhesives into a versatile bio-adhesive for a target tissue, where physi patibility, and the whole scaffold was elegant in adhesion to the porcine
cochemical characteristics of tissue adhesives are playing the main role. skin. They also demonstrated that the resulting scaffold could increase
All the biological limitations such as the host immune response, bacte the host tissue integration via angiogenesis enhancement (Kim, Lee, Lee,
rial activities and local environment characteristics should also be taken et al., 2020; Shokrani et al., 2022; Singh et al., 2021; Xi et al., 2021).
into account (Balkenende et al., 2019; Shokri et al., 2021). Several re However, since the surface of tissue has a net negative charge in phys
searchers addressed tissue specific adhesives by consideration of the iological conditions, HA with the same negative charge could not
chemistry and biology of the targeted tissue in terms of physiological satisfactorily interact with the tissue. To overcome this limitation, sci
responses (Nam & Mooney, 2021). entists have proposed mussel-inspired chemistry (Bagheri et al., 2020;
Pei et al., 2020; Wang et al., 2021). This approach works via the
2. Clinical and commercial glues oxidation of dopamine conjugated macromolecules to adhesive quinonic
groups, which can be facilitated using enzymatic oxidation (An et al.,
There are only a few bio-glues that reached the clinics despite 2018; Feng et al., 2016; Granskog et al., 2015; Zarrintaj et al., 2018).
considerable attempts made in academia, mainly because of some Enzymatic crosslinking is another option for crosslinking of polymer
inevitable weaknesses of bio-glues at the current state of the knowledge. catechol conjunctions in the presence of horseradish peroxidase (HRP)
To name but a few, we can address cyanoacrylate glue, 2-octyl cyano and H2O2. However, there are several variables in these reactions, such
acrylate (Dermabond), and fibrin sealants. Cyanoacrylate glue is a as biopolymer concentration, oxidizing enzyme, the design of
clinical glue repetitively, which has been used frequently by dentists. It biopolymer, catechol substitution degree, HRP concentration as well as
owns great wet adhesion, but produces toxic byproducts (like formal H2O2, which may change the final adhesiveness (Kim, Lee, Lee, et al.,
dehyde) after degradation. Likewise, Dermabond as a well-known clin 2020; Snider et al., 2021). Furthermore, cytotoxicity and pH de
ical skin closure and fibrin sealants was used in cartilage repair surgeries pendency of such reactions can limit their efficacy (Ryu et al., 2015). On
suffer from uncontrollable swelling ratio and low adhesion when sur the other hand, increasing the amount of sodium peroxide in reaction
rounded by blood components (Bhagat & Becker, 2017; Korde & Kan with aldehyde sodium alginate can bring about higher oxidation degree
dasubramanian, 2018; Taghizadeh et al., 2022). Albumin- leading to formation of more aldehyde groups. The excess aldehydes
glutaraldehyde is another example, which lacks bioactivity and in react with the amine groups of tissue (R-NH2), thereby a higher adhe
duces undesired inflammatory reactions. In addition to the mentioned siveness may be induced and correspondingly a more stable crosslinking
products, gecko- or worm-inspired glues are a class of nature-inspired network may cause a sort of slower degradation pattern (Wu et al.,
tissue adhesives, which enjoy from sufficient adhesion to the wet envi 2017). Addition of polydopamine (dopamine possessing catechol group)
ronment, but their strength is far beyond the standard defined for plenty nanoparticles is a well-known way to improve the adhesion character
of wound closing applications (Pourjavadi et al., 2020; Romano et al., istics of polysaccharides (Narayanan et al., 2020). Panday’s results
2016). Surgiflo and Floseal are two commercial bio-glues. Surgiflo is suggested that the addition of polydopamine nanoparticles (with a
reported as a gel-based hemostatic adhesive that can be excreted from controlled size of 200 nm) to HA hydrogel can significantly increase the
body after 6 weeks (this minimizes the body’s immunological re adhesion strength as a tissue glue (Fig. 1) (Pandey et al., 2021). How
sponses). However, its adhesion strength in humid environments is not ever, no antibacterial activity was detected for this platform. Notably,
desirable (Hao et al., 2022). Noteworthily, Floseal provides a very strong photo-crosslinkable thiolated chitosan adhesive hydrogel is another
tissue adhesion in a vascular surgery. However, its appropriate degra choice, which speedily forms an in-situ hydrogel after exposure to the
dation pattern is questioned (Binnetoğlu et al., 2022). Similarly, China UV lamp (Frost et al., 2016; Zeng et al., 2016). However, it is not easily
Perfectseal 2-Octyle glue owns the same limitation. It is a liquid-based operable. Notably, in-situ formed hydrogels reveal the highest ability to
adhesives that initiates the polymerization after being exposed to the adapt to the structural shape of the tears and wounds and appropriately
body moisture. Importantly, the chemical polymerization process un stick to the crack wall. However, they lack required level of mechanical
dermines its degradation capacity. Even if China Perfectseal could strength. For example, in cardiac bleeding, where the tissue strongly
decompose to its monomers (n-butyl cyanoacrylate), its toxicity moves, the mechanical properties are underscored (Kim, Ahn, Lee, et al.,
3
Fig. 1. (a) A general illustration of a bio-adhesive nanocomposite with polysaccharide base and possible interactions. (b) Dopamine nanoparticle size optimization
process. (c) By using carbodiimide chemistry, the dopamine can be conjugated on the surface of hyaluronic acid. (d) Crosslinking with sodium periodate assists to
form an adhesive nanocomposite. (e) The possible interactions between adhesive and tissue surface (Pandey et al., 2021).
2020). Table 1 (bottom) summarizes different functional groups on the 4. Gluing mechanisms
tissue surface and tissue adhesive biomaterials.
The adhesion of a tissue adhesive depends on the interface proper
ties, which itself can be divided into two components, adhesion layer
and adhesive matrix. Adhesion layer is the layer which directly contacts
Fig. 2. (a) A schematic illustration of tissue functional groups, which directly attach to the adhesive matrix; (b) A schematic illustration of chemical conjunction
between tissue functional groups (hydroxyl (OH),thiol (R-SH), amine (R- NH2), carboxylic acid (C(=O)OH), lysine (C₆H₁₄N₂O₂) and the reactive groups of adhesives
(catechol (C6H4(OH)2), aryl azide (N3) and cyanoacrylates (NC O₂CH3)).
4
with the tissue surface, whereas the adhesive matrix is the bulk network a combination of different types of interactions with one or two ones
responsible for a series of physical properties such as swelling ratio, dominantly controlling the whole phenomenon (Bao et al., 2020; Hyon
stiffness, as well as energy dissipation (Fig. 2a). The direct adhesion can et al., 2014; Seidi et al., 2018). However, designing efficient tissue ad
be driven via different mechanisms. The most outstanding adhesion hesive considering the main mechanism of gluing highly depends on the
