Coordination Chemistry Reviews 420 (2020) 213432

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Coordination Chemistry Reviews

journal homepage: www.elsevier.com/locate/ccr

Review

Natural polymers-based light-induced hydrogels: Promising

biomaterials for biomedical applications
Hadi Samadian a, Hassan Maleki a, Zahra Allahyari b, Mehdi Jaymand a,⇑
a
Nano Drug Delivery Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
b
Department of Biomedical Engineering, Rochester Institute of Technology, Rochester, NY, USA

a r t i c l e i n f o a b s t r a c t

Article history: There has been a significant increase in demand for biomaterials over the last decades. According to this
Received 4 February 2020 fact, the design and development of more efficient and sophisticated biomaterials have attracted a great
Accepted 2 June 2020 deal of interest. In this context, natural polymers-based hydrogels have received more attention due to
Available online 7 July 2020
their inherent physicochemical and biological features, as well as numerous biomedical applications
(e.g., wound healing, drug delivery, and tissue engineering). Various synthetic approaches, including ester
Keywords: or amide formation, radical polymerization, Michael addition, ‘‘Schiff-base”, and disulfide crosslinking
Biomaterials
have been introduced for the synthesis of natural polymers-based hydrogels. Amongst, the light-
Natural polymers
Photo-polymerization
induced radical polymerization (otherwise known as photo-polymerization) has received a considerable
Hydrogels attention due to its advantages such as solvent-free, easy and rapid network formation, energy-efficient,
Biomedical applications fast process, spatial and temporal control, in situ gelling viscoelastic systems in vivo with a minimally
invasive manner, and tenability of crosslinking density and matrix stiffness using light intensity, expo-
sure time and the illuminated area. This review article discusses the recent advances of the design, devel-
opment, as well as numerous biomedical applications of natural polymers-based light-induced hydrogels.
In addition, the advantages and disadvantages of light sources (near-infrared (NIR), visible light and ultra-
violet (UV)) as well as current status and challenges are discussed.
Ó 2020 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2. Hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
3. Synthetic strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
4. Photo-polymerization: fundamentals, current status, challenges, and recent progress. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
4.1. UV-light-induced photo-polymerization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
4.2. Visible-light-induced photo-polymerization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
4.3. NIR-light-induced photo-polymerization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
4.4. What is the best choice?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
5. Biomedical applications of light-induced hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
5.1. Polysaccharide-based photo-polymerizable hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
5.1.1. Alginate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
5.1.2. Starch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
5.1.3. Cellulose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
5.1.4. Chitosan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
5.1.5. Hyaluronic acid. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
5.1.6. Dextran . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
5.2. Polypeptide-based photo-polymerizable hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
5.2.1. Collagen. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

⇑ Corresponding author.
E-mail address: mehdi.jaymand@kums.ac.ir (M. Jaymand).

https://doi.org/10.1016/j.ccr.2020.213432
0010-8545/Ó 2020 Elsevier B.V. All rights reserved.
2 H. Samadian et al. / Coordination Chemistry Reviews 420 (2020) 213432

5.2.2. Gelatin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
5.2.3. Silk. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
6. Conclusions and future remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Declaration of Competing Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Appendix A. Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

