polymers
Review
Principles and Design of Bionic Hydrogel Adhesives for Skin
Wound Treatment
Chunxiao Wang 1 , Xinyu Zhang 1 , Yinuo Fan 1 , Shuhan Yu 1 , Man Liu 1 , Linhan Feng 1 , Qisen Sun 1
and Panpan Pan 1,2, *
Citation: Wang, C.; Zhang, X.; Fan, Y.;
Yu, S.; Liu, M.; Feng, L.; Sun, Q.; Pan,
P. Principles and Design of Bionic
Hydrogel Adhesives for Skin Wound
Treatment. Polymers 2024, 16, 1937.
https://doi.org/10.3390/
polym16131937
Academic Editor: Mikyung Shin
Received: 13 June 2024
Revised: 26 June 2024
Accepted: 3 July 2024
Published: 6 July 2024
Copyright: © 2024 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Polymers 2024, 16, 1937. https://doi.org/10.3390/polym16131937
1 Marine College, Shandong University, Weihai 264209, China; wcx17661512175@163.com (C.W.);
17835855549@163.com (X.Z.); 15165524884@163.com (Y.F.); m18214113186@163.com (S.Y.);
liuman0725@126.com (M.L.); 18953179141@163.com (L.F.); 13864419248@163.com (Q.S.)
2 National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai 200025, China
* Correspondence: pppan@sdu.edu.cn
Abstract: Over millions of years of evolution, nature has developed a myriad of unique features
that have inspired the design of adhesives for wound healing. Bionic hydrogel adhesives, capable
of adapting to the dynamic movements of tissues, possess superior biocompatibility and effectively
promote the healing of both external and internal wounds. This paper provides a systematic review of
the design and principles of these adhesives, focusing on the treatment of skin wounds, and explores
the feasibility of incorporating nature-inspired properties into their design. The adhesion mechanisms
of bionic adhesives are analyzed from both chemical and physical perspectives. Materials from natural
and synthetic polymers commonly used as adhesives are detailed regarding their biocompatibility
and degradability. The multifunctional design elements of hydrogel adhesives for skin trauma
treatment, such as self-healing, drug release, responsive design, and optimization of mechanical and
physical properties, are further explored. The aim is to overcome the limitations of conventional
treatments and offer a safer, more effective solution for the application of bionic wound dressings.
Keywords: adhesives; hydrogel; natural; bioinspired; wound healing
1. Introduction
The skin, as the body’s largest organ, performs multiple physiological and protective
functions, most notably as the first line of defense against external aggressions [1–3].
Effective treatment of skin wounds is essential for maintaining this barrier function, not
only by ensuring rapid wound closure but also by reducing the risk of infection, accelerating
the healing process, and minimizing scar formation [4–6]. However, conventional trauma
management methods, such as surgical suturing and staple fixation, although widely used
in clinical practice, have limitations when dealing with certain vulnerable organs or soft
tissue trauma. Specifically, surgical suturing may cause further damage to surrounding
delicate tissues, prolong wound healing time, and the removal process of sutures and
staples may increase the risk of secondary infections and potentially lead to significant scar
formation [7–9]. In light of these challenges, medical adhesives, including tissue adhesives,
hemostatic agents, and sealants, have emerged as revolutionary wound closure solutions,
especially in cases where traditional suturing methods are not applicable or desirable. These
adhesives have demonstrated significant advantages in clinical applications, such as the
ability to rapidly stop bleeding, reduce the risk of infection, eliminate the need to remove
sutures, and reduce postoperative scarring [10–12]. Nonetheless, some chemical adhesives
currently in widespread use, such as α-cyanoacrylates and polyethylene glycol-based
adhesives, despite their excellent adhesion properties, are limited in their application to
promote wound healing due to the potential toxicity of their degradation products, inherent
toxicity, incompatibility with wetted surfaces, and lack of dynamic adaptability [13–15].
https://www.mdpi.com/journal/polymers
Polymers 2024, 16, 1937 2 of 30

In recent years, wet dressings, particularly hydrogel-based dressings, have been

demonstrated to expedite the wound healing process by providing an optimal moist healing
environment. A moist environment aids in maintaining proper hydration, promoting
angiogenesis and collagen synthesis, and facilitating the debridement of necrotic tissue,
thereby accelerating the overall healing process [16–18]. Hydrogel adhesives, as a three-
dimensional cross-linked hydrophilic polymer network with high water content, offer a
wide array of potential applications in various biomedical fields due to their excellent
biocompatibility, manufacturing versatility, and favorable physical properties, such as
their resemblance to the natural matrix. By employing different crosslinking mechanisms
and functional group modifications, hydrogel adhesives can achieve diverse crosslinking
densities, mechanical properties, and porous structures to cater to the requirements of
various medical applications [19–22]. However, due to the high hydrophilicity and swelling
of hydrogel, its adhesion under water is low [23,24].
In response, the development of bionic hydrogel adhesives has received considerable
attention from researchers. These materials draw on the adhesion mechanisms of organisms
in nature, such as the adhesive proteins secreted by marine mussels and the microstructure
of gecko toes, with the aim of mimicking these mechanisms to improve the performance
of adhesives [25–27]. At the heart of biomimetic technology lies an understanding of the
principles of adhesion in nature and the application of these principles to the develop-
ment of new materials that address the challenges of non-degradability, cytotoxicity, and
compatibility with wetted surfaces found in traditional adhesives [28–31]. By mimicking
these natural adhesion strategies and incorporating advances in modern materials science,
researchers are working to develop a new class of bionic hydrogel adhesives that not
only outperform traditional materials in terms of adhesive performance but are also more
compatible with clinical applications in terms of safety and efficiency [32,33].
In this paper, we offer a comprehensive overview of the application of innovative
bionic hydrogel adhesives in the field of skin trauma therapy, including their design con-
cepts, principles, and future prospects. We examine the selection and use of natural and
synthetic polymers concerning biocompatibility and degradability. By analyzing the adhe-
sion mechanisms of bionic adhesives from both chemical and physical perspectives, this
paper further explores the design elements of hydrogel adhesives in skin trauma therapy,
such as self-healing, drug release, responsive design, and optimization of mechanical and
physical properties, with the goal of overcoming the limitations of traditional therapeutic
approaches and providing safer and more effective solutions.

2. Adhesion Mechanism of Bionic Hydrogel Adhesives

2.1. Direct Extraction and Mimicry of Organismal Chemistry
Life has evolved numerous powerful principles for controlling adhesion, many of
which have been applied to engineered materials. Many plants and animals secrete sticky
substances to ensure survival and adapt to their environments. Certain functional groups
within these compounds interact to establish strong surface affinity and high surface
specificity. In this chapter, we will explore natural plant and animal binders based on
carbohydrates, proteins, and glycoproteins. We will investigate the components and
mechanisms that enable these natural adhesives to function effectively and explore how
these principles can be applied to the development of bionic hydrogel adhesives for skin
wound treatment.

2.1.1. Protein-Based Natural Plant and Animal Adhesives

The mussel anchors itself to solid surfaces such as rocks and hulls using adhesive
proteins (mussel adhesive protein, MAP) secreted by its pedunculated filament glands
to withstand wind and wave action. These proteins solidify in seawater to form high-
strength, tough, water-resistant fibers. The main adhesion protein, Mefp-1, is enriched
with catechol amino acid residues and iron ions, enabling it to rapidly cure and form
adhesive structures underwater. A common feature of Mefp proteins is the presence of
Polymers 2024, 16, 1937 3 of 30

3,4-dihydroxyphenylalanine (DOPA), which allows crosslinking of MAP molecules and

ensures their curing and excellent water-resistant adhesive properties. DOPA is essential for
mussel adhesion and cohesion, forming strong hydrogen bonds with polar polymers and
irreversible organometallic complexes with the substrate surface through phenol groups.
For example, after the secretion of Mefp-3 and Mefp-5 onto the surface of solid substrates,
DOPA reacts with the substrate surface to form a stable complex that firmly adheres the
proteins to the surface. Additionally, DOPA in Mefp-2 and Mefp-4 oxidizes to form DOPA
quinone, which forms covalent cross-links with lysine and cysteine via a Michael addition
reaction or with other DOPA molecules through oxidative coupling. This further enhances
protein cohesion. The adhesion mechanism of mussels primarily involves the formation
of hydrogen bonds, organometallic complexation, and π–π interactions. The crosslinking
reactions between peptides include phenol coupling, Michael addition, and Schiff base
substitution. Through these pathways, the mussel enhances adhesion and cohesion in
seawater, ensuring it can firmly adhere to various surfaces, making it an effective natural
adhesive [34–37].
The sandcastle worm, known as the ‘mason under the waves’, lives in a mineral shell.
Instead of secreting the shell directly, like mollusks, it secretes a gelatinous mucus that binds
sand and shell fragments together to form a strong mineral shell. This mucus is produced by
the worm’s secretory glands, and each secretory cell contains numerous adhesive particles
capable of delivering ‘homogeneous’ or ‘heterogeneous’ particles on demand. The bio-
adhesive glue secreted by the sandcastle worm contains moderate amounts of DOPA and
includes six different types of adhesion proteins, polysaccharides, and magnesium ions.
The proteins responsible for adhesion include Sa-1, Sa-2, Sa-3A, and Sa-3B (each ≤ 22 kDa),
differing in their amino acid composition. Sa-1 and Sa-2 are cationic at pH 8.2 and rich in
glycine, alanine, tyrosine (functionalized by hydroxylation), and lysine. Sa-3A and Sa-3B
are anionic and mainly composed of serine (functionalized by phosphorylation). Tyrosinase
and peroxidase in the bio-adhesive link contain DOPA-containing proteins, enhancing
cohesion and adhesion. The sandcastle worm’s bio-adhesive undergoes a secondary curing
process within a few hours of the initial curing, further enhancing cohesion. Its color
gradually changes from off-white to brownish [38–41]. Eventually, the adhesive cures to
form a porous structure filled with interstitial fluid, allowing the sandcastle worm to attach
stably to its shell made of sand and shell fragments.
The strong and permanent adhesion of arthropod barnacles differs from that of mus-
sels in that it is achieved by a unique barnacle glue that provides strong and permanent
underwater attachment. The barnacle adhesive consists of a variety of adhesive proteins
produced by adult glandular cells and secreted through ducts at the interface between
the barnacle and the substrate. It undergoes aqueous displacement and solidifies with
the surface, thus ensuring that the barnacle is securely attached to a variety of substrates,
including metal oxides, glass, plastic, wood, and rock. The main components of barna-
cle glue are complex biomolecules, approximately 92% of which are proteins, with the
remainder being sugars and lipids [42,43]. Kamino et al. proposed a molecular model for
the underwater adhesion of barnacle adhesion proteins, with cp19k proteins responsible
for adhesion to external substrate surfaces and cp20k proteins responsible for binding to
the calcareous base of the barnacle [44]. Despite the low content of lipids and sugars in
the barnacle glue, they play an important role in barnacle adhesion to the substrate, and
Gohad et al. suggested that barnacle adhesion is a result of the synergistic action of lipids
and phosphoproteins. Liang et al. proposed a more refined model of barnacle underwater
adhesion based on Kamino’s model, which emphasizes that the barnacle secretes a phase-
separating solution during molting that consists of a phenol-rich gel phase and a lipid-rich
phase. This mixture removes biofilm from the substrate surface, cleaning it and preparing
it for strong adhesion of the barnacle glue. In this way, the barnacle glue achieves strong
adhesion to a variety of substrates [45].
Polymers 2024, 16, 1937 4 of 30