mechanisms are chemical conjunctions, biological and biochemical mechanical properties of tissue, which is often overlooked. For instance,
coupling, electrostatic bonding, diffusion and physical entanglement the elastic modulus and stiffness of tissue adhesives should match those
(Aziz et al., 2015; Lih et al., 2012; Simson et al., 2013; Yang et al., 2020). of tissue to avoid deformation when the body’s normal stresses are
The chemical conjunctions are also called covalent bonding, while the applied (Guimarães et al., 2020).
physical ones are usually called noncovalent interaction. The key func
tion of all the mentioned mechanisms is to form firm connections with
the tissue surface under physiological conditions, which usually is 4.1. Chemical conjunctions
involved with blood or body fluid (Nam & Mooney, 2021; Villou et al.,
2020). Additionally, the competition between blood (or body fluid) and During the early stages of studying tissue adhesives, chemical con
tissue surface to interact with the functional groups of adhesive should junctions where usually considered as the dominant mechanism of
also be taken into consideration (Yang et al., 2020; Yuk et al., 2019). Due gluing (Blacklow et al., 2019; Kim et al., 2018). The chemical con
to the fact that a real and practical adhesion is far more complicated than junctions were usually reported between the chemical functional groups
what theories predict, the gluing mechanisms typically take into account of bio-adhesives and the biological surface. However, some other types
of chemical conjunctions were reported as well (Fig. 2b). For instance,
Fig. 3. (a) A general illustration of adhesives and cohesive forces (Cohesive crosslinking is within adhesive’s thickness and adhesive bonding is between adhesive-
adherent item interfaces); (b) The possible interaction mechanisms between chitosan, polyethylene glycol and N-hydroxysuccinimide (Strehin et al., 2010; Zhu
et al., 2018).
5
the chemical reactions between amino groups and carbonyl groups, the condition (especial temperature or pH) and can occur under completely
chemical reactions between the functional groups of tissue adhesives mild condition. Among common examples of adhesion with biological
with the crosslinking agents, the enzyme-mediated reactions, as well as mechanism are fibrinogen-thrombin interaction that happens during
free-radical polymerizations (photo-initiated polymerization and clotting cascade, biotin-avidin, and disulfate bonds with proteins (Gill
thermo-initiated polymerization) were reported (Zhu et al., 2018). man et al., 2020; Zhu et al., 2018). The biological coupling usually oc
Interestingly, in addition to supporting adhesion, the chemical covalent curs at the same time as all other mechanisms because it is a part of the
bonds contribute to the formation of adhesively integrated matrix. metabolic process. However, they are never enough where there is a
Indeed, chemical conjugations prevent the disintegration of the bio- serious demand for a bio-adhesive such as an extreme bleeding. Hence,
adhesives themselves (García & Smulders, 2016). more of effective mechanisms must be considered when designing an
As mentioned earlier, one way to reinforce the chemical conjunctions efficient adhesive (Wang et al., 2022).
in polysaccharides is to introduce aldehyde groups onto polysaccharide
molecules using oxidation (Liu et al., 2021). Oxidation can take place
4.3. Electrostatic bonding
after addition of sodium periodate. For instance, Hyon et al. introduced
aldehyde functional group onto dextran, which interacted with amino
Electrostatic bonding happens because of the existence of oppositely
groups on the tissue surface. Moreover, the existence of epsilon-PL
charged molecules present on the tissue surface and the adhesives
(ε-PL), an oligomer of L-lysine within their matrix brought about addi
(Fig. 4b). This oppositely charged components cause a double layer of
tional amino groups to support the cohesiveness (Aziz et al., 2015; Hyon
electrons leading to dispersive force induction and electrostatic bonds.
et al., 2014). As an example of enzyme-mediated polysaccharide-based
Alginate‑calcium and starch‑calcium are two important examples of
bio-adhesive, Li et al. provided a chitosan-polyethylene glycol amine
electrostatic bonding of polysaccharide-based tissue adhesives (Gao
(PEG)-tyramine (CPT) hydrogel in which horseradish peroxidase and
et al., 2019; Lin et al., 2019). Although this kind of bond formation does
tyramines tied with each other through enzymatic oxidation (Lih et al.,
not play a key role in adhesion strength, reports indicate that it is
2012). Elsewhere, Strehin et al. prepared a N-hydroxysuccinimide
determinative in muco-adhesion, which is very useful in drug delivery
(NHS)-grafted chondroitin sulfate (CS-NHS) and six-arm PEG (PEG-
platforms (Yang et al., 2020).
(NH2)6) as a crosslinker. The cohesive strength was supported by the
covalent amid bonds such that the NHS groups could effectively connect
to the tissue surface to boost adhesive strength (Fig. 3) (Simson et al., 4.4. Diffusion
2013; Zarrintaj et al., 2019; Zhu et al., 2018).
When the adhesive and adherent surface are compatible enough, the
interdiffusion of chains across the interface of adhesive occurs that can
4.2. Biological couplings affect the adhesion strength (Fig. 4c). An important condition in this
mechanism is the mobility of chains of both surfaces. Additionally, the
There are plenty of biomolecule-biomolecule interactions during surface of adhesive and adherent chains should be completely compat
metabolism of organisms, all of which can form bonds, known as ible with each other. However, this mechanism can be highly affected by
possible biological mechanisms of gluing (Fig. 4a). Due to the fact that the mobile chains’ concentration, the chains’ molecular weight, the
these bonds are originated from natural body metabolism, they are chains’ length, interface temperature as well as glass transition tem
intensively biocompatible. They also do not require any specific perature (Tg), all of which can directly affect the mobility of chains (Bal-
Fig. 4. (a) A schematic illustration of biological interactions between the biomolecules such as biotin-avidin and thrombin-fibrinogen; (b) A schematic illustration of
electrostatic bonding between the tissue adhesive and the tissue glycoproteins (such as chitosan and mucin); (c) A schematic illustration of diffusion of adhesive’s
chains into tissue surface (it is strongly dependent on the molecular weight of chains, chains’ length as well as tissue surface temperature); (d) A schematic illus
tration of physical entanglements between the adhesive (chains, nanofibers and nanoparticles) and tissue components.
6
Ozturk et al., 2021). Finally, the contact time of polymer chains (ad translation (Taboada et al., 2020). Silica (SiO2) and iron oxide are ex
hesive and adherent chains) is another critical factor in diffusion process amples of biomaterials that can participate in this mechanism (Gao
(Mansuri et al., 2016). et al., 2017).
5. Applications of tissue adhesives in biomedical engineering