1. Introduction sections. Hydrogels can mimic the native extracellular matrix

Demand for biomaterials has grown continuously during the
last decade and several new strategies for developing more effi-
cient biomaterials have been developed. This intense interest orig-
inated from their wide range of applications in the healthcare and
medical industries including, wound healing therapies, plastic
surgeries, regenerative medicine, orthopedic disorders, diagnoses,
implantable devices, tissue engineering (TE), and drug delivery
systems (DDSs) [1–6]. A biomaterial should possess general
biological features such as non-toxicity, non-carcinogenicity,
non-allergenicity, non-inflammatory, biocompatibility, and
biodegradability in the case of in vivo applications [7,8]. Generally,
biomaterials are divided into metallic (used in orthopedics and den-
tal applications), ceramic and glasses (used in dental restorations
and bone repair), polymeric, and composite classes [9,10]. Accord-
ing to the consensus in the field, the most important issues that
should be addressed in the case of any biomaterial are as follows:
a) Relationships between the molecular structures, physico-
chemical as well as biological features of biomaterial
b) Effect of interfacial interactions between biological systems
and biomaterial on its function
c) Controlled conversion of biomacromolecules into a hierar-
chical structure
d) Engineering of biomaterials for stimulating specific cellular
response
e) Tuning of cell/tissue bioadhesive property
It should be pointed out that the recent advances in materials
science (e.g., new synthetic and semi-synthetic strategies), as well
as the advent of nanotechnology, can address some of the above-
mentioned issues [5,9,11].
Among the biomaterials, a great deal of research activities has
attempted to develop polymeric biomaterials mainly due to their
abundances and superior physicochemical, as well as biological,
features that capable of addressing most of the above-mentioned
issues. The most important advantages of polymeric biomaterials
are biocompatibility, sterilizability, adequate mechanical and
physical properties, excellent processability in most cases, and
manufacturability [1–4]. These types of biomaterials are divided
into three main categories known as synthetic, semi-synthetic,
and natural polymers [1,2]. However, numerous drawbacks have
limited their applications in biomedical fields. The most important
drawbacks, as well as the modification strategies, of natural and
synthetic polymeric biomaterials have been described in our previ-
ous work [1]. In brief, naturally occurring polymeric biomaterials
do not typically offer the cytotoxicity issues in comparison with
synthetic polymers. Besides, they have specific protein binding
sites as well as other biochemical signals that play pivotal roles
in many biomedical processes [1,12].
Among the various type of polymer-based biomaterials, consid-
erable efforts are being made to develop hydrogels mainly due to
their inherent physicochemical, as well as biological features
[13–16], which will be described extensively in the corresponding
(ECM) environment of the host in the case of soft tissues. There-
fore, hydrogels are extensively used in various areas of regenera-
tive medicine and TE (the mentioned concepts are referred to
regeneration or replacement of failed tissue/organ, respectively)
[17–19]. This types of biomaterials can be fabricated through var-
ious approaches, including ester or amide formation, radical poly-
merization, Michael addition, ‘‘Schiff-base”, and disulfide
crosslinking [13,17,19]. Amongst, the light-induced radical poly-
merization (known as photo-polymerization) for the fabrication
of natural polymers-based hydrogels has been received consider-
able interest due to its some advantages over other aforemen-
tioned approaches [20–22].
According to the above-mentioned facts, the naturally occurring
polymers-based hydrogels have huge potential to translate into
clinical applications in the near future. Therefore, in this review,
we focus on natural polymers-based light-induced hydrogels as
promising biomaterials for medical applications. To the best of
our knowledge, numerous reviews are available regarding the
introduction and fundamentals of hydrogels as well as their vari-
ous application fields. However, this is the first up-to-date compre-
hensive overview on the recent developments in the fabrication as
well as biomedical applications of natural polymers-based light-
induced hydrogels. Furthermore, the fundamentals of hydrogels
and natural polymers and various fabrication methodologies are
also briefly highlighted.
2. Hydrogels
Hydrogel is a three-dimensional (3D) crosslinked network that
can imbibe large quantities of water or any other biological fluid
with maintaining owns 3D architecture, mainly due to the pres-
ence of hydrophilic moieties (e.g., carboxyl, hydroxyl, ether, and
amino groups) in its polymeric backbone [23–25]. As known,
hydrogels are swollen and distended due to the absorbing of any
fluid and become soft and rubbery, which leads to low interfacial
tension with water and other biological fluids. Another advantage
of swollen is reducing mechanical friction between tissues and
implanted hydrogel mainly due to its elastomeric consistency in
the case of in vivo purposes [26,27].
Hydrogels can be categorized into various classes based on
polymeric composition (homo-polymeric, co-polymeric or multi-
polymeric), source (natural, synthetic or hybrid), crosslinking
(chemical, physical, and enzymatic), configuration (crystalline,
semi-crystalline or amorphous), physical appearance (matrix, film
or microsphere), and network electric charge (ionic, neutral,
amphoteric electrolyte or zwitterionic) [28–30]. The physicochem-
ical, as well as biological properties of a hydrogel, strongly depend
on the chemical composition, type and number of functional
groups, fabrication method, molecular weight of each polymeric
chain, the rigidity, and intermolecular and intramolecular forces
strengths [13,27].
From the source’s point-of-view, the natural hydrogels have
some superior physicochemical as well as biological features over
 H. Samadian et al. / Coordination Chemistry Reviews 420 (2020) 213432
synthetic hydrogels. The most important advantages of natural
hydrogels are low immunogenicity, excellent biocompatibility
and cytocompatibility, biodegradability, specific cellular/tissue
response (due to functional groups within their structures), anti-
genicity, adequate stability, superior structural design, variable/-
controllable solubility, and 3D geometry [31,32]. However, the
most important drawbacks of these hydrogels are difficult to con-
trol reproducibly due to their natural origin, weak mechanical
properties (in most cases), poor processability (e.g., cellulose and
chitosan), source limitations as well as high production costs in
some cases, high biodegradation and catabolization rates in some
cases (e.g., gelation), and microbial spoilage (especially in the case
of polypeptides) [1,13,27].
In contrast, synthetic hydrogels can be produced in a large scale
with low costs, more reproducible, more flexibility for tuning the
chemical composition and mechanical properties, and tuning capa-
bility to be hydrolyzed or biodegrade over variable periods. Despite
these advantages, the main concern regarding the synthetic hydro-
gels is their biological aspects (e.g., biocompatibility and
biodegradability), because each foreign material without proper
biological aspects is inherently thrombogenic in vivo. The main
reason for this phenomenon is the denaturation of proteins, prop-
agation of thrombi, activation of coagulation factors, provocation
of inflammatory responses, and accumulation of debris [1,33,34].
In general, hydrogels can be applied in various fields, including
agriculture, hygienic products, food additives, sensing, separation,
as well as biomedical applications (e.g., DDSs, TE, wound dressing,
and diagnostics) [13,20,24,33,34]. Among the wide verity of appli-
cations, this review highlights the biomedical purposes of light-
induced natural polymers-based hydrogels.
3. Synthetic strategies
Hydrogels can be synthesized through in situ crosslinking or
post-crosslinking approaches. In situ crosslinking can be achieved
through two main strategies of physical and chemical crosslinking
methods. This approach involves the polymerization and simulta-
neous crosslinking of multifunctional monomer(s) or mono-
functional monomer(s) in the presence of bi-functional or multi-
functional crosslinking agents [35–37]. In contrast, the post-
crosslinking approach involves two or more phases, including the
synthesis of a polymer chain with reactive functional groups in
its backbone followed by reticulation using specific crosslinking
agents [37–39].
Generally, in physical hydrogels ionic interactions, hydrogen
bonding, hydrophobic forces, host–guest interactions, as well as
combinations of these plays the main role in forming the network.
These types of hydrogels are often reversible and may be dissolved
through the change in environmental conditions such as ionic
strength, pH, and temperature [40–44].
In contrast, chemical hydrogels are more stable and polymeric
chains are joining through covalent bonds. Some synthetic
approaches, including ester or amide formation, radical polymer-
ization, Michael addition, ‘‘Schiff-base”, and disulfide crosslinking
have used for the synthesis chemical hydrogels. Additionally, ‘‘click
chemistry”, and ‘‘native chemical ligation” approaches are intro-
duced as efficient and novel strategies mainly due to their ease
of use and high conversion.
Another synthetic strategy that may be achieved using the
above-mentioned approaches is Interpenetrating (IPNs) or Semi-
Interpenetrating Networks (Semi-IPNs). In these approaches, a
pre-polymerized hydrogel is placed into a solution of monomers
and a polymerization initiator with (IPNs) or without (Semi-IPNs)
crosslinking agent. In comparison with homo-polymeric hydrogels,
3
these types of hydrogels have higher absorbance potential and
mechanical strength [37,39,45].
Among the above-mentioned approaches, radical polymeriza-
tion can be achieved using both conventional free radical polymer-
ization and photo-polymerization reactions through external
radiation sources such as near-infrared (NIR), visible light, and
ultraviolet (UV) in the presence of a photoinitiator [45–47]. The
fundamentals and challenges of this polymerization approach
toward the fabrication of hydrogels are discussed in the following
section.
4. Photo-polymerization: fundamentals, current status,
challenges, and recent progress
Photo-polymerization is a versatile and powerful tool for the
rapid fabrication of a hydrogel. In this strategy, the spatiotemporal
formation of the hydrogel and its network features such as the
crosslinking density and matrix stiffness can be controlled using
light intensity, exposure time, and the illuminated area. The con-
ventional photo-polymerization method is based on the chain-
growth mechanism. The most important drawbacks of this
approach are lack of control over the crosslinking kinetics, oxygen
inhibition, and the generation of heterogeneities within the hydro-
gel network, which significantly affect the mechanical integrity
and swelling behavior of the resultant hydrogel [48–50].
The oxygen inhibition is one of the most important drawbacks
of this approach due to the production of peroxy radicals and the
significant contribution of these radicals to the polymerization
reaction that reduces both polymerization rate and final conver-
sion ratio, which lead to the production of undesirable and highly
viscous substances [51,52].
The emergence of ‘‘thiol-ene” reaction circumvents some of the
above-mentioned problems mainly due to its step-growth mecha-
nism. This strategy can produce structurally uniform hydrogels
with minimal network defects. Despite this, the main drawback
of this strategy is poor shelf-life that makes it difficult to provide
room temperature stable one-component systems [53,54].
In general, photo-polymerization is divided into three main cat-
egories known as free radical photo-polymerization (FRP), cationic
photo-polymerization (CP), and hybrid initiating system (FRCP). It
should be pointed out that the FRP is the most common approach
in this category of polymerization technique [22,50]. In general,
three different systems can be designed toward the synthesis of
hydrogels using a photo-polymerization approach as follows:
a) Use of hydrophilic reactive monomers and bi-functional
crosslinkers
b) Use of polyfunctional cross-linkers with or without reactive
monomers
c) Use of non-functionalized polymer chains [55–57].
This type of polymerization allows rapid network formation
under physiological conditions, with efficient temporal and spatial
control. Other advantages of this approach are solvent-free,
energy-efficient, fast process (taking usually only seconds to min-
utes), spatial and temporal control, and economical. In addition,
due to the irradiation capacity of various types of light (UV, visible
or NIR), this approach can be applied for the preparation of in situ
gelling viscoelastic systems in vivo with a minimally invasive man-
ner [57,58].
In general, photo-polymerization is initiated through the
decomposition of the photoinitiator upon exposure to light (UV,
visible or NIR) with suitable wavelength, leading to the generation
of radicals. Afterward, a hydrogel can be fabricated through one of
4 H. Samadian et al. / Coordination Chemistry Reviews 420 (2020) 213432