2.1.2. Carbohydrate-Based Natural Plant and Animal Adhesives

Polysaccharide and carbohydrate components are also commonly found in natural
binders of plant and animal origin, which consist mainly of long chains of straight and
branched monosaccharide units bound together by different glycosidic bonds. Their high
molecular weight and high density of polar functional groups allow these biopolymers
to form unique secondary structures (e.g., helical, laminar, or helical conformations) that
enhance the cohesive properties of carbohydrate-based binders [40].
Alginate is a polymer composed of long chains of (1→4)-β-linked D-mannuronic
acid (M units) and (1→4)-α-linked L-guluronic acid (G units). This polymer’s molecular
configuration allows it to absorb water up to 100 times its own weight and form gels when
exposed to divalent cations like Ca2+ . The crosslinking reactions involve the chelation of
calcium ions with carboxyl groups on adjacent polymer chains, thereby stabilizing the gel
structure [46].
The properties of alginate depend on its viscosity and the ratio of mannuronic and
guluronic acids (M/G). High molecular weight increases viscosity, while conformational
differences between M and G units result in three chain segments with different properties:
MM segments have a linear structure and are elastic; GG segments are helical and rigid;
and MG alternating segments are intermediate (Figure 1). Alginate gels with high MM
chain segments have good elasticity, while high GG chain segments produce hard, friable,
and thermally stable gels. The M/G ratio, sequence, chain length, and molecular weight
all affect the properties of the gels, which in turn determine their performance in applica-
tions [47,48]. A composite hydrogel adhesives based on sodium periodate-oxidized sodium
alginate combined with dihydrazide-modified γ-polyglutamic acid and bio-glass has been
developed by Gao et al. This gel was able to achieve strong adhesion to a wide range
of tissues and implantable surfaces to promote wound healing [49,50]. On the one hand,
the bio-glass provides an alkaline microenvironment to stimulate the binding of oxidized
sodium alginate to amino acids in the surrounding tissues, thereby increasing the tissue
binding strength. On the other hand, the bio-glass chelates with the carboxyl groups in
the oxidized sodium alginate by releasing Ca2+ , thus conferring strong adhesion to the
hydrogel adhesives. The remarkable characteristics of alginate, including its biocompatibil-
ity, biodegradability, non-toxicity and easy gelation, make it an ideal material for various
applications. It can be used in various forms, such as hydrogel and sponge, and has a wide
range of applications in the biomedical field.
Polymers 2024, 16, 1937
Polymers 2024, 16, x FOR PEER REVIEW 5 5ofof32
30

Figure 1.
Figure 1. (A)
(A)Chemical
Chemicalstructure
structureofofalginate;
alginate;
(B)(B) Effect
Effect of 2+
of Ca Caon
2+ on MG, MM, and GG alginate units
MG, MM, and GG alginate units [51].
[51].
2.1.3. Glycoprotein-Based Natural Plant and Animal Adhesives
2.1.3.Tuo
Glycoprotein-Based Natural
et al. collected and Plant and
freeze-dried Animal
natural Adhesives
hydrogel substances secreted by snails,
whichTuowereet al. collected
sterilized to and
obtainfreeze-dried natural
a porous and hydrogel substances
high-adhesion performance secreted
adhesiveby snails,
(dried
which
Snail were Gel,
Mucus sterilized
d-SMG).to obtain
It was aanalyzed
porous and found
high-adhesion performance
to be mainly composedadhesive (dried
of biomolecules,
Snailas
such Mucus Gel, d-SMG).
heparin-like It was analyzedsnail
glycosaminoglycans, and found
mucin,toand
be mainly composed ofSubstances
snail hemocyanin. biomole-
with
cules,different
such as charges in d-SMG
heparin-like form a unique dual
glycosaminoglycans, network
snail mucin,gel system,
and which endows
snail hemocyanin. the
Sub-
snail mucin
stances withgel with strong
different chargesadhesion andform
in d-SMG toughness [52].dual
a unique Thenetwork
adhesivegelcansystem,
firmly adhere
which
to wet tissue
endows surfaces
the snail mucin with
gelbetter adhesive
with strong strength
adhesion andthan fibrin glue
toughness [52].commonly
The adhesiveused in
can
clinical practice and can effectively bind rat skin incisions with better overall
firmly adhere to wet tissue surfaces with better adhesive strength than fibrin glue com- results than
sutures
monly usedand inmedical
clinical508 glue. and
practice d-SMG
can can also reduce
effectively bleeding
bind rat caused with
skin incisions by liver damage
better over-
and has better
all results thanhemostatic
sutures and function
medical(Figure 2). Further
508 glue. d-SMG studies
can alsohave shown
reduce that this
bleeding natural
caused by
Polymers 2024, 16, 1937 6 of 30

bio-adhesive, composed of positively charged proteins and polyanionic glycosaminogly-

cans, has excellent hemostatic properties, is biocompatible, biodegradable, and significantly
accelerates the healing of chronic wounds. d-SMG has remarkable functions, including
promoting the transformation of macrophages to anti-inflammatory phenotype, alleviating
inflammation of chronic wounds, and promoting epithelial cell regeneration and angiogen-
esis. Its main active ingredient is rich in heparin-like glycosaminoglycan, which has high
Polymers 2024, 16, x FOR PEER REVIEW
affinity and can bind with inflammatory cytokines. The discovery of d-SMG provides 7 of 32
a
highly important advance in the development of adhesives and dressings.

Figure2.2.Adhesion
Figure Adhesionmechanism
mechanismofoffreeze-dried
freeze-dried snail
snail mucus
mucus (d-SMG)
(d-SMG) and
and its its mechanism
mechanism in promot-
in promoting
ing wound healing
wound healing [52]. [52].

Adhesive materials, especially underwater adhesive materials, as an advanced func-

tional material have extremely important applications in biomedical fields, such as wound
healing. Many kinds of organisms in the marine ecosystem can secrete adhesive proteins
with strong underwater adhesion ability, such as mussels, sandcastle worms, barnacles,
and blind eels. These organisms provide inspiration and ideas for the development of bi-
omic adhesive materials. Compared with conventional adhesives, marine bio-adhesives
Polymers 2024, 16, 1937 7 of 30

When ivy climbs objects such as rocks, it secretes tiny particles that cling to the contact
surface. These nanoparticles are highly uniform in size and low in viscosity, allowing them
to penetrate into the nooks and crannies or cracks of porous surfaces. The researchers found
that the arabinogalactan proteins in the nanoparticles play a key role in the subsequent
molecular bonding process. As water evaporates, the proteins interact with the pectin and
calcium in the ivy secretion to firmly adhere the particles to the surface. After solidifying,
this binder is highly tolerant of temperature and environmental changes, allowing ivy to
survive natural disasters. Due to ivy’s ability to adapt to a wide range of environmental
conditions, its adhesive is considered ideal for the development of protective coatings [53].
The blind eel, which usually lives in deep water up to 100 m below the surface, has an
elongated, white appearance and an oval-shaped, sucker-like mouth. When in danger, it
secretes natural mucus through glands on both sides of its abdomen, which quickly mixes
with water to form a polymer that expands nearly 25,000 times in mass, effectively blocking
enemy attacks. From a microstructural point of view, the main components of the mucus
are mucin and water, with the mucin being modified by sugar molecules to give the mucus
its stickiness. Unlike complex 3D-structured proteins, mucins are usually in the form of
long rods, with sugar molecules attached along the protein backbone to form a ‘sugar
coating,’ giving mucins excellent water retention and resistance to protein hydrolysis. The
concentrated secretion of the blind eel contains discoidal vesicles a few micrometers in size,
accompanied by a small number of keratin filaments up to 30 cm in length. After secretion,
the structure of keratin filaments changes from α-helical to β-lamellar, forming a stable
interconnecting network that attracts large amounts of water and forms hydrogels in the
presence of divalent calcium ions [54]. This unique structure provides strong protection for
the defense system of the blind eel and offers valuable insights into the development of
novel biomedical materials [55].
Adhesive materials, especially underwater adhesive materials, as an advanced func-
tional material have extremely important applications in biomedical fields, such as wound
healing. Many kinds of organisms in the marine ecosystem can secrete adhesive proteins
with strong underwater adhesion ability, such as mussels, sandcastle worms, barnacles,
and blind eels. These organisms provide inspiration and ideas for the development of
biomic adhesive materials. Compared with conventional adhesives, marine bio-adhesives
are non-toxic, biodegradable, and have strong adhesion. Their most important feature is
that they can maintain stable bonding ability under different humidity conditions, which is
highly valuable for the development of underwater adhesives.