4.5. Physical entanglements
To date, existing tissue adhesives have plenty of applications in
Recently, an outstanding study from Leibler et al. demonstrated that
biomedical engineering including wound dressing, antibacterial closure,
the presence of nanoparticles within the adhesive matrix can induce a
drug delivery, cell delivery, cartilage treatment as well as hemostasis
new gluing mechanism useful for increasing the adhesion strength.
agent (Zhu et al., 2017). These applications can be classified to internal-
Technically speaking, the presence of nanoparticles or nanofibers can
use and external-use applications of adhesives. External ones are usually
play the role of connectors among protein chains of tissue surface (Kim
utilized for sealing surgical wounds, in order to close the body surface.
et al., 2022; Wang, Liu, & Guo, 2018). Unlike the chemistry-based tissue
These adhesives (external) cannot be applied in inner cavities. In fact,
adhesion mechanism that occurs almost in all bio-adhesives, this type of
limited by their biological properties, they cannot be in a direct contact
adhesion mechanisms is relied on the physical entanglements (this kind
with the inner organs (Han et al., 2017; Zhang et al., 2020). Unlike
of interlocking also includes hydrogen bonding and hydrophobic in
external adhesives, internal ones are utilized in a direct contact with the
teractions (Daristotle et al., 2020)) and only occurs in the platforms that
organs inside the body. Hemostasis agent during heart surgery is an
contain nano-scale components (Fig. 4d). However, it is indeed benefi
example of internal-use adhesives (Annabi et al., 2015; Zhang et al.,
cial in terms of low-cost, convenient and applicable features for clinical
Fig. 5. (a) A general illustration of the origins of catechol (C6H4(OH)2) and methacrylate (CH2 = C(R) COOCH3)-modified chitosan/gelatin antibacterial actions. (b)
The preparation process of gelatin methacrylate-dopamine and chitosan methacrylate-dopamine (He, Sun, et al., 2020).
7
2015). They have to possess a super biocompatibility and more of glues using photo-gelation method is an effective and compatible tech
adhesion strength in comparison to the external ones. Generally nique of crosslinking for a wide variety of macromolecules without the
speaking, in addition to a desirable adhesion, they have to have no toxic need for chemical modification processes (Zhang, Zheng, et al., 2021).
byproduct after degradation, no inflammatory or carcinogenic response,
no irritating reaction, and be degradable by hydrolysis or enzymatic
5.3. Hemostasis agents
degradation (Pascual et al., 2016). Considering the mentioned re
quirements, polysaccharide-based tissue adhesives are of a great interest
Tissue adhesives have a high potential for rapid hemostasis. These
among the state of art studies. In this section, we will summarize
platforms can rapidly diminish the hemorrhage without any immune
different applications of polysaccharide-based tissue adhesives.
responses. However, their blood clotting rate, degradability (if they are
injected to the internal sites, such as cardiac surgery), injectability,
5.1. Antibacterial dressings
adhesiveness, irritation risks, as well as long-term inflammatory re
actions are very important in clinical uses (Kamoun et al., 2017). Among
Bacteria-infected wounds and antibiotic abuse are worldwide issues
all the natural biomaterials, polysaccharides, and especially oxidized
for clinics and medical systems. So, designing a kind of multifunctional
cellulose, hyaluronic acid as well as chitosan are the most appealing
wound dressing with non-antibiotic-dependency is highly demanded.
options, to the extent that most of commercialized products are made of
Plenty of studies have been conducted toward designing such systems.
cellulose and oxidized cellulose (MacDonald et al., 2017; Narayanan
However, these systems require a specific mechanism of antibacterial
et al., 2020; Zhang, Fu, et al., 2021). There exist some good studies that
activity or biomolecules delivery to fight against drug resistant bacteria
have minimized the inflammatory responses while maximizing the
(Han et al., 2020). Among all the proposed systems, polysaccharide-
adhesiveness and hemostatic ability. For instance, Chitosan-catechol,
based platforms are more interesting to scientists due to their compati
inspired from mussel-adhesive-proteins, is a suggested platform by a
bility and inherent antimicrobial activities (Fig. 5) (He, Sun, et al.,
group of scientists. Their reports show that this hemostatic structure has
2020). For instance, a group of researchers proposed a tissue adhesive
negligible toxicity and excellent adhesiveness. However, it suffers from
nanocomposite with remarkable photothermal antibacterial features.
unoptimized mechanical properties (Park et al., 2019). To overcome
They suggested that combination of N-carboxyethyl chitosan (CEC) and
weak mechanical properties, Pang et al. proposed the addition of
benzaldehyde-terminated Pluronic F127/carbon nanotubes (PF127/
dextran dialdehyde (DDA) to chitosan (Pang et al., 2020). Also, reports
CNT) will provide a nice system for healing infected wounds. Based on
show that combination of quarternized Chitosan with polydopamine as a
their reports, this platform owns hemostatic features, stable mechanical
cryogel can induce antioxidation properties to the excellent hemostasis
properties, excellent tissue adhesiveness, pH responsiveness, high water
performance and adhesiveness (Li et al., 2020). Despite adequacy of the
absorbance as well as great biodegradability. Its photothermal anti
studies conducted in designing hemostatic adhesives, the arterial and
bacterial activities is derived from the inherent antibacterial activities of
cardiac bleeding are still serious concern in view of the application
N-carboxyethyl chitosan and release of moxifloxacin hydrochloride,
criterion suggested for bio-adhesives, where they must adhere to a wet
which was already loaded in the hydrogel (He, Shi, et al., 2020). Ac
and strongly mobile surface. This is why the cardiac uncontrollable
cording to Wang et al. reports, utilization of injectable adhesive
hemorrhage is a hassle. In this regard, Hong et al. designed a photo-
polysaccharide-based hydrogel is a promising platform for sustained
reactive hyaluronic acid-based adhesive greatly mimicking the extra
exosome release which has re-epithelization properties in addition to
cellular matrix and strongly adhering to the cardiac surface under UV
antibacterial ones. However, being non-self-healable and lacking self-
light. Interestingly, this platform is able to withstand up to 290 mmHg
recovery characteristics are two main constrains of plenty of the exist
pressure, which is extensively higher than (almost three times) the
ing platforms (Suneetha et al., 2022; Wang et al., 2019).
normal blood pressure (60–160 mmHg). However, the drug loading
capacity of the mentioned system needs to be under further investigation
5.2. Wound healing
(Hong et al., 2019).
There exist plenty of clinical wound dressing hydrogels that suffer