Scheme 1. The overall mechanism of photo-polymerization.

the above-mentioned approaches. The overall mechanism of

photo-polymerization is illustrated in Scheme 1.
In the case of natural polymers-based hydrogels, these poly- O P P
mers should be functionalized by photo-reactive side groups, O O
including acrylates, methacrylates, vinyl esters, and fumarates. O
(BAPO: Irgacure 819; ~ 370 nm)
The reactivity of these functional groups in photo-polymerization
is as acrylate > vinyl ester > vinyl carbonate > vinyl
carbamate > methacrylate > fumarate [48]. (TPO; ~ 380 nm)

O
O N
4.1. UV-light-induced photo-polymerization N

The UV-light-induced photo-polymerization (200–400 nm) is

HO
the most commonly used strategy for the fabrication of hydrogels O
through photo-polymerization approach, especially for biomedical (Irgacure 184; ~ 246 nm)
purposes. This approach allows the fabrication of hydrogels in low (Irgacure 369; ~ 324 nm)
initiating radical doses under mild reaction conditions (i.e., in
physiological aqueous solution at room temperature) both in vivo O
and in vitro with tunable physicochemical (e.g., composition and
CH3
mechanical) as well as biological (e.g., degradation rate) features CH3
[59,60]. HO
HO
O
The chemical structures of the most popular UV-light-sensitive
photoinitiators are shown in Scheme 2. In general, photoinitiators (Irgacure 2959; ~ 276 nm)
are divided into two main classes depending on their cleavage fea-
Scheme 2. The chemical structures of the most commonly used UV-light-sensitive
ture as follows:
photoinitiators.