2.2. Mimicking the Physical Structure of Organisms

Bionic hydrogel adhesives can be classified into chemically based biomimetic adhe-
sives and physically based biomimetic adhesives. In this section, we will focus on adhesion
designs that mimic the physical structures of organisms, exploring biomimetic strategies
and their potential clinical applications. In nature, various structure-related adhesion
mechanisms have evolved on bio-adhesive surfaces. Depending on whether the adhesion
is derived from interfacial interactions or involves a fluid medium, structure-based bio-
adhesion strategies can be primarily categorized into physical adhesion based on interfacial
interactions, physical adhesion based on interfacial hydrodynamics, and physical adhesion
based on negative pressure adsorption (Table 1).

2.2.1. Physical Adhesion Based on Interfacial Interactions

Physical adhesion formed by interfacial interactions is achieved through the enhance-
ment of mechanical interlocking or van der Waals forces between interfaces via ordered
structures. Mechanical interlocking refers to the formation of adhesion through the surface
penetration of the adhesive material, which mechanically interlocks with microscopic holes
or irregularities on the surface of the substrate material, creating an interaction similar to
that of a lock and key [56]. Mechanical interlocking can be accomplished by geometrically
connecting two adherends without the need for either covalent or non-covalent bonding.
Polymers 2024, 16, 1937 8 of 30

Mechanical interlocks can be broadly classified into two categories: a lock-and-key topology
between adhesive and closed pore adherends (Figure 3A), and a threaded hole topology
between adhesive and open pore adherends (Figure 3B) [57]. Mechanical interlocking
adhesion between rough surfaces can be enhanced by removing weak surface layers and
increasing contact area [58]. Organisms that utilize mechanical interlocking adhesion in
nature include planktonic larvae and echinoderms. The microneedle patch, one of the
representatives of medical hydrogel adhesives, is inspired by the mechanical interlock-
ing strategy [59,60]. At the molecular scale, polymer molecular chains pass through the
adhesion zone and form a molecular interlocking structure on the surface of a highly
robust physical gel, which allows the interfacial interaction energy to be transferred to the
substrate and dissipated, thus achieving high adhesion strength (Figure 3C) [61]. At the
macroscopic level, it is also possible to modify the soluble gel coating on the surface of
the microneedle. After insertion into the skin, the hydrogel coating dissolves,
Polymers 2024, 16, x FOR PEER REVIEW forming a
9 of 32
mechanical interlocking mechanism (Figure 3D) [62].

Figure 3.
Figure 3. (A,B)
(A,B)Key-lock
Key-lockand threaded
and holehole
threaded topology adhesion
topology structure
adhesion [57]; (C,D)
structure [57];Interlocking
(C,D) Interlocking
interface adhesion mechanism [58,62].
interface adhesion mechanism [58,62].

2.2.2. Physical Adhesion Based on Interfacial Hydrodynamics

Physical adhesion related to interfacial hydrodynamics is achieved by generating ca-
pillary forces or Stefan adhesion with the help of ordered structures [63]. Typical examples
include tree frogs, laryngeal discus fish, and beetle flies, whose adhesive organs usually
have special micro- and nanoarray structures and corresponding mucus glands. The re-
 Polymers2024,
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2.2.2. Physical Adhesion

micrometer-wide grooves Based on Interfacial
between Hydrodynamics
the polygonal structures (Figure 4A). These channels
can drain
Physicalthe adhesion
liquid at the contact
related interface, achieving
to interfacial direct contact
hydrodynamics between
is achieved solids and
by generating
thereby providing
capillary highadhesion
forces or Stefan adhesionwithor friction
the help[63,65]. Liu et
of ordered al. developed
structures a gradient
[63]. Typical com-
examples
include tree frogs, laryngeal
posite micropillar array inspired discusby fish,
treeand beetle
frogs flies,4B),
(Figure whose adhesive
which organs
achieves usually
2.3-fold dry
have special
adhesion andmicro- andwet
5.6-fold nanoarray
adhesion structures
compared andwith
corresponding mucus glands. The
pure polydimethylsiloxane release
micropil-
of
larviscous
arrays fluids forms
[66]. This many
study fluid
also bridgesa at
provides newinterfaces containing
design strategy forthese specialadhesives
reversible structures,in
providing adhesion forces based on capillary
robotics, semiconductor processing, and medical engineering. forces and Stefan adhesion [59].
AInthin layer to
addition of this,
fluidthe between the pads
laryngeal discusoffish
thehas
treeafrog’s feet similar
structure and theto attached substrate
that of tree frogs,
provides
allowinggood adhesion
it to adhere and friction
to rough, wet, or onsticky
soft, wet surfaces,
surfaces. enabling the
By analyzing thetree frogoftothe
ability climb
lar-
flexibly [64]. Tree
yngeal discus frog foot
to rapidly andpads have protruding
reversibly adhere to polygonal epithelial
various surfaces cells withRao
underwater, several
et al.
micrometer-wide
designed hexagonal grooves
facetsbetween
separated theby polygonal structures
interconnected (Figure
grooves on 4A). These channels
the hydrogel surface
can drain the liquid at the contact interface, achieving direct contact
(Figure 4C). These interconnected surface grooves serve as pathways for the rapid drain- between solids and
thereby providing high adhesion or friction [63,65]. Liu et al.
age of water during underwater contact. In addition to forming good contact, the discon-developed a gradient
composite micropillar
tinuous hexagonal array
facets inspired
improve thebycompliance
tree frogs (Figure 4B),and
of the gel which achieves
prevent cracks2.3-fold dry
from con-
adhesion and 5.6-fold wet adhesion compared with pure polydimethylsiloxane
tinuously expanding across the interface. By combining energy-dissipating hydrogels micropillar
arrays [66]. This
with dynamic studyand
bonds alsoa provides a new design
surface drainage strategy
structure for reversible
inspired adhesives
by the laryngeal in
discus
robotics, semiconductor processing, and medical engineering.
fish, the hydrogel material provides fast, strong, and reversible adhesion underwater [67].

Figure4.4. (A)
Figure (A) Polygonal
Polygonal microstructures
microstructures on the tree frog’s footpad [63]; (i) (B)Tree frog (Litoria
Gradient caerulea)
composite mi-
and capillarity on its toe pad at (ii) 100 µm and (iii) 10 µm. (B) Gradient composite micropillar
cropillar array inspired by the tree frog [66]; (C) Rapid drainage structure inspired by the clingfish [67]. array
inspired
(i) by(Litoria
Tree frog the treecaerulea)
frog [66];
and(C)capillarity
Rapid drainage structure
on its toe pad at inspired
(ii) 100 µm the clingfish
byand [67].
(iii) 10 µm.
Polymers 2024, 16, 1937 10 of 30

In addition to this, the laryngeal discus fish has a structure similar to that of tree frogs,
allowing it to adhere to rough, wet, or sticky surfaces. By analyzing the ability of the
laryngeal discus to rapidly and reversibly adhere to various surfaces underwater, Rao et al.
designed hexagonal facets separated by interconnected grooves on the hydrogel surface
(Figure 4C). These interconnected surface grooves serve as pathways for the rapid drainage
of water during underwater contact. In addition to forming good contact, the discontinuous
hexagonal facets improve the compliance of the gel and prevent cracks from continuously
expanding across the interface. By combining energy-dissipating hydrogels with dynamic
bonds and a surface drainage structure inspired by the laryngeal discus fish, the hydrogel
material provides fast, strong, and reversible adhesion underwater [67].