from poor adhesiveness and cannot withstand the entered external 5.4. Drug delivery
damages. Moreover, their fixation process on the surface of wound is
challenging due to lack of appropriate adhesiveness (Wu et al., 2018). Wound dressing materials have been widely utilized to cover the
Most of hydrogels with a single component cannot meet the required wounds, not to be in direct contact with the external environment.
criteria. Therefore, recently attention has been directed toward com However, plenty of the conventional dressings lack the anti-
posite hydrogels. Polysaccharide-based hydrogels are well-known for inflammatory functions, which can cause fibrosis and stricture, when
their biocompatibility, antibacterial activities and biodegradability it comes to deep wounds such as gastrointestinal wounds after endo
(Jung et al., 2021). Hence, modification of these systems with catechol scopic surgery. This is the exact reason behind the fact that practical
group-containing materials such as dopamine (because these materials delivery of drugs (e.g., corticosteroid) is necessary for improving healing
increase the adhesion strength through oxidation and connecting to process (Nishiguchi & Taguchi, 2020). Injectable hydrogels have
thiol (R-SH) containing substrates) will provide us with a great wound attracted attention as delivery platforms. Among different poly
dressing platform (Kamoun et al., 2017; Shi et al., 2018; Xu et al., 2017). saccharides, hyaluronic acid has attracted scientists due to great
Among all the mentioned polysaccharides, sodium alginate and chitosan injectability, anti-inflammation profile, as well as self-healing perfor
are the most prevalent ones. Reports indicate that sodium alginate has mance (Mi et al., 2022). However, for internal cases, injectable hydro
good toughness and self-healing properties (in addition to biocompati gels face some challenges. One important limitation is that they may
bility and biodegradability) and chitosan owns antioxidant properties detach from their location due the high blood shear stress and also, they
which strongly supports the healing process (He, Sun, et al., 2020). For may not be able to maintain their gel state for a long period of time at a
instance, a photo-induced adhesive hydrogel from carboxymethyl chi location, where there exist a large amounts of body fluid (Fujiwara et al.,
tosan has recently been recommended. Accordingly, carboxymethyl 2021). This limitation will be highlighted when it comes to drug delivery
chitosan combined polyethylene glycol (as crosslinker) was approved to aims. Indeed, failing to maintain the gel state will bring about changing
be an antibacterial and antioxidant gel promoting wound healing pro in release pattern and also, detaching from the desired location (because
cess and upregulating Vascular Endothelial Growth Factors (VEGF). of blood flow pressure or presence of body fluid) will totally disturb the
Such a smart system also demonstrated great angiogenesis effect as well delivery profile. This is why the adhesion strength to the native tissue is
as hemostatic performance (Wei et al., 2022). Notably, fabrication of bio of a great importance for such systems (Boda et al., 2020).
8
5.5. Cartilage and tendon injuries treatment mechanical properties and regulate the kinetics of degradation (Fig. 6)
(An et al., 2018). This platform also enhanced the cartilage specific gene
Cartilage is a tissue with limited regenerative capacity when it is expression which is an efficient step toward its treatment. However,
damaged and tendon repair is a kind of unacceptably high failure pro lacking antibacterial properties is a major threat to a highly inflamed
cess because of being unable to recreate the load transfer mechanisms, area. Technically speaking, polysaccharide-based mussel inspired ad
which necessitates fabrication of mechanically optimized tissue adhe hesives can be administered to the cartilage–tendon interface in anterior
sives (Linderman et al., 2018). There exist two main treatment options cruciate ligament (ACL) reconstruction (it is a kind of tissue graft located
for articular regeneration, arthroscopic meniscectomy or surgical in in knee to restore its functionality after damage) not only to enhance
terventions. However, results obtained from these two methods are not tendon-bone bonding strength, but also to improve the bony inward
satisfactory (Sánchez-Fernández et al., 2019). Researchers are trying to growth as well as both chondrogenesis and osteogenesis capacity of the
design injectable biomaterials in order to provide a system with proper bone–tendon interface (Yuan et al., 2021). For instance, 3,4-dihydroxy
biological and chemical cues, regenerating a damaged cartilage. Reports phenyl chitosan (BGC) bio-adhesive is designed not only to provide a
indicated that hydrogels have high water content and great swelling very biocompatible media, but also to enhance the bio adhesion after
kinetics which is able to provide a biomimetic extracellular media being combined with soluble oxidants or cross-linking agents. Although
similar to the native cartilage tissue. It is also able to absorb the nutrient this platform supports tenogenesis, it additionally increases the
and metabolites, easily (Li et al., 2016). However, hydrogel adhesive expression of collagen I and upregulates tenogenic markers, the me
ness to the native tissue is a main key factor. Otherwise, the diffusion chanical optimizations need to be addressed (Fang et al., 2022). Ac
process of nutrients will be failed and also, the scaffold will be scattered cording to another study, utilization of chitosan in tendon healing
and will not be fixed in its accurate place. Hence, different chemical or platforms can reduce inflammation, modulate chemokine secretion and
physical cross-linking strategies of polymers have been employed to recruit tendon stem cells (Freedman et al., 2022).
prepare an adequate cartilage regeneration system with high adhesive
ness (Ren et al., 2015). Among biomaterials, the natural ones, especially 5.6. Tissue adhesive sensors
agarose, silk fibroin, chitosan, alginate, gelatin, elastin, hyaluronic acid
(HA), and chondroitin sulfate (CS) have shown a great performance due High stretchability, high adhesiveness, conductivity as well as sta
to great cell interactive properties (Kim et al., 2017). Noteworthily, CS is bility are the important criteria for implantable hydrogel sensors (Yu
the most outstanding option because it is contained units of β-1,4-linked et al., 2022; Zhang, Liu, et al., 2019). Combination of synthetic and
glucuronic acid and β-1,3-N-acetyl-D-glucosamine, which are the major natural polymers, metal nanomaterials, and carbon nanomaterials is
components of cartilage. According to reports, glucosamine has a key referred to as a suitable platform for hydrogel sensors and monitoring
role cell migration and receptor binding. However, chitosan suffers from applications (Agnol et al., 2019; Nam & Mooney, 2021). For instance,
weak mechanical properties and cannot withstand a long-term in vivo adhesive and healable soft human motion sensors have been under wide
duration (Han et al., 2018). As a good instance for application of investigations in order to be used as healthcare monitoring devices
polysaccharide-based tissue adhesives for cartilage treatment, An et al. (Wang, Gao, et al., 2018; Zhang, Sheng, et al., 2019). There exist some
proposed an enzymatic approach for fabrication of an adhesive hydro studies that offer human-friendly hybrid hydrogels with robust adhe
gel. Regarding the capability of hyaluronic acid and gelatin for meniscus siveness (Liao et al., 2017; Liu et al., 2017). However, three main bar
repair, they utilized a tyrosinase mediated crosslinking to enhance the riers have limited their application. Firstly, these systems require super
Fig. 6. A Schematic illustration of an injectable hydrogel from tyrosinase-mediated hyaluronic acid/gelatin for meniscus repair and the possible functional groups
that attract each other (An et al., 2018).
9
stretchability, secondly, they need to be highly sensitive and conductive, diminishes the exposure of adjacent healthy tissue to the drug. This
and thirdly, they must own excellent adhesiveness. Otherwise, they polysaccharide-based system is consisted of two main components,
cannot be applied as large-range human motion monitoring systems doxorubicin (DOX) loaded phenylboronic acid-modified mesoporous
because weak adhesion makes them unable to induce firm contact with silica nanoparticles (PBA-MSNs), and dopamine-conjugated hyaluronic
skin and so, they fail to record weak signals (Liu & Li, 2017). The next acid (DOP-HA). This platform is reported to have unique adhesion
main problem is that peeling adhesion tests have revealed that the more properties because of acid-cleavable dynamic boronate bonds between
we increase the toughness, the more adhesion and cohesion decrease. catechol group and PBA groups, which plays the main role for mini
Therefore, it is challenging to prepare a hydrogel sensor that has both mizing the drug uptake of healthy cells (Fig. 7) (Wu et al., 2019). From a
adhesiveness and toughness (Wang, Gao, et al., 2018; Zhang, Liu, et al., practical point of view, this novel platform seems to be a desirable and
2019; Zhang, Sheng, et al., 2019). Some studies have reported that potent platform for local anticancer delivery.
cellulose-based hydrogel sensors support us to have both options
together (toughness and adhesiveness). For instance, Yang et al.
demonstrated that presence of cellulose nanocrystals not only enhances 6.3. Cornea regeneration
all the mechanical properties, but also increases adhesive strength be
tween different substrates such as skin, plastic, glass as well as steel Eyes have different protective mechanisms (such as producing tears)
(Amer & Chen, 2020; Yang & Yuan, 2019). Several polysaccharide- which rapidly washout the entered drugs. This is why conventional
based adhesive sensors combined with tannic acid support fabrication methods (such as suspension) cannot effectively deliver drugs to the
of a platform with high reproducible adhesion strength, as well as targeted areas of eye. Likewise, ointments are not good options owing
oxidation resistance. Table 2 shows different applications of the fact that they undesirably change the tear’s refractive index. To
polysaccharide-based adhesives. resolve the existing problems for ocular drug delivery, delivery agents
must have bio-adhesive properties, which extend the contact time of
6. The latest advances in tissue adhesive applications drug in the eyes’ media. Notably, the existing methods of treatment
include using sutures and adhesives. Sutures are not only invasive,
6.1. Cell therapy especially for such a sensitive tissue, but also cause astigmatism and
carry a risk of infection. This is why utilization of soft and smart bio-
HA can be easily functionalized with different functional groups via adhesives is in the core of attention. (Barroso et al., 2022). Among all
its carboxyl or hydroxyl group. This property causes HA to be a nice the natural biomaterials, chitosan and sodium alginate own great
option for producing tissue adhesives. Additionally, HA poses some cell characteristics such as bio-adhesiveness, and inherent antibacterial ac
surface receptors such as CD44, ICAM-1, and RHAMM through which it tivity, which make them potent options for ophthalmic formulations.
can accelerate the cell-matrix interactions. Also, using the cell-matrix For instance, Motwani et al. reported that chitosan and sodium alginate
interactions, HA can activate the signal transductions that are integral nanoparticles loaded with brimonidine (Celecoxib™), not only exhibi
for cell survival. Regarding these properties, are used as tissue adhesives ted a desirable sustained release pattern (for 24 h), but also they
for cell therapy and cell delivery (Samanta et al., 2022). For instance, revealed high level of bio-adhesiveness (Fig. 8 shows examples of
using oxidative crosslinking, HA can be functionalized with catechol polysaccharide-based adhesives for ocular drug delivery) (Trujillo-de
amine (C6H9NO2) motif. This functional group can firmly bind to pep Santiago et al., 2019).
tides and proteins on the tissue surface. The resultant hydrogel not only In addition to drug delivery, cell delivery to the damaged cornea is
has great adhesion properties, but also it can provide a great media for very important because regeneration of cornea is dependent on delivery
human adipose-derived stem cells and hepatocytes viability after of both epithelium-renewing limbal epithelial stem cells (LESCs) and
encapsulation. It also accelerates angiogenesis. Noteworthily, HA re human adipose-derived stem cells (hASCs). Because of the existing risks
veals an outstanding viscoelastic behavior in addition to immunomod relevant to suturing of corneal implants, there is a serious need for
ulatory characteristics. Hence, this platform can be addressed as a fabrication of tissue adhesive platform in order to regenerate cornea. A
practical scaffold for minimally invasive cell therapy. However, more of group of scientists modified hydrazone-crosslinked hyaluronic acid (HA-
smart and innovative scaffolds are required modulating the local in DOPA) hydrogels with dopamine. In order to increase the quality of
flammatory microenvironment well as suppressing the potent oxidative hASCs encapsulation, they conjugated thiolated collagen IV on the
stress in order to reach the clinical translation of regenerative and effi surface of hydrogel. Their results indicated that this novel platform own
cient cell therapy (Chen et al., 2020; Shin et al., 2015). an excellent tissue adhesion when implanted to the porcine corneal
organ. It also has the ability to deliver cells to the targeted media,
6.2. Cancer therapy properly (Koivusalo et al., 2019).
Recently, application of hydrogels as chemotherapy delivery plat