a) Unimolecular homolytic cleavage (Type I)

b) Bimolecular reaction with a hydrogen donor such as an
amine or thiol (Type II) [61,62].
Despite the most application ranges of UV-light-induced photo-
polymerization approach, the low penetration depth and loss of
power with the square of the distance, as well as cytotoxicity
and poor solubility of the UV-light-sensitive photoinitiators are
the most important drawbacks of this method. In this context, 1-
[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1-propane-1-
one (Irgacure 2959), lithium (phenyl-2,4,6-trimethylbenzoylpho
sphinate) (LAP), and 2,2-azobis[2-methyl-N-(2-hydroxyethyl)
propionamide]) (VA-086) are the most popular water-soluble type
I initiators for the fabrication of cell encapsulated hydrogels mainly
due to their superior initiation efficiency as well as cytocompatibil-
ity. However, low absorption at wavelengths > 370 nm is the main
drawback of Irgacure 2959 that leads to long cure times. In con-
trast, LAP has good absorption at both 365 and 405 nm light, and
low cytotoxicity [61].
4.2. Visible-light-induced photo-polymerization
This type of photo-polymerization is proposed in the 1970s and
then extensively employed for curing dental composites [20,63].
The photoinitiator systems for visible-light-induced photo-
polymerization are classified into three main categories known
as free radical initiating, ionic initiating and hybrid initiating sys-
tems. Among these approaches, the free radical initiating systems
are the most commonly used approach. In this type of photo-
induced polymerization method, the most popular light sources
are as follows:
 H. Samadian et al. / Coordination Chemistry Reviews 420 (2020) 213432 5

a) Laser diodes with the light intensity of 100 mWcm
2 at 457,
473, 532, and 635 nm
b) Laser diode with the light intensity of 2–10 mWcm
2 at
405 nm
c) Halogen lamp with the light intensity of 12 mWcm
2
d) Light-emitting diode (LEDs) with the light intensity of 10
mWcm
2 at 462, 514, 591, and 630 nm [50,63].
Among the numerous photoinitiator systems, metal-based (e.g.,
copper, zinc, germanium, ruthenium or iridium) photoinitiators
have received a great deal of interest mainly due to excited-state
visible light absorptions and high excited-state energy levels
and/or lower oxidation potentials. However, this type of photoini-
tiator system is expensive [64]. In this context, incorporation of
organic dyes (any molecule that absorb light between 380 and
700 nm wavelength) can be considered as an alternative candidate
mainly due to their cost benefits and commercial availability,
proper biocompatibility, good stability, and solubility, as well as
easier extractability [50]. Amongst these organic dyes, cam-
phorquinone, benzophenone, anthraquinone, pyrene, carbazole,
and thioxanthone derivatives are the most important and widely
used members. The developed visible-light-sensitive photoinitiat-
ing systems have been extensively discussed recently [50,65,66].
The chemical structures of the most commonly used visible-
light-sensitive photoinitiators are shown in Scheme 3.
4.3. NIR-light-induced photo-polymerization
Generally, in the NIR-initiated photo-polymerization the pho-
toinitiator system involves a cyanine as photosensitizer (Sens)
and an iodonium salt as a radical initiator. It is an indisputable fact
that the NIR-initiated photo-polymerization has not received sig-
nificant attention due to poor solubility of Sens and radical initiator
(RI) in a high viscous monomeric substrate. The most commonly
used light sources in the NIR-light-induced photo-polymerization
approach are NIR laser with emission at either 808 or 830 nm as
well as NIR LEDs with emission at 750, 790, 850, and 940 nm.
The chemical structures of the most commonly used NIR sensitiz-
ers are shown in Scheme 4. In comparison with visible-light-
induced photo-polymerization and especially UV-initiated
approaches the NIR-initiated photo-polymerization has very low
harmful side effects on the cells/tissues that discussed in the next
section [60,67].

4.4. What is the best choice?

NH2
2
HN The most important issues regarding the UV-light-induced
O
N S
2
HN N photo-polymerized hydrogels in the biomedical purposes are as
O O
N
follows [66,68]:
S
O or O
O a) The low penetration depth and loss of power with the square
(NDP2; ~ 417 nm) O O of distance due to great absorption by biological systems
(ATNA1; ~ 419 nm) b) Potential harmful side effects of UV light irradiation
c) Cytotoxicity of radicals generated by the dissociation of
photoinitiators
C8H17
d) Local inflammation due to unreacted monomers or double
N bonds
N