2.2.3. Physical Adhesion Based on Negative Pressure Adsorption

Bionic adhesives that use physical interaction methods to achieve adhesion can in-
clude both dry and wet adhesion [68]. Dry adhesion does not allow for firm adhesion in
humid environments, so dry bio-adhesives are limited to external applications on human
tissues. For example, gecko footpads gain adhesion through their topology, which involves
interfacial adhesion across arrays of footpad fibers [69]. These arrays consist of setae with
different profiles and spatulate protrusions, where the spatulate protrusions are believed to
generate adhesion by van der Waals forces. By mimicking the fibrous structure of gecko
footpads and incorporating additional features, the adhesive properties can be extended to
a variety of biomedical applications.
Under dry conditions, adhesion relies mainly on van der Waals forces, hydrogen bond-
ing and electrostatic forces. Some terrestrial and marine organisms utilize their natural
structures as the fundamental basis for adhesion, employing unique mechanisms (e.g., cap-
illarity, adsorption, and mechanical interlocking) to achieve wet adhesion. Cephalopods,
for example, can actively control the grabbing and releasing of a target object by using
visual or pressure sensing to learn information about the state and position of the object.
Multiple suction cups possessed by cephalopods, such as octopuses, can be independently
controlled [70]. The synergy between the independently controllable adhesion devices
and the sensing, processing, and control components is key to their ability in flexibly
manipulating underwater objects [71].
Octopus tentacles are densely distributed with negative pressure suction cups fea-
turing rounded internal protrusions and wrinkled microstructural arrays on the inner
bottom edge, which are super-adhesive in both wet and dry environments [26]. Inspired
by the super-adhesive capacity of the blue-ringed octopus, Zhu et al. designed a bionic
microneedle patch in combination with bio-3D printing technology to achieve controlled
topical medication administration in a wet environment (Figure 5). Inspired by the teeth
and venom secretion of the blue-ringed octopus, the study prepared gel microneedles that
can sense body temperature for active injection to achieve on-demand release of local drugs.
The flexible suction cups of the bionic octopus tentacles provide a stable wet bonding effect
to ensure the stability of the patch in a wet environment, ultimately enabling controlled
and efficient drug delivery to local lesions [72].
Polymers 2024, 16,
Polymers 2024, 16, 1937
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Figure 5. (A)
(A)AAhydrogel
hydrogelmicroneedle
microneedlesuction cup
suction delivery
cup platform
delivery platformmimicking
mimickingthethe
blue-ringed oc-
blue-ringed
topus, which is able to adhere to wet tissues and autonomously control the multi-stage release
octopus, which is able to adhere to wet tissues and autonomously control the multi-stage release of of
the drug; (B) tissue adhesion is achieved by hydrogel chucks by negative pressure and covalent
the drug; (B) tissue adhesion is achieved by hydrogel chucks by negative pressure and covalent or or
hydrogen bonds between phenolic hydroxyl groups and tissue proteins; (C) composition of bionic
hydrogen bonds between phenolic hydroxyl groups and tissue proteins; (C) composition of bionic
hydrogel microneedle suction cups and their effect on drug release [72].
hydrogel microneedle suction cups and their effect on drug release [72].
Table 1.
Table 1. Sources
Sources of
of inspiration
inspiration and
and adhesion
adhesion mechanisms
mechanisms of
of common
common bionic
bionic hydrogel
hydrogel adhesives
adhesives
based on physical structure.
based on physical structure.
Biology Inspiration Adhesion Mechanism Ref.
Biology Inspiration Adhesion Mechanism Ref.
Gecko footpad arrays consist of hydrophobic se-
tae withGecko footpad
different arrays
profiles consist
and of hydrophobic
spatulate protru- setae with different
Geckos
Geckos Footpad fiber
Footpad arrays
fiber arrays [73]
profiles and spatulate protrusions, where the spatulate protrusions [73]
sions, where the spatulate protrusions generate
generate adhesion through van der Waals forces.
adhesion through van der Waals forces.
The footpads have protruding polygonal epithelial cells with
The footpads
severalhave protruding grooves
micrometer-wide polygonal epithe-
between the polygonal structures,
Tree frog Tree frog’s footpads lial cells with several micrometer-wide grooves [65]
which can drain the liquid at the contact interface, enabling direct
Tree frog Tree frog’s footpads [65]
betweencontact
the polygonal structures,
between solids which can
and achieving high adhesion or friction.
drain the liquid at the contact interface, enabling
Polymers 2024, 16, 1937 12 of 30

Table 1. Cont.

Biology Inspiration Adhesion Mechanism Ref.

Serrated microstructure to prepare hydrogel microneedle patches
Insects Mosquito stinging mouthparts [74]
for transdermal drug delivery.
The viscoelastic sucker-like tube feet use negative pressure to
adhere and promote adhesion. Additionally, the tube feet can
Sea urchin Tube feet of sea urchins [75]
regulate adhesion and detachment behaviors by secreting different
types of mucus.
The mucus secreted by the epidermis of abalone gastropods is
slightly sticky. Combined with the adsorption force generated by
Abalone Abalone gastropod negative pressure, this allows the desired attachment state to be [76]
maintained. When it is necessary to change position, the abalone
moves through wave-like contractions of its foot.
The suction cups are primarily composed of funnels. The surface of
Octopus Conical sucker on the carpal foot each funnel features numerous grooves and a finely toothed chitin [77]
keratin layer. This unique folded surface enhances adsorption.
The vacuum negative pressure suction cup structure consists of an
external lip ring and internal fins. Inside the suction cup,
Remora Back Suction Cup [78]
continuous pectinate fins can be actively controlled and play an
important role in enhancing adhesion.

3. Common Materials for Bionic Hydrogel Adhesives

3.1. Natural Polymers
Natural polymers are widely found in plants, animals, and microorganisms and have
been widely used in biomedical and other fields due to their many excellent properties.
They are commonly used as materials for synthetic hydrogel adhesives. Common natural
polymers include chitosan, sodium alginate, hyaluronic acid, cellulose, dextran, xanthan
gum, and gelatin. One of the characteristics that these materials share is their structural
similarity to biological tissues, making them more easily degradable, which aids in cell
growth and tissue healing. These natural polymeric materials are briefly described below
(Table 2).
Chitosan is a naturally positively charged polysaccharide polymer composed of glu-
cose units linked by a β-1,4-glucoside bond, and it is commonly extracted from the shells
of crustaceans, such as shrimp, crabs, and shellfish. Due to its low toxicity, biocompatibility,
antibacterial activity, and mucosal adhesion properties, chitosan has been widely used
in biomedical and drug delivery fields [79]. As a natural polysaccharide, its structure is
similar to that of polysaccharides in the body, making it less likely to trigger an immune
response. The positive charge of chitosan enables it to form electrostatic interactions with
other molecules, which also enhances its antibacterial properties [80]. In the body, chi-
tosan is primarily degraded by enzymatic hydrolysis. It is hydrolyzed by a variety of
enzymes, including chitinase, chitosanase, and lipase [81]. Once broken down by these
enzymes, chitosan is reduced to harmless metabolites that do not cause lasting damage to
the organism.
Sodium alginate is a naturally occurring anionic polymer typically obtained from
brown seaweeds, such as kelp. It is widely used in the production of hydrogel adhesives
due to its biocompatibility, relatively low cost, and mild gelation upon the addition of diva-
lent cations (e.g., Ca2+ ) [47]. However, a major limitation of physical sodium alginate is its
very low degradability in the body. When sodium alginate is oxidized, its biocompatibility
is greatly improved [82]. Oxidized sodium alginate can be more readily degraded by or-
ganisms through hydrolysis reactions, enhancing its suitability for biomedical applications.
Xanthan gum is a natural polysaccharide polymer produced by Xanthomonas fermen-
tation, which has good biocompatibility, water solubility, water retention and acid and
alkaline resistance [83]. Xanthan gum is non-toxic and does not cause skin irritation or al-
Polymers 2024, 16, 1937 13 of 30

lergies. Its rich hydroxyl and carboxyl groups make it easy to modify by physical, chemical,
enzymatic or plasma irradiation treatment to enhance its biomaterial properties [84]. The
modified xanthan gum can be combined with other materials, such as polyvinyl alcohol, to
form a multifunctional hydrogel adhesive.

Table 2. Common natural polymers used for hydrogel adhesives’ formation.

Natural Polymer Chemical Structures Preparation Ref.

A linear polymer chain consisting of β-(1→4)
Chitosan
linked 2-amino-2-deoxy-D-glucose units.
A linear polymer chain consisting of alternating
Sodium alginate residues of β-D-mannuronic acid and
α-L-guluronic acid.
A high molecular weight polysaccharide
composed of D-glucuronic acid and
Hyaluronic acid
N-acetyl-D-glucosamine linked alternately by
β-1,3 and β-1,4 glycosidic bonds.
It is composed of 1,6-linked D-pyranose residues
Dextran and a few percent of 1,2, 1,3 or 1,4-linked
side chains.
It is composed of D-glucose, D-mannose and
Xanthan gum D-glucuronic acid connected by specific
glycosidic bonds.
It is composed of three α-helical strands, which
are connected by hydrogen bonds and other
Gelatin
non-covalent bonds to form a triple
helix structure.
It is generally obtained from crustacean
[79]
shells, such as shrimp, crab, shellfish, etc.
It is generally obtained from brown algae,
[51]
such as kelp, macroalgae, sargassum, etc.
Extracted from animal tissue and fermented
with microorganisms using pathogenic and [85]
non-pathogenic bacteria.
It is generally produced by gram-positive,
[86]
facultative anaerobic cocci and other strains.
Produced by fermentation of a strain
[83]
called Xanthomonas.
Generally, it is made from animal bones, raw
hides, connective tissues and hard bone
[87]
tissues, and is obtained by partial hydrolysis
and extraction of natural collagen.

3.2. Synthetic Polymers

In addition to natural polymers, synthetic polymers are also widely used as hydrogel
adhesives with more controllable structure and stronger properties. Common synthetic
polymers include polyethylene glycol, polyacrylic acid, and polyethyleneimine, etc.
Polyethylene glycol is a non-ionic synthetic polymer made by the polymerization
of ethylene glycol monomers. Polyethylene glycol is soluble in water and many organic
solvents and has good solubility. In addition, it has good biocompatibility, low immuno-
genicity, and is non-toxic [88]. Polyethylene glycol can be rapidly eliminated from the
body without causing damage. The hydroxyl functional groups on the molecular chain of
polyethylene glycol can be modified, enhancing the biocompatibility and degradability of
polyethylene glycol-based hydrogel adhesives.
Polyacrylic acid is an anionic synthetic polymer formed by the polymerization of
acrylic monomers. It has good biocompatibility, high water absorption, non-toxicity, and
can be dissolved in water [89]. Polyacrylic acid contains many carboxyl groups, which are
highly bioavailable and can be modified using bio-nanomaterials. Polyacrylic acid can be
copolymerized with a variety of polymers to form block polymers, and it can also form
hydrogen-bonded complexes with various polymers [90]. Due to its excellent properties,
polyacrylic acid is widely used in the synthesis of hydrogel adhesives.
Polyethyleneimine is a cationic synthetic polymer, highly alkaline, produced by the
polymerization of vinylamine monomers. Polyethyleneimine contains many repeating units
of ethylamine and has good water solubility. The molecular toxicity of polyethyleneimine
depends on its molecular weight as well as its structure; low molecular weight poly-
ethyleneimine is less toxic and is safer for use in humans and animals, but its cytotox-
icity still restricts its application [91]. Polyethyleneimine is a cationic polymer that is
able to combine with negatively charged biomolecules, such as drugs and nucleic acids,
to form polyelectrolyte complexes through electrostatic action [92]. Polyethyleneimine
Polymers 2024, 16, 1937 14 of 30

also has the disadvantage of being non-degradable, but it has been shown that short
polyethyleneimine chains can be introduced into longer chains using a linker to obtain
biodegradable polyethyleneimine derivatives [93]. The multi-level amino functional groups
contained in polyethyleneimine allow it to undergo a variety of chemical modifications
to obtain desirable physicochemical properties, and it can be used in the synthesis of
hydrogel adhesives.