form is questionable. It is due to the fact that hydrogels suffer from 6.4. Clinical imaging
instable network structure, weak mechanical properties as well as weak
tissue adhesiveness (Buckner et al., 2016; Shalumon et al., 2018). A Although tissue adhesives have been under plenty of investigations
good chemotherapy platform not only owns a sustained release pattern, from different aspects, there is an essential demand for detecting them
but also has a good tissue adhesiveness so as not to expose healthy cells via clinical imaging modalities. To overcome the clinical barriers, in
to hazardous drugs. However, the fixation process of the platform is ternal tissue adhesives need to be monitored over time. It helps scientists
usually unsuitable being restricted by plenty of nerve networks, blood to regularly check their chemical and biological status using state of art
vessels, multiple glands such as lymph nodes as well as the mobility of imaging methods like bioluminescence imaging technique (Mirzaei
the organs. (Li, Chandra, et al., 2022). Having high bio-adhesive prop et al., 2022). However, very few studies have followed this topic.
erties can enhance the efficiency of the fixation and minimize the drug Although Shin et al. have reported a good internal adhesive platform
exposure to the adjacent healthy tissue and simultaneously, it maximizes that is detectable via image guided procedures, their proposed system is
the drug penetration into the cancerous media (Wu et al., 2019; Zeng not natural. Indeed, we believe that such an internally used systems
et al., 2021). For instance, a group of scientists fabricated a multifunc must be super biocompatible. So, polysaccharide-based bio-adhesives
tional nanoparticle-hydrogel (NP-gel) hybrid system for targeted de may be a better option in comparison to tantalum oxide/silica core/shell
livery of anticancer drugs. They claimed that this new system can nanoparticles (TSNs) (Shin et al., 2017). However, their studies can be
remarkably increase the tumor-specific drug penetration while it so inspiring for further investigations.
10
Table 2
Different applications of polysaccharide-based adhesives.
Application Materials Pros Cons Refs.
Antibacterial Chitosan, N,N -Methylenebisacrylamide