It is well documented that applying light sources emitting in

the UV-A range can be considered as an efficient strategy for reduc-
(C2; ~ 374 nm) ing deleterious effects on the biological systems. In addition, cell
damage caused by UV irradiation can be significantly reduced or
(AZ3; ~ 390 nm)
even eliminated through selection of proper light wavelengths,
intensity and irradiation time as well as the developing suitable
photosensitive systems [48,69].
+
- In contrast, visible light is absorbed with orders of magnitude
Ph Ph BF4 N N less efficiency than UV light in tissue that leads to non-
N PH Zn thermogenic, less damage to cells and more readily transmitted
N
N
Cu O N through tissues, which allows the dipper curing process. It is worth
N
PH noting that visible light initiators such as eosin Y have been used to
Ph gel solutions under the dermis, but its effective depth is limited to
CF3 Ph
millimeters as the light still absorbs significantly [70–72].
(CuC-4; ~ 355 nm) The most important advantages of NIR initiation over UV initi-
(ZnTPP; ~ 420 nm)
ation are curing with a thickness of>1 cm, fast curing process as
well as the incorporation of fillers and additives with significant
UV absorption. On the other hand, in comparison with UV-light-
N induced photo-polymerization, NIR-light-induced photo-
2Cl-
O O
N N polymerization showed significantly lower reactivity. This draw-
Ru2+
Ge
back may be circumvented through the structural improvements
N . 6H2O
N of both NIR sensitizer and a radical initiator [73,74].
O O
N In conclusion, if some improvements achieved in the case of
NIR-light-induced photo-polymerization approach in terms of pho-
(Ivocerin; ~ 408 nm)
toinitiator system and light sources, this method can be considered
(Ru; ~ 453 nm)
as the first choice for the fabrication of hydrogels in biomedical
Scheme 3. The chemical structures of the most commonly used visible-light- purposes both in vivo and in vitro due to its less significant side
sensitive photoinitiators. effects to the biological systems.
6 H. Samadian et al. / Coordination Chemistry Reviews 420 (2020) 213432

N Cl N Cl

+ +
N N N N
BF4-
F F
(S1; 792 nm) F P F (S2; 796 nm)
F F
O O
O
+
Na +
- Na N N
OS -
3 SO3 -
O O
+ +
N N N N

C2H5 C2H5
(S3; 768 nm) (S4; 791 nm)

- + - +
SO3 Na SO3 Na

N N
Cl Cl Cl -
O O
+ +
N N N N

C2H5 C2H5
(S5; 789) (S6; 791 nm)
O O

N N
N N

S Cl

+
+ N N
N - N BF4-
Cl

(S7; 798 nm) (S8; 816 nm)

Scheme 4. The chemical structures of the most commonly used NIR sensitizers. S1: 1-Butyl-2-(2-[3-[2-(1-butyl-3,3-dimethyl-1,3-dihydro-indol-2-ylidene)-ethylidene]-
2-diphenylaminocyclopent-1-enyl]-vinyl)-3,3-dimethyl-3H-indolium tetrafluoroborate; S2: 5-Chloro-2-[2-(3-{2-[5-chloro-1-(2-methoxy-ethyl)-3,3-dimethyl-1,3-dihydro-
indol-2-ylidene]-ethylidene}-2-diphenylamino-cyclopent-1-enyl)-vinyl]-1-(2-methoxy-ethyl)-3,3-dimethyl-3H-indolium hexafluorophosphate; 2-[2-(3-[2-[3,3-Dimethyl-
5-sulfo-1-(4-sulfobutyl)-1,3-dihydro-indol-2-ylidene]-ethylidene]-2-phenylcyclohex-1-enyl)-vinyl]-3,3-dimethyl-5-sulfo-1-(4-sulfobutyl)–3H-indolium hydroxide, inner
salt, trisodium salt; S4: 5-(6-(2-(3-Ethyl-1,1-dimethyl-1H-benzo[e]indol-2(3H)-ylidene)ethylidene)-2-(2-(3-ethyl-1,1-dimethyl-1H-benzo[e]indol-3-ium-2-yl)vinyl)
cyclohex-1-en-1-yl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-olate; S5: 5-Chloro-2-[2-(2-chloro-3-{2-[5-chloro-1-(2-methoxy-ethyl)-3,3-dimethyl-1,3-
dihydro-indol-2-ylidene]-ethylidene}-cyclohex-1-enyl)-vinyl]-1-(2-methoxy-ethyl)-3,3-dimethyl-3H-indolium 4-methylbenzenesulfonate; S6: 5-(6-(2-(3-Ethyl-1,1-
dimethyl-1H-benzo[e]indol-2(3H)-ylidene)ethylidene)-2-(2-(3-ethyl-1,1-dimethyl-1H-benzo[e]indol-3-ium-2-yl)vinyl)cyclohex-1-en-1-yl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-
tetrahydropyrimidin-4-olate; S7: 2-[2-[3-[2-(1,3-Dihydro-1,3,3-trimethyl-2H-indol-2-ylidene)-ethylidene]-2-(1-phenyl-1H-tetrazol-5-ylsulfanyl)-1-cyclohexen-1-yl]-
ethenyl]-1,3,3-trimethyl-3H-indolium chloride; S8: 2-(2-[2-Chloro-3-[2-(3-ethyl-1,1-dimethyl-1,3-dihydro-benzo[e]indol-2-ylidene)-ethylidene]-cyclohex-1-enyl]-vinyl)-
3-ethyl-1,1-dimethyl-1H-benzo[e]indolium 4-methylbenzenesulfonate).