4. Optimal Design of Bionic Hydrogel Adhesives Suitable for Skin Wound Treatment
4.1. Self-Healing Property
The role of self-healing hydrogel adhesives is crucial in modern medical applications,
especially in the field of wound management. These adhesives are capable of automatically
repairing damaged areas and maintaining their structural and functional integrity after
damage caused by mechanical forces. The application of self-healing technology not only
ensures that the dressing remains intact but also prevents bacterial invasion that may result
from damage to the dressing [94]. Additionally, these adhesives maintain peri-wound
protection and provide a constant moist environment, creating ideal conditions for cell
growth and wound healing. These adhesives adapt to changes in wound shape, increasing
patient comfort while reducing the frequency of dressing changes, thereby improving
the ease and efficiency of treatment [95]. To further understand how these functions are
achieved, the two main design strategies for self-healing hydrogel adhesives are described
in detail below:

4.1.1. Design Strategies for Physical Crosslinking

One design strategy for self-healing hydrogel adhesives involves crosslinking through
non-covalent bonds, such as hydrogen bonding, metal ion coordination, host-guest interac-
tions, and electrostatic interactions. These interactions enable the material to automatically
reconnect broken chains after mechanical damage, rapidly restoring its original func-
tion [96]. The self-healing properties of hydrogel adhesives depend on the number and
strength of their physical crosslinking interactions. This approach not only quickly restores
the hydrogel’s original function but also significantly enhances its mechanical strength.
The power of this mechanism is demonstrated by the interaction of marine bio-catechol
groups with metal ions, which is common in bionic adhesives. Yang et al. successfully
synthesized a multifunctional hydrogel adhesive using dopamine-functionalized oxidized
hyaluronic acid (OD), EPL, and Fe3+ . The catechol moiety in the hydrogel adhesives
provided strong wet adhesion through π–π stacking, metal crosslinking, and hydrogen
bonding [97]. At the same time, this multi-crosslinked network improves the mechanical
elasticity and cohesion of the hydrogel adhesive, extending the service life and functionality
of the dressing. Khodai and his coworkers utilized the reaction of oxidized carrageenan
with the formation of a Schiff base from dopamine, adding Zn2+ with metal-catechol
complexation of the catechol moiety to prepare antimicrobial and self-healing hydrogel
adhesives. Alternating strain confirmed its self-healing ability through the reconstruction
of imines and other non-covalent bonds in hydrogel adhesives [98].
Hydrogen bond crosslinking is a common synthetic strategy for self-healing hydro-
gel adhesives because hydrogen bonds are widely present in natural and synthetic com-
pounds. Hydrogen bonds are formed by electrostatic interactions between hydrogen atoms
and electronegative atoms, with a bond energy of about 42 kJ·mol−1 ,and their formation
and fracture speed is very fast. For example, Guo et al. developed antioxidant, anti-
inflammatory, and antimicrobial tannin-crosslinked mussel mimetic medical adhesives by
utilizing the hydrogen bonding interactions between natural plant polyphenol tannins (TA)
and citrate-based mussel-inspired adhesive prepolymers capable of instantaneous (<25 s)
gel formation. Rheological tests confirmed the self-healing ability of the adhesive, with its
storage modulus (G’) mostly recovering even after four cycles of large strain (100%) for
one minute, followed by one minute of relaxation [99]. Additionally, Dai et al. designed a
collagen-based tissue adhesive with rapid removal of interfacial water and multiple dynam-
Polymers 2024, 16, 1937 15 of 30

ically reversible osmotic cross-links by simulating key processes in adhesives secreted by

mussels and oysters. Rheological test confirmed the self-healing behavior. With the increase
of shear strain from 1% to 500%, the hydrogel network broke. However, when a low strain
of 1% is applied, the loss modulus and storage modulus quickly return to their initial values.
This combination of collagen and starch depends on reversible hydrogen bonding, dynamic
coordination and electrostatic interaction, showing excellent self-healing performance and
dynamic coordination [100]. Professor Bruce P. Lee’s group developed a composite gel
tissue adhesive with remarkable plasticity and adhesive properties, showing potential
for biomedical applications. The innovative material consists of two key components: a
dopamine-capped, multi-armed polyethylene glycol (PEG-D) and lithium saponite [101].
These two components rapidly interact to form a highly viscous, malleable composite gel.
Once applied to a wound, the dopamine portion stabilizes the gel’s morphology by forming
a covalent crosslinking structure. Additionally, the higher number of PEG-D arms and the
content of lithium saponite significantly increase the number of physical crosslinking sites,
where hydrogen bonding and dispersion forces are the main forces. The gels exhibited
excellent plasticity, rapidly recovering their original energy storage modulus after a day of
exposure to 1000% shear once the shear force was removed. This property demonstrates
the ability of PEG-D and lithium saponite nanoparticles to rapidly re-establish physical
crosslinking points, highlighting their potential in medical adhesive design. Xiao et al.
achieved the desired self-healing and stretchable properties of frequently moving joints by
blending polyacrylic acid copolymers, isopentenyl polyethylene glycol ethers and tannic
acid (TA) into hydrogel adhesive with strong wet adhesion. The PEGylated chain segment
on the polyacrylic acid prevents electrostatic repulsion between the ionized carboxylate
group and the adsorbed TA, thus forming a bonding layer, and the structure recovers
quickly even after five alternating repeated load stress cycles.

4.1.2. Design Strategies for Chemical Crosslinking

Another strategy is to design self-healing hydrogel adhesives through reversible
chemical crosslinking, utilizing mechanisms such as the Diels–Alder (DA) reaction, borate
bonding, hydrazone bonding, and Schiff base reaction. The core advantage of the reversibil-
ity of these chemical reactions is that they allow the material to automatically rebuild its
chemical structure after damage without external intervention. Taking the Diels–Alder
reaction as an example, this reaction is widely used in the preparation of self-healing
urethanes due to its thermal reversibility, mild reaction conditions, and low degree of
side reactions. Specifically, the DA reaction allows the conjugated diene and unsaturated
carbon-carbon double bonds of the polyurethane molecular chain to reorganize after dam-
age via a 1,4-addition reaction, leading to self-healing on a macroscopic scale. When driven
by heat, the DA bonds in polyurethanes can break in the reverse direction to form short
molecular chains, which are able to bridge the cracks quickly due to their high mobility.
These chains then rejoin and revert to long chains when the temperature drops slightly,
achieving self-healing. In addition, the mobility of the DA-bonded polyurethane molecular
chain segments significantly affects their self-healing ability. At a certain temperature, the
higher mobility of the molecular chain segments increases the probability of DA bond
encounters, thus enhancing the self-healing rate. The addition of ionic liquids (EMITFS) as
plasticizers can further improve the mobility of the chain segments and effectively reduce
the temperature required for self-healing [102]. Hydrogel adhesives based on the DA
reaction can self-heal at room temperature and are suitable for long-lasting skin-fitting
applications. In their study, Liu et al. selected deferoxamine (DFO) as the backbone and
used polyethylene glycol (PEG) as a crosslinker to modify hyaluronic acid (HA) to prepare
a biocompatible material. They added imidazole polymer (ionic liquids) (PILs) to the
modified HA/PEG precursors through a DA click reaction to prepare a hydrogel adhesive
with excellent self-healing properties and mechanical properties [103].
In addition, self-healing hydrogel adhesives can be synthesized using borate ester
bonds. Boron esters and borate esters are pentagonal or hexagonal rings in which the
Polymers 2024, 16, 1937 16 of 30

boronic acid is bonded to cis-1,2- or 1,3-diols. Specifically, in environments where the pH

is higher than the pKa of the boronic acid-based materials, these polymers form hydrogel
adhesives by crosslinking with the diols and can reach a dynamic equilibrium between
the boric acid and the diols depending on the pH. The non-rigid nature of the borate bond
allows it to interact with the surrounding free diols and boric acid during hydrolysis to
form new crosslinking sites. Thus, depending on the pH or the heat-sensitive aqueous
medium, the borate bonds in hydrogel adhesives can exhibit self-healing properties in
the absence of external stimuli [104]. This self-healing ability is particularly significant for
hydrogels composed of rigid nanofibrillar cellulose and polyvinyl alcohol (PVA) networks,
which are synthesized with borax as a crosslinking agent. These hydrogels are capable of
rapidly eliminating the interface upon contact and self-healing to restore the hydrogel’s
ionic conductivity and mechanical properties within a short period of time. In the absence
of an external force, the interfaces of the two types of hydrogels disappear after 5 min of
contact. The ionic conductivity and mechanical properties of the hydrogels were restored
by 89.8% and 93.0%, respectively, after healing. The healing rate remained at 83.0% after
five repetitions [105]. In addition, the hyaluronic acid hydrogel based on the phenylboronic
acid–diol ester bond developed by Gu’s team shows excellent self-healing performance,
injectability, and compressive strength through rheological and compressive tests, which
proves the application potential of this kind of hydrogel in the biomedical field [106].
Schiff base bonds are formed by the reaction of reactive carbonyl groups with amino
compounds. This process of forming imine or alkyl-imine structures ensures the self-healing
ability of hydrogels and is widely used in their synthesis. For example, the formation of
oxidized sodium alginate (OSA) and carboxymethyl chitosan (CMCS) Schiff base bond com-
bined with the free radical polymerization of acrylamide (AM) monomer forms a unique
multi-network structure, which makes the hydrogel exhibit excellent mechanical properties
and self-healing ability in flexible open wounds [107]. In addition, acyl-hydrazone bonds
are formed by the condensation reaction of hydrazine with carbonyl groups (such as alde-
hydes or ketones). These bonds have also been used to construct self-healing hydrogel
adhesives. Although acyl-hydrazone bonds are similar to Schiff base bonds, they are more
reactive and more stable in water. For example, the hydrogel adhesive developed by using
the catalyst-free crosslinking reaction between phthalaldehyde and amine (hydrazines) can
quickly close wounds and promote healing, and the effect is better than that of commercially
available fibrin glue and cyanoacrylate glue [108].
With these two main design strategies, self-healing hydrogel adhesives exhibit signifi-
cant advantages in wound healing applications. However, single chemically or physically
crosslinked hydrogel adhesives have limitations in aspects such as elasticity, tensile proper-
ties, and self-healing rates. Specifically, although single chemically crosslinked hydrogels
have high rigidity and toughness, they often lack sufficient stretchability and elasticity for
practical applications and have slow self-healing rates due to the absence of an effective en-
ergy dissipation mechanism. Physically crosslinked hydrogels are easy to handle but often
have poor mechanical properties, making them inadequate for medical applications [109].
In contrast, the synergistic effect of using multiple dynamic bonds not only enhances the
overall performance of the hydrogel but also improves its self-healing rate, allowing the
hydrogel to rapidly recover its structure and function without external intervention. This
multi-dynamic bonding strategy has gradually become a mainstream trend in the prepara-
tion of self-healing hydrogel adhesives [110,111]. By combining different types of reversible
bonds, these hydrogels can quickly respond to physical damage and automatically repair
fractures or damages while maintaining excellent mechanical properties. Furthermore, this
design approach not only enhances treatment efficacy and reduces the risk of infection
but also lowers overall treatment costs due to less frequent replacement. Going forward,
research will likely focus on further enhancing the self-healing speed and efficiency of these
hydrogels. Overall, through these studies, it is expected that more powerful self-healing
materials with a wider range of applications will be developed to provide more effective
treatment options in the clinic.
Polymers 2024, 16, 1937 17 of 30