′
Robust mechanical strength, antibacterial and High dependency on crosslinker Sharma et al. (2019)
antifungal activity concentration
Antibacterial Hydro caffeic acid-modified chitosan Optimized gelation time, good mechanical No drug release profile Du et al. (2020)
properties, homogenous microstructure and
high tissue adhesion properties, anti-infection
capability, no significant cytotoxicity, situ
antibleeding efficacy
Antibacterial N-Carboxyethyl chitosan, benzaldehyde- Potential option for photothermal therapy, a No drug release capability He, Shi, et al.
terminated Pluronic, carbon nanotubes suitable gelation time, stable mechanical (2020)
properties, hemostatic efficacy, high water
absorbency, and good biodegradability
pattern, anti-infection capability,
angiogenesis effect
Antibacterial Aldehyde pullulan, polyethylenimine Thermosensitive, injectable, self-healing, Mechanical properties were not Wang et al. (2019)
(PEI)-linked PEO–PPO–PEO (Pluronic tissue adhesive, antibacterial, hemostatic, and optimized
F127) UV-shielding polysaccharide-based scaffold,
long-term exosome release
Wound Dopamine-grafted oxidized sodium Efficient self-healing ability, exceptional No antibacterial effect or drug release Chen et al. (2018)
dressing alginate, polyacrylamide tissue adhesiveness, tissue regeneration pattern
capability
Wound Catechol- and methacrylate-modified Injectable, applicable at body temperature Lower adhesiveness compared to the He, Sun, et al.
dressing gelatin and chitosan without activation by UV, good adhesion to exceptional ones, reported by other (2020)
tissues, inherent antibacterial activity studies
Wound Gelatin, adipic acid dihydrazide, oxidized Good adhesiveness, good biocompatibility, No antibacterial effect or drug release Xing et al. (2021)
dressing sodium alginate appropriate swelling ratio, good injectability pattern
Wound Oxidized dextran, poly-L-lysine Low toxicity, well-controlled degradation rate, No antibacterial effect or drug release Matsumura et al.
dressing good mechanical properties, water stability, pattern (2014)
high tissue adhesiveness
Wound Aldehyde sodium alginate, amino gelatin Good gelling time, good swelling behavior, No antibacterial activity, no well-defined Yuan et al. (2017)
dressing tunable bonding strength by varying the degradation pattern and no drug release
content of aldehyde groups, high tissue profile
adhesiveness
Wound Poly(ethylene glycol), chitosan Dissolvable in neutral aqueous media, good No antibacterial activity, no well-defined Kim, Lee, Lee, et al.
dressing mechanical properties, facile gelation kinetics degradation pattern and no drug release (2020)
and high tissue adhesiveness profile
Hemostasis Chitin nano-whiskers, carboxymethyl High compressive stress, great adhesive No antibacterial effect or drug release Pang et al. (2020)
agent chitosan, dextran dialdehyde strength, negligible cytotoxicity, degradable pattern
without long-term inflammatory responses,
injectable, hemostatic efficacy
Hemostasis Glycol chitosan-catechol Reduced adhesion of immune cells, great No antibacterial activity, no well-defined Park et al. (2019)
agent tissue adhesion and hemostatic ability degradation pattern and no drug release
profile
Hemostasis Polydopamine, sodium Highly interconnected porous structure (~94 Adhesiveness was checked using adhesion Suneetha et al.
agent alginate–polyacrylamide % porosity), improved the cell proliferation, to plastic, skin, glass, computer screens, (2019)
cell attachment, cell spreading, and functional and leaves which can be far more different
expression of human skin fibroblasts, good with human organs, no antibacterial
hemostatic properties, rapid blood activity, no well-defined degradation
coagulation ability, great tissue Adhesion pattern and no drug release profile
Hemostasis Chitosan and dextran Negligible cytotoxicity and minimal swelling No antibacterial activity Balakrishnan et al.
agent in phosphate buffered saline, good tissue (2017)
adhesive properties, good storage modulus, a
good drug delivery vehicle,
Hemostasis Quaternized chitosan and polydopamine Excellent hemostatic performance, No well-defined degradation pattern Li et al. (2020)
agent multifunctional tissue-adhesiveness,
outstanding mechanical strength and easy
removability, antioxidant activity, and NIR
photothermal-enhanced antibacterial
performance
Hemostasis Chitosan, tunicates High platelet adhesion and blood clotting No antibacterial effect or drug release Sanandiya et al.
agent ability, two-fold greater adhesion ability in pattern (2019)
wet condition than did fibrin glue, the
electrospinning capability, fibrous structure
Hemostasis Starch, succinic anhydride and dopamine Biological adhesive and hemostatic capability, No antibacterial effect or drug release Cui et al. (2020)
agent ease of operation, rapid sol–gel transition, pattern
porous microscopic morphology, good
swelling ratio, good biodegradability, tissue-
like elastomeric mechanical properties and
excellent cyto-, hemocompatibility
Drug delivery Gelatin-hyaluronic acid, tyrosinase High mechanical properties, tissue adhesive No antibacterial effect Kim et al. (2018)
function, good delivery to the desired area,
sprayable hydrogel, good ability for cell and
growth factor delivery
(continued on next page)
11
Table 2 (continued )
Application Materials Pros Cons Refs.
Drug delivery Chitosan, pectin Mucoadhesive properties and oral therapeutic No well-defined degradation pattern Boda et al. (2020)
delivery capability, antimicrobial properties,
pH-responsive delivery
Cartilage Tyramine, hyaluronic acid, gelatin Modulated mechanical properties and Lower adhesiveness compared to the An et al. (2018) and
treatment degradation kinetics, tissue-adhesive exceptional ones, reported by other Sánchez-Fernández
properties, strong biocompatibility, enhanced studies et al. (2019)
cartilage-specific gene expression
Cartilage Polydopamine–chondroitin Good cell affinity, high tissue adhesiveness, No well-defined degradation pattern Han et al. (2018)
treatment sulfate–polyacrylamide facilitated cell adhesion and tissue integration,
super resilience and toughness, biomimetic
microenvironment for chondrocyte growth
and cartilage regeneration
Cartilage Tyrosinase-crosslinked alginate sulfate A strong increase in the expression of No well-defined degradation pattern Öztürk et al. (2020)
treatment tyramine chondrogenic genes such as collagen 2,
aggrecan and Sox9, human chondrocytes
encapsulation capability, enzymatic
crosslinking, strong adhesion to native
cartilage and chondrogenic re-differentiation
Implantable Titanium oxide polydopamine–perfluoro Capacitive reversibility that follows finger No well-defined degradation or Pei et al. (2020) and
Adhesives silica carbon dot-conjugated motion, strong adhesion to native skin, useful depreciation pattern Ryplida et al.
chitosan–polyvinyl alcohol-loaded tannic for artificial electronic skin (2019)
acid
Implantable Cellulose nanocrystals Rapid UV initiation, compressive cycling No well-defined degradation or Amer and Chen
adhesives sensibility at diverse pressure during 0.5, 1.0, depreciation pattern (2020) and Yang
and 1.5 Hz, flexible, applicable and Yuan (2019)
mechanosensory electronics and artificial
intelligence, strong adhesion to native skin
Fig. 7. A Schematic illustration of a nanoparticle-hydrogel hybrid formulation from silica nanoparticles and dopamine-conjugated hyaluronic acid which is loaded