5. Biomedical applications of light-induced hydrogels
The naturally occurring polymers-based hydrogels have
emerged immense potential in dealing with a range of multifarious
biomedical problems/applications, specially intended for thera-
peutics agent delivery, wound healing/dressing, cell encapsulation
and TE [6,75]. Such structures have got attention due to their
inherent physicochemical and biological properties, the mentioned
special benefits of hydrogels, versatile fabrication approaches and
so on [23,25,31,35,38]. In particular, photo-crosslinkable hydrogels
are developed as exclusive constructs with tunable mechanical and
chemical properties thanks to controlling over the spatiotemporal
formation and network features of the hydrogels [33,48,50].
Photo-crosslinked alginate-based hydrogels were engineered to
produce tunable constructs for TE and other regenerative medicine
applications [76–82]. Many of the features required for these appli-
cations are provided by these structures such as tunable biodegra-
dation rate and mechanical properties with controlled cell
adhesivity for encapsulation and delivery of cells and bioactive
growth factors. However, in order to achieve appropriate stability,
alginate has been modified that it seems to be necessary. Photo-
crosslinked starch-based hydrogels have not developed enough
 H. Samadian et al. / Coordination Chemistry Reviews 420 (2020) 213432
possibility due to its undesirable characteristics [83]. The 2-
isocyanatoethyl methacrylate-modified starch was developed to
ophthalmic applications as a sustained DDS [84]. Moreover, the
starch-based IPN hydrogel systems modified with methacrylic
and pentenoic anhydride for stem cell engineering was fabricated
to support the adhesion and the proliferation of adipose-derived
mesenchymal stem cells (AdMSCs) [85].
The most use of photo-crosslinked cellulose-based hydrogels
was seen in the field of wound healing/dressing. The studies sug-
gested this type of hydrogels is a promising material that can be
applicable to heal wound injuries [86,87]. Also, the hydrogels could
be incorporated with Ag nanoparticles (NPs) intended for preven-
tion of microbial infection [88], as well as could be incorporated
with epithelial cells intended for wound healing acceleration by
promoting neovascularization, re-epithelialization, and prolifera-
tion of fibroblasts [89]. Photo-crosslinked chitosan-based hydro-
gels have been more used for TE and therapeutics delivery. These
structures have shown high potential as drug delivery devices for
ocular diseases [90], periodontal antibacterial agents [91] and
enzyme proteins [92]. In addition, they have been designed to pro-
mote cell attachment and proliferation and employed as hydrogel
matrices for bone and cartilage TE [93–96].
Among the photo-crosslinked hydrogels, hyaluronic acid (HA)-
based hydrogels have most widely used to create more desirable
structures for TE applications. Since HA is a native component of
cartilage, HA-based hydrogels have been mostly applied for pro-
motion of chondrogenesis and cartilage regeneration or repair
[97–104]. Besides, HA-based hydrogels have been constructed to
provide a 3D cell culture or microenvironment to fibroblasts
and tumor cell encapsulation [105,106]. Photo-crosslinked
dextran-based hydrogels have presented great potential for effec-
tive delivery of various therapeutic agents. The studies indicated
chemical drugs such as theophylline [107] and vancomycin
[108], and also protein components such as insulin [109,110]
could be reserved in the hydrogels and released in controlled
and self-regulated manner. Moreover, siRNAs can be entrapped
in the dextran hydrogels to achieve localized and time-
controlled release profile [111–114].
Polypeptide-based photo-polymerizable hydrogels have used
less than polysaccharide-based hydrogels for biomedical applica-
tions. Among them, gelatin-based hydrogels mostly utilized for
designing innovative 3D biomimetic structures and applying them
for cell encapsulation and TE. It was able to provide the microenvi-
ronment and scaffolds for stem/progenitor/endothelial cells encap-
sulation, confinement, differentiation and proliferation, intended
for skin flap regeneration, tooth regeneration and neural TE
[115–120]. Furthermore, several types of cells, including kerato-
cytes, adipose stem cells, and mesenchymal stem cells have been
loaded into photo-polymerizable gelatin-based hydrogels used to
treat corneal blindness [121], adipose TE [122] and cardiac regen-
eration [123], which visualize a significant potential of such con-
structs. Also, the photo-polymerizable hydrogels based on silk
fibroin have been developed as a promising biomaterial with
regard to TE applications for bone [124], cartilage [125,126] and
load-bearing soft tissues [127].
Recently, cell-laden hydrogel (bioink) bioprinting provides a
powerful tool that allows precise fabrication of customized and
biomimetic 3D tissue constructs. In this context, photo-
polymerizable hydrogels based on collagen, gelatin, and alginate
have been used for 3D bioprinting that exhibited favorable
biological and rheological properties [128–131]. Thus, photo-
polymerizable hydrogels would be ideal building blocks to
fabricate 3D printed cell-laden hydrogel constructs to forming
complicated tissue constructs for TE and regenerative medicine
applications.
7
5.1. Polysaccharide-based photo-polymerizable hydrogels
5.1.1. Alginate
Alginate is an important member of polysaccharide-based
biopolymers and widely used in industry as well as medicine. It
is an anionic biopolymer with the linear structure composed of
b-(1 ? 4)-linked D-mannuronic acid (M) and a-(1 ? 4)-linked L-
guluronic acid (G) residues. It is typically extracted from brown
seaweed cell walls [132]. The industrial applications of alginate
are due to its high water retention capacity, the viscosifying fea-
ture, gelling form, relatively low cost, and stabilizing activity.
Whereas, the biocompatibility, good scaffold-forming property,
mild gelation condition, biodegradability, along with the above-
mentioned properties, have been mad alginate as a fascinating
biomaterial in various biomedical fields. Different forms of
alginate-based biomaterials such as micro/nanofibers, film, and