4.2. Drug Release and Biological Activity

In the field of wound therapy, bionic hydrogel adhesives have been endowed with
excellent skin repair capabilities by mimicking the key structures and chemical composi-
tions of natural plants and animals. However, wound healing is a highly complex cascade
process that involves the spatially and temporally synchronized collaboration of various
cell types during the hemostasis, inflammation, growth, re-epithelialization, and remodel-
ing phases. The complexity and variability of the wound environment mean that simply
mimicking natural mechanisms is not sufficient to meet all the challenges. For this reason, a
variety of therapeutic components have been incorporated into bionic hydrogel adhesives
to enable them to play key roles in the various stages of wound healing. These components
include hemostatic factors to control bleeding, antimicrobial agents to effectively fight in-
fection, bioactive substances to promote cell regeneration and tissue repair, and intelligent
systems to precisely regulate drug release. The combined use of these design elements
significantly enhances the therapeutic efficiency and effectiveness of bionic hydrogel adhe-
sives in wound management, while broadening their scope of application in promoting
wound healing.
Bleeding after injury is often unavoidable, making hemostasis one of the key steps in
wound management. The development of bionic hydrogel adhesives effectively promotes
hemostasis and prevents the reopening of wounds through their unique bio-adhesive
function and ability to absorb wound exudates. In the hemostatic application of hydrogels,
materials with hemostatic properties are usually added to enhance their performance.
Examples include chitosan, gelatin, and collagen—natural polymerizations that not only ac-
celerate the clotting process but also provide protection to wounds and support their rapid
healing by forming a stable cover layer [109,112,113]. In addition, silicon-based inorganic
hemostatic materials (kaolin, zeolite, etc.), which have mesoporous structures that can
absorb blood and promote coagulation, and metallic hemostatic materials, commonly Ca2+
ions that accelerate thrombosis by promoting the conversion of prothrombin to thrombin,
can further enhance the hemostatic effect. The use of these hemostatic materials not only
enhances the functionality of the hydrogel but also brings a more efficient and safer solu-
tion for wound treatment. A specially designed hydrogel contains thrombin concentrate
(polymerization inducer) and fibrinogen (coagulation component), a combination that not
only rapidly stops bleeding but also forms a stable overlay on the wound surface and cures
rapidly. This design optimizes the hemostatic function of the hydrogel while providing
effective protection and support to the wound, thus promoting a faster healing process. The
hydrogel developed by Wei et al. used oxidized konjac glucomannan (OKGM) and dodecyl
modified N-carboxyethyl chitosan (DCEC). This hydrogel was prepared by a Schiff base
reaction and showed excellent hemostatic effects and adhesion properties. The introduction
of DCEC made the hydrogel not only hemostatic but also antimicrobial. However, DCEC–
OKGM hydrogels have anti-adhesion properties, which are attributed to their formation of
a physical barrier between damaged tissues and adjacent organs (Figure 6A). This barrier
action prevents direct adhesions caused by cell proliferation and migration during wound
healing and inhibits tumor necrosis factor (TNF) expression [114]. Another innovative
approach was proposed by Zhang’s team, who constructed a multifunctional hydrogel
patch with Janus asymmetric adhesion, combining the properties of both adhesive and
non-adhesive hydrogels. This design allows the adhesive hydrogel portion to firmly adhere
to the wound through hydrogen bonding and electrostatic interactions, rapidly stopping
bleeding and promoting healing, while the non-adhesive portion acts as a physical barrier
to protect the wound from external contamination (Figure 6B). This asymmetric design
not only enhances hemostasis but also optimizes the efficiency and safety of hydrogel
application in clinical treatment [115].
Polymers 2024,16,
Polymers2024, 16,1937
x FOR PEER REVIEW 18 of 30
20 32

Figure 6.6.(A)
Figure (A)Schematic
Schematicdiagram
diagramofofinjectable
injectable hydrogel
hydrogel adhesives
adhesives [114];
[114]; (B) (B) schematic
schematic diagram
diagram of
of the
the preparation
preparation process
process ofJanus
of the the Janus asymmetric
asymmetric adhesive
adhesive HGO
HGO–C –C hydrogel
hydrogel patchpatch
[115];[115]; (C) syner-
(C) synergistic
gistic of
effect effect of the BT–OHA/THM–APMH
the BT–OHA/THM–APMH hydrogel
hydrogel and ultrasound-triggered
and ultrasound-triggered piezo-catalytic
piezo-catalytic ther-
therapy in
apy in repairing
repairing infectedinfected
woundswounds [116];
[116]; (D) (D) diagram
diagram showingshowing
hydrogelhydrogel
adhesives adhesives
structurestructure and
and mussel-
mussel-inspired
inspired self-healing
self-healing mechanism mechanism
[117]. [117].

Photothermal
As the primarytherapy (PTT) is an
line of defense attractive
between the and
bodypromising methodenvironment,
and the external of localized heat-
the
ing. plays
skin The main
a keyphotothermal agentsmicrobial
role in preventing now usedinvasion.
to prepare NIR-responsive
When photothermal
the skin’s intrinsic protec-
agents
tive include transition
mechanisms metal sulfide–oxide
are compromised, wounds are nanomaterials (e.g., CuS,
highly susceptible TiO2, and
to bacterial MnO2),
infection,
which may slow down the healing process. Traditionally, antibiotics are added carbon
metal nanostructures (e.g., Cu NPs and Au NPs), carbon-based materials (e.g., to hy-
nanotubes
drogel and graphene
excipients to conferand graphenecapacity,
bactericidal oxide), conjugated polymers
but this approach may(e.g.,
leadpoly-pyrrole,
to problems
PDA,asand
such polyaniline),
uncontrolled iron–catechol
drug release and complexes, and Prussian
multi-drug resistance bluebynanoparticles.
caused Zhao
antibiotic overuse.
et al. developed
Therefore, a photothermally
in recent years, researchersactive
have dual network
sought hydrogel antimicrobial
non-antibiotic for treating wounds in-
strategies
fected
to with multi-drug-resistant
overcome bacteria.
these limitations. These newItstrategies
is photothermally responsive
include the through
use of metal ions cate-
and
non-traditional antimicrobial
chol–iron ion metal agents
coordination, such
which as silver
raises (in the form
the hydrogel of silverduring
temperature nanoparticles
near-in-
frared irradiation, thereby killing the bacteria at the wound site and protecting the wound
Polymers 2024, 16, 1937 19 of 30