with doxorubicin. The system will be activated in an acidic media and in the presence of hyaluronidase and it will release tumor-targeting and penetrative doxo
rubicin (Wu et al., 2019).
7. Concluding remarks and future challenges affordable price. In this review article, we have presented the chemistry
of polysaccharide-based adhesives, their main mechanisms of action,
Tissue adhesives have been widely used to prevent wound leaks, their biomedical applications (wound dressing, hemostasis agent adhe
sever bleeding, bacterial activities, as well as to enhance drug delivery sives, antibacterial closures, drug delivery adhesives, cartilage treat
and healing process. Although they have been under plenty of detailed ment applications of adhesives, as well as implantable adhesives), and
investigations, still there exist no platform with ideal properties for the most recent or most innovative developments of polysaccharide-
clinical uses. An ideal bio-adhesive needs to have sufficient adhesion based adhesives. Overall, polysaccharides due to some inherent prop
strength, biocompatibility, non-toxicity of byproducts, acceptable anti erties such as antibacterial (chitosan), angiogenesis (HA), wound heal
bacterial properties, controllable degradation, encapsulation capacity, ing (alginate), and hemostasis (cellulose) are appropriate platforms for
detectable by image-guided procedures (for internal uses) as well as tissue adhesive formulations. Moreover, biodegradability of
12
Fig. 8. Examples of polysaccharide-based adhesives for ocular drug delivery. (A) Chondroitin sulfate-based hydrogels; (B) NHS-modified chondroitin sulfate/amine
PEG; (C) Dextran-based sealant; (D) Hyaluronic acid-based glue (Trujillo-de Santiago et al., 2019).
polysaccharides resolves the shortcoming of degradation in biological multiple crosslinking strategies. Remarkably, economic limitations
media, which is the case when using adhesives of other families like play a vital role in this pathway.
PEG. Another interesting feature of polysaccharides is their tunable 3. Fabrication of magnetic and conductive responsive adhesives for
surface functionality, which facilitates coupling with complementary growth factor delivery is a serious clinical shortcoming, which needs
biomaterials used in tissue adhesive formulation (Xu et al., 2019). to be under further investigations.
Almost in all the literature on polysaccharide-based adhesives the 4. As mentioned above, a tissue adhesive as an anticancer delivery
chemical mechanism of gluing has been highlights, which is promising platform is highly required for clinical application of these systems.
indeed. However, the main challenge is the need for minimizing the toxic
After careful review of the literature, we understood that there exist drug exposure to the adjacent uncancerous tissue. Indeed, the drugs
some specific unresolved problems and unanswered questions, which quite often are accumulated by the adjacent healthy tissue nonspe
can be numbered: cifically, because of the drug concentration gradient.
5. The advent of advanced methods for developing bio-adhesives is
1. Successful fabrication of the next-generation adhesives requires a highly demanded. The available fabrication techniques are required
deep understanding of biomaterials and tissue surface properties, all to be time and cost effective, efficient, facile and tunable in terms of
possible adhesion mechanisms, and clinical limitations. We need to ultimate properties. In this regard, utilization of 3D printing tech
consider the physical and biological properties of each specific tis niques for fabricating curved structures, 4D printing strategies for
sue, which vary markedly among tissue types. The adhesion efficacy creating stimuli-responsive platforms (which perform shape change
is strongly dependent on the tissue-specific properties, which needs as a function of time) as well as exploring design strategies via ma
to be under further investigation. chine learning seem to own a most promising outlook.
2. Despite considerable advancements in tissue adhesives fabrication 6. Monitoring the long-term efficacy of the implanted adhesives is
methods, there exist some unmet needs such as non-controllable another issue. In fact, there is a need for monitoring the chemical,
polymerization. Scientists need to focus on development of bio physical and biological properties of the implanted adhesives over
mimetic adhesives, externally activated tissue adhesives, as well as time. Any change in tissue response, compatibility, adhesion and
13
cohesion can be integral. Investigations in this regard are still inad Bu, Y., Zhang, L., Sun, G., Sun, F., Liu, J., Yang, F., Tang, P., & Wu, D. (2019). Tetra-PEG
based hydrogel sealants for in vivo visceral hemostasis. Advanced Materials, 31(28),
equate for an explicit conclusion.
Article 1901580.
Buchaim, D. V., Cassaro, C. V., Shindo, J. V. T. C., Coletta, B. B. D., Pomini, K. T.,
Accordingly, there exist a huge gap between the number of in Rosso, M. P. D. O., Campos, L. M. G., Ferreira, R. S., Barraviera, B., & Buchaim, R. L.
vestigations and the practical and standard clinical products. To bridge (2019). Unique heterologous fibrin biopolymer with hemostatic, adhesive, sealant,
scaffold and drug delivery properties: A systematic review. Journal of Venomous
this gap, there is a necessity to better apprehend the barriers to clinical Animals and Toxins including Tropical Diseases, 25.
translation of tissue adhesives. It is believed that polysaccharides can be Buckner, J. C., Shaw, E. G., Pugh, S. L., Chakravarti, A., Gilbert, M. R., Barger, G. R.,
taken as game changers. Coons, S., Ricci, P., Bullard, D., & Brown, P. D. (2016). Radiation plus procarbazine,
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cardiac surgery. Journal of Cardiac Surgery, 18(6), 500–503.
Chen, J., Wang, D., Wang, L. H., Liu, W., Chiu, A., Shariati, K., Liu, Q., Wang, X.,
Hanieh Shokrani, Amirhossein Shokrani, Farzad Seidi (Correspond Zhong, Z., & Webb, J. (2020). An adhesive hydrogel with “Load-sharing” effect as
ing author), Muhammad Tajammal Munir, Navid Rabiee, Yousef Fatahi, tissue bandages for drug and cell delivery. Advanced Materials, 32(43), Article
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Justyna Kucinska-Lipka (Corresponding author), Mohammad Reza Saeb Chen, T., Chen, Y., Rehman, H. U., Chen, Z., Yang, Z., Wang, M., Li, H., & Liu, H. (2018).
(Corresponding author), the authors of the work entitled “Biomedical Ultratough, self-healing, and tissue-adhesive hydrogel for wound dressing. ACS
Engineering of Polysaccharide-based Tissue Adhesives: Recent Applied Materials & Interfaces, 10(39), 33523–33531.
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Advances and Future Direction” published in Carbohydrate Polymers
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declare that they have no known competing financial interests or per outcomes of transcatheter arterial embolization with N-butyl cyanoacrylate glue for
sonal relationships that could have appeared to influence the work re non-variceal gastrointestinal bleeding: A systematic review and meta-analysis.
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Daristotle, J. L., Zaki, S. T., Lau, L. W., Ayyub, O. B., Djouini, M., Srinivasan, P., Erdi, M.,
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Wang, L. (2020). Anti-infective and pro-coagulant chitosan-based hydrogel tissue
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Carbohydrate Polymers 295 (2022) 119787