hydrogel have been fabricated and employed in biomedical
applications. The swollen feature and the structural similarity of
alginate hydrogels to ECM of living tissues introduce them as the
promising biomaterials for drug delivery, wound healing, cell ther-
apy, and TE applications [133]. Different crosslinking approaches
are available for the preparation of alginate-based hydrogels,
which generally categorized into physical and chemical methods.
The chemical crosslinking produces more stable hydrogels than
physical approaches. Hence, various chemical crosslinking tech-
niques such as radical polymerization, enzymatic crosslinking,
and chemical reactions between complemented groups have been
developed to alleviate the poor mechanical properties of physically
crosslinked alginate-based hydrogels [134,135].
For the first time, Jeon et al. have fabricated the methacrylate
alginate to produce photo-crosslinked biodegradable alginate,
and modulated the swelling ratio, degradation rate, and elastic
moduli for cell encapsulation application. They also reported that
the concentration of alginate methacrylate adjusted the physical
properties [80]. In another study, Jeon et al. proposed that photo-
crosslinking technique is beneficial for in situ crosslinking and fill-
ing the irregular-shaped defects in a minimally invasive manner.
They fabricated heparin incorporated photo-crosslinked methacry-
late alginate as a carrier for delivery of the growth factors (bone
morphogenetic protein-2 (BMP-2) and vascular endothelial growth
factor (VEGF)) and scaffold for bone TE [81]. They reported that the
fabricated carrier provided a sustained and controlled delivery pro-
file without any burst effect. In addition to the in vitro studies, the
in vivo evaluation of the osteogenesis potential of the fabricated
hydrogels confirmed by the new bone formation and calcium con-
tent assessments. In another successful study, E. Coates et al. fab-
ricated HA incorporated photo-crosslinked alginate as the
scaffold for mesenchymal stem cell (MSCs) differentiation and
delivery. They observed that the fabricated hydrogel provided a
suitable 3D microenvironment for MSCs viability and also, the
incorporation of HA induced the chondrogenic differentiation.
Moreover, proteins and genes related to the chondrogenic pheno-
type were enhanced during the study [78].
Yuan et al. synthesized a double crosslinked network hydrogel
from aldehyde methacrylate sodium alginate (AMSA) and
ethylenediamine modified gelatin (AG). The AMSA was synthe-
sized via a two-step process: oxidization to form an aldehyde
sodium alginate, and then functionalization with methacrylate
groups. In the next step, AG was added to the AMSA and the pri-
mary network was formed through the reaction between amino
groups in AG and aldehyde groups in AMSA via the ‘‘Schiff-base”
reaction. The hydrogel stricture with the double crosslinked net-
work was formed through the radical reaction of methacrylate
groups in AMSA initiated by a 365 nm UV light. The results demon-
strated that the double crosslinked hydrogels were stronger than
8 H. Samadian et al. / Coordination Chemistry Reviews 420 (2020) 213432
single ‘‘Schiff-base” networks hydrogels and exhibited controllable
degradation rate, biocompatibility, and improved mechanical
properties [136]. In a similar study, Somo et al. [82] fabricated 2-
aminoethyl methacrylate hydrochloride (AEMA)-modified alginate
to fabricate dual crosslinked hydrogel. They reported that the UV
crosslinked (dual crosslinked) alginate was more stable than the
ionic crosslinked one. Jeon et al. covalently conjugated methacry-
lated alginate with RGD motif (Arg-Gly-Asp amino acid sequence)
to fabricated cell adhesive photo-crosslinkable hydrogel. They
reported that the conjugation had no adverse effects on the
mechanical properties such as elastic moduli, degradation profiles,
and swelling ratios. While the conjugation improved the chondro-
genic differentiated function and the proliferation revealed by DNA
content and glycosaminoglycans production assessments. They
proposed that the fabricated hydrogel is effective for insoluble
(e.g., cell adhesion ligands) and soluble (e.g., growth factors) factors
delivery [79].
The in situ polymerization systems are highly applicable for
suture-less closure of wounds and TE. The photo-polymerizable
hydrogels can seal wounds, which are located at sites not easily
accessible, for instance, the wounds of eye, lung, and ear. More-
over, further manipulation of the formed hydrogel is alleviated
since theses hydrogels conform to complex shapes and sizes
in vivo. In this regard, Smeds et al. fabricated methacrylated algi-
nate hydrogel through UV or visible photolysis as the corneal
wound sealant. They reported that the mechanical properties
(swelling, compression, and creep compliance) depend on the
degree of methacrylate modification and the fabricated hydrogel
is suitable for sutureless ophthalmic surgical procedures [56]. It
was found thet the combination of light-crosslinking chemistry
with the bioprinting concept improved the stability of the pro-
duced structures [137,138]. Innovatively, Yu et al. combined the
UV-crosslinking chemistry with a 3D printing fabrication tech-
nique. They modified alginate with poly(ethylene glycol) diacrylate
(PEGDA) and poly(vinyl alcohol) (PVA) to improve the molding
properties and cytocompatibility of the resultant hydrogel. The
modified hydrogel was processed to a 3D scaffold by a bioprinter
equipped with four longwave (365 nm) UV lamps to provide
in situ photo-polymerization during the printing. They reported
that the incorporation of PEGDA and PVA not only improved the
mechanical properties and scaffolding ability but also increased
cell attachment and viability [128]. In a similar approach, Joen
et al. [131] combined cell-laden oxidized and methacrylated algi-
nate hydrogel with a 3D printing technique to construct compli-
cated 3D tissue structures. They suspended human bone
marrow-derived mesenchymal stem cells (hMSCs) into the modi-
fied alginate and utilized freeform reversible embedding of sus-
pended hydrogels (FRESH) 3D bioprinting to fabricate a 3D
structure. They applied dual crosslinking, ionic and covalent, to