and silver nitrate) and zinc. These metal ions exert bactericidal effects by interfering with
bacterial proteins through complexation. Although using metal ions to kill bacteria is a
well-established area of research, there are concerns about their use in the body due to
potential toxicity and allergic reactions (hypersensitivity).
Photothermal therapy (PTT) is an attractive and promising method of localized heat-
ing. The main photothermal agents now used to prepare NIR-responsive photothermal
agents include transition metal sulfide–oxide nanomaterials (e.g., CuS, TiO2 , and MnO2 ),
metal nanostructures (e.g., Cu NPs and Au NPs), carbon-based materials (e.g., carbon nan-
otubes and graphene and graphene oxide), conjugated polymers (e.g., poly-pyrrole, PDA,
and polyaniline), iron–catechol complexes, and Prussian blue nanoparticles. Zhao et al. de-
veloped a photothermally active dual network hydrogel for treating wounds infected with
multi-drug-resistant bacteria. It is photothermally responsive through catechol–iron ion
metal coordination, which raises the hydrogel temperature during near-infrared irradiation,
thereby killing the bacteria at the wound site and protecting the wound from infection. In
addition, metformin-containing CuPDA NPs composite hydrogels (Met@CuPDA NPs/HG)
were prepared by dynamically combining dopamine-modified gelatin (Gel-DA), Cu-loaded
polydopamine nanoparticles (CuPDA NPs), and phenyl borate-modified hyaluronic acid
(HA-PBA). These hydrogels not only exhibit an excellent photothermal effect but also
slowly release Cu2+ to protect the wound from infection for a long time and effectively
reduce inflammation, showing great potential for treating chronic diseases, such as dia-
betes mellitus [118]. Another innovative strategy is ultrasound-triggered piezo-catalytic
therapy, such as the multifunctional hydrogel designed by Liu et al. Its loaded barium
titanate nanoparticles exhibit excellent antimicrobial effects due to a strong inbuilt electric
field, which rapidly generates reactive oxygen species (ROS) under ultrasonic vibration
(Figure 6C). This significantly improves the biosafety of the treatment compared to conven-
tional photodynamic therapy and shows great potential for harmless treatment of bacterial
infections [116]. Additionally, the catechin-functionalized polyethylene glycol hydrogel
is self-repairing and has excellent thermal sensitivity, effectively inhibiting the growth of
E. coli (killing efficiency > 99.8%) and preventing cell adhesion. It also autonomously heals
from repetitive damage through mussel-inspired catechol-mediated hydrogen bonding
and aromatic interactions. Importantly, the material is metal-free and therefore has low
cytotoxicity (Figure 6D). Overall, these findings demonstrate that polyethylene glycol (PEG)
has great potential for bioengineering applications [117]. Furthermore, inspired by the
natural extracellular matrix (ECM), Liu et al. coupled glucomannan with endogenous
antimicrobial peptides via dynamic, acid-sensitive imine bonds, and hyaluronic acid (HA)
grafted with collagen tripeptide (GPHyp). This combination developed an ECM-mimicking
hydrogel that provides structural support for the adhesion, migration, and proliferation of
cells, as well as the essential amino acids for collagen reconstruction. The ability to remodel
damaged tissues, reduce inflammation, and promote angiogenesis without the need for
additional drugs and exogenous cytokines provides an effective therapeutic strategy for
chronic wounds, especially Methicillin-resistant Staphylococcus aureus (MRSA)-infected
diabetic and burned skin [119].
In traditional drug delivery systems, instability in drug concentration and large fluc-
tuations in active drug levels often affect therapeutic efficacy. To address these problems,
controlled drug delivery systems (DDS) have been developed to improve drug utilization
efficiency and effectiveness while reducing costs and side effects. Smart/stimuli-responsive
hydrogels show great potential in this field due to their high water content, sensitivity,
and adjustable structure. These hydrogels can be loaded with bioactive ingredients and
react to specific signals (such as pH, temperature, and light) to release drugs or activate
bio-adhesives [120–124]. They can quickly respond to environmental stimuli by swelling,
contracting, or undergoing sol-gel phase transitions, thus promoting wound healing. In
addition, hydrogel adhesives can stop bleeding, seal wounds, maintain tissue function, and
provide antibacterial protection, making them a key area of research and development. The
selection of raw materials and the loading of bioactive substances (such as cells and drugs)
Polymers 2024, 16, 1937 20 of 30

are critical factors affecting their effectiveness. In the future, the application of hydrogel
adhesives may become more personalized and diversified, incorporating features such as
electrical conductivity for electrically active tissues and contractility to assist in wound
closure. These advancements highlight the potential of hydrogel adhesives in improving
therapeutic outcomes and patient rehabilitation.

4.3. Stimulus–Response Design

Wound healing involves complex changes influenced by factors like temperature, pH,
oxygen, and glucose levels. Conventional hydrogel dressings often fail to meet the needs
of complex wounds. Stimuli-responsive hydrogel adhesives can actively respond to the
wound environment by sensing and adjusting to these factors. For example, temperature-
sensitive hydrogel adhesives can change their physical properties and release built-in
drugs when body temperature rises to inflammatory levels, while pH-sensitive hydrogel
adhesives can adjust their solubility or structure to adapt to different stages of the healing
process when the wound environment shifts from acidic to alkaline. In addition, ROS-
responsive hydrogel adhesives can trigger drug release when local ROS concentrations
increase, effectively responding to oxidative stress. For specific diseases such as diabetes,
it is particularly important to develop hydrogel adhesives that are responsive to changes
in glucose levels because of persistently high blood glucose levels and accompanying
impaired healing. These hydrogel adhesives can modulate drug release in response to
changes in blood glucose, thereby optimizing therapeutic efficacy [125,126]. This intelligent
adjustment promotes effective healing, reduces chronic wound recurrence, and alleviates
patient pain and financial burden, offering a personalized and targeted therapeutic strategy
for future wound treatments.
Stimuli-responsive hydrogel adhesives are becoming increasingly important in the
field of wound therapy, especially in the management of chronic and heavily infected
diabetic wounds. Diabetic wounds are complex environments that are difficult to treat.
The complexity of these wounds stems from their unique microenvironment, including
persistent hyperglycemia, low local pH, and excess reactive oxygen species (ROS), which
may lead to persistent inflammation, abnormal vascular endothelial function, and tissue
necrosis, collectively slowing down the natural healing process. Single stimulus-responsive
hydrogel adhesives, although capable of responding to specific physiological changes, often
struggle to achieve efficient and precise targeted drug release, especially in variable wound
environments(Table 3). Therefore, the development of composite stimulus-responsive
hydrogel adhesives that can simultaneously respond to multiple physiological signals is
particularly critical. For example, Kong et al. prepared an injectable glycopeptide hydrogel
adhesive with pH and ROS responsiveness using phenyl-boric acid-grafted glucan oxide
(POD) and caffeic acid-grafted ε-poly-lysine (CE) materials (Figure 7A). The adhesive was
cross-linked via dynamic borate and Schiff base bonds and loaded with diclofenac sodium
(DS) with anti-inflammatory properties and pH-responsive micelles (MICs) containing
mangiferin (MF) that promote angiogenesis. In the process of wound healing of diabetic
infection, with the break of borate and Schiff base bonds sensitive to acidic and oxidizing
environment, antibacterial substances CE and anti-inflammatory substances DS and MIC
are released, effectively inhibiting inflammation and antibacterial. Subsequently, the con-
tinuous acidic environment gradually releases MF, promoting neovascular formation and
accelerating chronic wound healing [127]. Similarly, Fan et al. developed a novel TA–siRNA
nanogel based on the self-assembling interaction of tannic acid (TA) with short interfering
RNA (siRNA). This nanogel, combined with polyvinyl alcohol (PVA), human-like collagen
(HLC), TA, and borax crosslinking, forms an adaptive and conductive PHTB hydrogel. It
is designed to maximize therapeutic effects by responding to stimuli, such as ROS and
electrical stimulation (ES). In a high ROS environment, the hydrogel’s borate bond breaks,
releasing TA-siRNA nanogels that reduce matrix metalloproteinase-9 (MMP-9) expression,
while TA and HLC promote collagen expression and reduce inflammation (Figure 7B).
Electrical stimulation further enhances the release and endocytosis of TA-siRNA nanogel,
Polymers 2024, 16, 1937 21 of 30

activates macrophage polarization and neointimal formation, and accelerates diabetic

wound healing [128].
In the field of diabetic wound therapy, multi-stimulus responsive hydrogel adhesives
have demonstrated significant benefits in terms of their ability to rapidly respond to
environmental changes and release therapeutic agents at the right time. These hydrogel
adhesives adapt to dynamic changes in the wound microenvironment, thereby improving
the relevance and efficacy of the treatment [129]. In combination with sensing technology,
the range of applications and functionality of these hydrogel adhesives is further extended.
By integrating sensors, these hydrogel adhesives can not only serve as carriers of therapeutic
agents but also monitor the state of the wound in real-time, such as changes in temperature,
stress, and biochemical markers, providing richer data support for treatment, and thus
offering a more comprehensive treatment plan.
For example, Zhu et al. developed a zwitterionic hydrogel for monitoring pH and
glucose concentration in diabetic wounds. This hydrogel contains phenol red dye, which
is sensitive to pH changes, and encapsulates glucose oxidase (GOx) and horseradish
peroxidase (HRP). These enzymes catalyze the oxidation of glucose to produce fluorescent
products. Due to the hydrogel’s anti-biofouling properties, the immobilized enzymes
maintain high activity and stability when treating wound exudates, whereas free enzymes
are unstable. For ease of use, color and fluorescence signals can be accurately measured via a
spectrophotometer or smartphone (Figure 7C). Clinical trials have shown that the hydrogel
not only provides better monitoring results but also significantly accelerates the healing
of diabetic wounds compared to DuoDerm dressings [130]. In contrast, Zhang’s team
expanded the sensing technique to synthesize a multi-stimulation-responsive conductive
hydrogel (SB–N–MB) composed of sulfonated betaine (SBMA), n-isopropylacrylamide
(NIPAAm), and methyl-acrylamide phenyl-boric acid (MPBA).They further developed an
ion skin sensing system with a ‘sandwich’ structure that is able to monitor temperature,
strain and glucose levels in real-time and effectively distinguish between these signals.
The layered design of the system ensures precise transmission of temperature changes
(inflammation), strain changes (wound swelling) and glucose concentration changes (blood
glucose) without signal interference (Figure 7D).This sensor-integrated hydrogel system
not only improves the efficiency of local drug delivery, but also helps health care workers
better understand microenvironmental changes during wound healing by continuously
monitoring key physiological indicators [131].
Stimulus–responsive hydrogel adhesives are crucial for treating chronic refractory
wounds. By regulating drug release and dressing performance, they can effectively respond
to changes in the wound microenvironment, thus reducing wound recurrence, pain, and
the economic burden on patients [132,133]. Combined with sensing technology, hydro-
gel adhesives demonstrate potential for precision treatment and personalized medicine,
providing a new direction for future wound care.

Table 3. Applications of bionic hydrogel adhesives for various wound types.