Contents lists available at ScienceDirect

Biomedical engineering of polysaccharide-based tissue adhesives: Recent

Cyanoacrylates Amine Pros: Rapid polymerization process Korde and Kandasubramanian

Transglutaminases Glutamine and Pros: Biocompatibility McDermott et al. (2004)

5. Applications of tissue adhesives in biomedical engineering

There exist plenty of clinical wound dressing hydrogels that suffer

Recently, application of hydrogels as chemotherapy delivery plat

Antibacterial Chitosan, N,N -Methylenebisacrylamide

You might also like

1 s2.0 S0144861722006920 Main

Uploaded by

Copyright:

Available Formats

1 s2.0 S0144861722006920 Main

Uploaded by

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Original Title

Copyright

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1 s2.0 S0144861722006920 Main

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Carbohydrate Polymers 295 (2022) 119787

Contents lists available at ScienceDirect

Biomedical engineering of polysaccharide-based tissue adhesives: Recent

Cyanoacrylates Amine Pros: Rapid polymerization process Korde and Kandasubramanian

Transglutaminases Glutamine and Pros: Biocompatibility McDermott et al. (2004)

5. Applications of tissue adhesives in biomedical engineering

There exist plenty of clinical wound dressing hydrogels that suffer

Recently, application of hydrogels as chemotherapy delivery plat­

Antibacterial Chitosan, N,N -Methylenebisacrylamide

You might also like

Recently, application of hydrogels as chemotherapy delivery plat