Bionic Hydrogel
Wound Type Characteristics Ref.
Adhesives Applications
Infection prevention,
Full-thickness skin defects Clean, controlled environment [134]
scar minimization
Acute, high risk of infection, excessive tissue Antibacterial, pain relief, intelligent
Burns fluid exudation, tissue necrosis, delivery of stem cells, growth [135]
hypoxia–ischemia, and decreased immunity factors, etc.
Chronic, excessive chronic inflammatory
Adhesion, self-healing, intelligent
response, impaired angiogenesis, excessive
Diabetic wounds response release, ROS scavenging [136,137]
oxidative stress, and hypoxia in the
and oxygen production
wound environment
 Polymers
Polymers 2024, 16, x FOR 16, 1937
2024,PEER REVIEW 24 of 32 22 of 30

Figure
Figure 7. (A) 7. (A) Schematic
Schematic diagram ofdiagram of the manufacturing
the manufacturing process forprocess for embedding
embedding DS and MIC@MF
DS and MIC@MF into into
POD/CE hydrogel [127]; (B) [127];
POD/CE hydrogel repairing chronic chronic
(B) repairing diabeticdiabetic
woundswounds
using ES therapy
using and adaptive
ES therapy and adaptive con-
conductive PHTBPHTB
ductive (TA-siRNA) hydrogel
(TA-siRNA) [128];
hydrogel (C)
[128]; (C)scheme
scheme for detectingthe
for detecting thepHpHandand glucose
glucose concentration
concentration of wound exudate using PCB hydrogel dressing [130]; (D) schematic diagram
of wound exudate using PCB hydrogel dressing [130]; (D) schematic diagram of a sandwich-structureof a
sandwich-structure sensor based on a multi-responsive zwitterionic
sensor based on a multi-responsive zwitterionic epidermis [131]. epidermis [131].

4.4. Regulation of Mechanical

4.4. Regulation and Physical
of Mechanical andProperties
Physical Properties
Improving the mechanical
Improving and adhesion
the mechanical properties
and adhesion of bionicof
properties hydrogel adhesivesadhesives
bionic hydrogel is is
crucial for skin wound
crucial for skinhealing. These properties
wound healing. not only not
These properties directly
only impact
directlythe functional
impact the functional
effectiveness of hydrogel
effectiveness adhesivesadhesives
of hydrogel but are alsobutkey
are factors
also keyinfactors
facilitating wound closure,
in facilitating wound closure,
reducingreducing
the risk of infection, and accelerating the healing process [138,139].
the risk of infection, and accelerating the healing process [138,139]. Specifically,
Specifically,
the mechanical properties
the mechanical of hydrogel
properties adhesives,
of hydrogel especiallyespecially
adhesives, their strength
their and elasticity,
strength and elasticity,
ensure that they
ensure can
that withstand
they the physical
can withstand stresses
the physical in the
stresses wound
in the wound area
areaand
andprevent
prevent fracture
fracture or
or deformation,
deformation,thus thusmaintaining
maintainingthe thewound
wound in in
a stable
a stablestate. At the
state. At same time,time, the
the same
the excellent adhesion
excellent properties
adhesion of theofhydrogel
properties adhesives
the hydrogel ensure
adhesives that they
ensure that fit tightly
they to to the
fit tightly
the wound, forming
wound, an effective
forming barrier
an effective to isolate
barrier it from
to isolate it fromthetheexternal
externalenvironment
environmentand and prevent
prevent microbial invasion and other other possible
possible infection
infectionfactors
factors[136,140].
[136,140].InInaddition,
addition,adhesion
adhesionfacilitates
facilitates the hydrogel’s
hydrogel’sinteraction
interactionwithwithcells
cellsonon
thethe
woundwound surface,
surface, supporting cell
supporting
migration
cell migration and newand new
tissuetissue production,
production, which which are important
are important stepssteps in wound
in wound healing.
healing.
Polymers 2024, 16, 1937 23 of 30

To further enhance these properties, several commonly used methods include dual
reticulated hydrogel adhesives, dual physicochemical crosslinked hydrogel adhesives, and
the construction of nanocomposite hydrogel adhesives. Dual reticulated hydrogel adhe-
sives technology improves the mechanical strength of the overall structure by combining
two polymer networks: a stiff but brittle polymer and a flexible, ductile polymer that
interact with each other. Dual physicochemical crosslinking hydrogel adhesives, on the
other hand, not only enhance the tensile strength and toughness of the hydrogel adhesives
through a dual mechanism of chemical and physical crosslinking but also ensure its dura-
bility and stability under extreme conditions. Nanocomposite hydrogel adhesives utilize
nanomaterials, such as inorganic salt particles or metallic nanomaterials, as crosslinking
points, which enhance the network structure and allow some of the polymer chains to
break and consume energy under stress, thereby increasing overall elongation and tough-
ness [141,142]. These techniques significantly enhance the tensile properties of hydrogel
adhesives. To prevent hydrogels from flaking off during skin surface activity or stretching,
the chemical composition, polymer content, molecular weight, and crosslink density need
to be adjusted from the early stages of design to ensure a good match with the skin tissue.
When designing bionic hydrogel adhesives, it is crucial to consider their mechanical
properties. The degree of matching between bionic adhesion materials and tissue adhesion
materials will significantly affect their adhesion effect. If a mechanical mismatch exists,
interfacial stress concentrations may lead to tissue damage or premature material failure.
One solution is to introduce an elastic modulus gradient in the biomimetic adhesive so
that the interface between the material and the tissue has a better mechanical match
(i.e., softer), while the part covering the wound has a higher stiffness to resist deformation
(i.e., harder) [143]. In addition, the rheological properties of bionic hydrogel adhesives are
also critical to their adhesive properties, which determine their fluidity, ability to adapt to
irregular tissue surfaces, and ability to form mechanical interlocks with uneven surfaces.
In this regard, the viscosity of the bionic adhesive precursor should be carefully adjusted:
overly viscous materials may not penetrate or conform to the tissue efficiently, whereas
overly flowable materials may be washed away or form inadequate adhesion. Modulation
of rheological properties, for example, through the addition of rheology modifiers, can
optimize the bionic adhesive to ensure that it effectively covers and tightly conforms to
irregular tissue surfaces, thereby improving adhesion performance [144]. In addition, the
crosslinking kinetics of an adhesive are critical for its suitability in different clinical scenarios.
Rapidly crosslinking adhesives are suitable for emergency situations and dynamic tissues,
whereas a slower crosslinking process is appropriate for situations where precise application
is required [137]. Adjusting the type of crosslinking agent, its concentration, and the
availability of crosslinking sites allows for fine control of the reaction kinetics to meet
different clinical needs.

5. Conclusions and Outlook

Bionic hydrogel adhesives hold great potential in skin wound therapy by exhibiting
excellent biocompatibility and strong adhesive properties, while also overcoming many
limitations of conventional adhesives, such as non-degradability, cytotoxicity, incompatibil-
ity with moist surfaces, and inability to adapt to dynamic tissue movement. Consequently,
these bionic adhesives can be used to create innovative wound dressings and serve as
medical glues to facilitate wound closure. Through bionic strategies, researchers have
significantly improved the adsorption, mechanical interlocking, and electrostatic interac-
tions of hydrogel adhesives to enhance adhesion properties. With functionalities such as
self-healing, drug release, mechanical strength, and responsiveness, these adhesives can
flexibly adapt to complex and changing wound environments, significantly accelerating
wound healing.
However, due to the complexity and variability of the wound repair process, it is
difficult to fulfill the needs of the entire healing process with a single dressing. For example,
controlling inflammation is critical during the inflammatory phase but may not be needed
Polymers 2024, 16, 1937 24 of 30

during the subsequent repair phase. Additionally, the cells, cytokines, and functional
components of a dressing usually only work at specific stages and may even have adverse
effects at other stages. Therefore, providing function on demand has become a focus
of further research. In addition, precisely controlling the degradation or separation of
hydrogel adhesives from the skin surface when needed during practical application remains
a challenge, especially for delicate and fragile skin, such as that of infants and patients with
chronic wounds. Traditional adhesives are often difficult to control in real-time during
the process of debonding and degradation, which limits their application flexibility and
potential for personalized treatment. In the future, hydrogel adhesives will require a more
sensitive response. Once their mechanical function is no longer needed (for example, when
a skin wound has healed), the ideal hydrogel adhesives should be able to automatically
trigger detachment or degradation. This triggering mechanism can be based on an external
stimulus (such as a change in temperature or pH) or an intrinsic biological signal (such as
the presence of a specific enzyme). With this design, the hydrogel adhesive can be easily
removed without damaging the skin, thus reducing secondary damage and discomfort
for patients. This unique personalized design may be one of the important directions for
future adhesives. Chronic wounds are usually alkaline, but most pH response systems are
better suited to acidic environments. Therefore, developing hydrogel adhesive dressings
that can function effectively under alkaline conditions is of great significance. In the
future, hydrogel adhesives will pay more attention to the development of personalized
treatment, customizing hydrogel adhesives with exclusive functions and formulations for
the specific conditions of patients to meet clinical needs. For example, for patients with
chronic wounds requiring long-term care, such as diabetes patients, hydrogel adhesives
with long-acting slow-release drugs could be designed to reduce the number and frequency
of dressing changes. At the same time, this would respond to changes in blood glucose
levels to enhance drug release and antibacterial function in a hyperglycemic environment.
Combined with sensing technology, the status of wound healing could be monitored in
real-time, allowing the function of the hydrogel adhesive to be adjusted based on this data,
enabling precise treatment and timely detection of potential infection risks.
Although hydrogel adhesives have great potential in the treatment of skin wounds,
there are still many shortcomings and challenges in the development of on-demand strip-
ping, real-time control of the degradation process, personalized therapy, and integration
with sensing technology. Future research and development should focus on these direc-
tions to further explore complex bionic bonding mechanisms and develop personalized
hydrogel adhesives for different trauma environments to achieve safer, more effective, and
personalized skin trauma treatment.

Author Contributions: Conceptualization, C.W. and P.P.; writing—original draft preparation, C.W.,
X.Z., S.Y. and M.L.; writing—review and editing, C.W., X.Z. and P.P.; investigation, Y.F. supervision,
L.F. and Q.S. All authors have read and agreed to the published version of the manuscript.
Funding: This work was financially supported by the Natural Science Foundation of Shandong
Province (ZR2022QD057), China Postdoctoral Science Foundation (2023T160492, 2022M722434), the
Foundation of National Center for Translational Medicine (Shanghai) SHU Branch (No. SUITM-
202410), and Physical-Chemical Materials Analytical and Testing Center of Shandong University
at Weihai.
Conflicts of Interest: The authors declare no conflicts of interest.

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