provide suitable mechanical strength and stability. Interestingly,
they reported that the fabricated cell-laden hydrogels were cryop-
reserved evaluated by freeze-thawing the cell-laden hydrogels and
confirmed by proliferation and differentiation potential, DNA con-
tent, and alkaline phosphatase (ALP) activity measurement of
hMSC-laden microgels derived from cryopreserved. They demon-
strated the promising potential of the developed highly innovative
bottom-up strategy to construct cell-laden 3D structures with var-
ious shapes applicable for TE of different tissues (Fig. 1).
Stimuli-responsive hydrogels are fascinating for biomedical
applications, especially for drug/cell delivery and TE applications.
Boddupallia et al. [77] synthesized photo-crosslinked stimuli-
responsive methacrylated alginate hydrogel through step-growth,
and mixed-mode as the TE scaffold for chronic wound healing
treatment. Their findings demonstrate that the fabricated hydro-
gels exhibited compressive moduli in the range of 8.3 ± 0.3 to 22.
6 ± 0.3 kPa. Moreover, they reported that the hydrogels were pH-
responsive, which swelled the most at the pH 9 condition com-
pared with the acidic conditions. The authors proposed that, since
chronic wound has an alkaline environment the prepared hydro-
gels are beneficial for the drug delivery due to their excellent swel-
ling at alkaline conditions.
Visible light cross-linkable alginate hydrogels are more cell-
compatible than UV light ones and can circumvent the possible
damage induced by UV light. Etter et al. [76] fabricated b-
cyclodextrin (b-CD) conjugated methacrylated alginate hydrogel
as the carrier for MSCs. They also utilized custom microfluidic
devices (MFDs) to optimize the fabrication process and adjust both
the mechanical properties and size of the microspheres. They con-
jugated b-CD using a multistep process based on carbodiimide
chemistry. They reported that the combination of alginate hydro-
gel crosslinking with proper MFDs provides additional options to
control the desired properties such as size and mechanical fea-
tures. They observed that increasing the continuous flow resulted
in smaller droplets while increasing dispersion flow produced big-
ger droplets. This study implied that MFDs provide the possibility
to tune the size and mechanical properties of photo-crosslinked
alginate to effectively encapsulate various cells to different
biomedical applications.
5.1.2. Starch
Starch is an inexpensive hydrophilic, biocompatible, and
biodegradable polysaccharide composed of linear amylose and
branched amylopectin segments [84,139–141]. It has been exten-
sively used for a variety of biomedical purposes, including con-
trolled drug delivery [84,142,143], tissue regeneration [144–146],
wound dressing [147–149], and cell encapsulation [150,151]. How-
ever, there are some limitations such as low mechanical properties
and the difficulty in obtaining homogenous solutions that have sig-
nificantly lowered the popularity of starch for various biomedical
applications [83]. Due to these undesirable properties, polymeric
blends involving starch, matrix reinforcements as well as physical
and chemical modifications have been proposed and implemented
to compensate for the pitfalls, while also taking advantage of desir-
able aspects of this material [83,152].
Starch-based hydrogels have received considerable interest due
to their similar mechanical properties to soft tissue and their
potential for other applications such as injectable polymeric blends
for tissue regeneration [153–155]. Despite the aforementioned
challenges of starch hydrogels and lack of significant works on
preparing starch-based hydrogels in the literature as compared
to other similar polymers, photo-crosslinking remains one of the
few strategies which seems to result in hydrogels with an accept-
able range of properties [85]. Sodium benzoate and methacry-
lamide are two most investigated modifications for preparing
photo-crosslinkable starch-based hydrogels [85,156].
Methacrylamide modification has been directly and indirectly
employed to create starch-based photo-crosslinkable hydrogels
[85,157]. Li et al. used UV polymerization of acryloylated starch
blend with 3-dimethyl(methacryloyloxyethyl)ammonium propane
sulfonate to fabricate photo-crosslinkable hydrogels designed for
potential industrial applications [157]. Nieuwenhove et al. devel-
oped starch-based IPN hydrogel using methacrylic and pentenoic
anhydride as photo-sensitive materials for stem cell engineering.
They showed that the presence of the starch increased cell detach-
ment, while this phenomenon can be adjusted and engineered by
changing the ratio of starch to the other polymer(s) in the blend
[85].
Unlike other polymers, such as cellulose, sodium benzoate is a
fairly established choice for fabrication of photo-crosslinkable
starch-based hydrogels, which has proved to result in proper
crosslinking as compared to other photo-sensitive materials
[156,158–160]. For instance, Follain et al. prepared a blend solution
 H. Samadian et al. / Coordination Chemistry Reviews 420 (2020) 213432 9

Fig. 1. 3D printed hMSC-laden alginate hydrogel. (a) (i) Graphical illustration of FRESH 3D printing set up; (ii) 3D printed star-shaped structure after UV crosslinking; (iii)
heated release of the assembled structure from the gelatin slurry bath. (b) (i) 3D printed letters (CWRU) and (ii) a Live/Dead image of 3D printed cell-laden hydrogel, green
and red colors indicate live and dead cells, respectively. (c) 3D printed femur; (i) digital image; (ii) Alizarin red S stained hMSC-laden hydrogel after osteogenic differentiation.
(d) 3D printed skull; (i) digital image; (ii) Alizarin red S stained hMSC-laden hydrogel after osteogenic differentiation. (e) 3D printed ear; (i) digital image; (ii) Toluidine blue O
stained hMSC-laden hydrogel. The white scale bar and black scale bars indicate 100 mm and 1 cm, respectively. hMSC, human bone marrow-derived mesenchymal stem cell.
Reproduced with permission from reference [131].

of starch/PVA and added sodium benzoate as the photo-sensitive
material and the optimized ratio of starch/PVA/sodium benzoate
led to desired improved mechanical properties [160].
Overall, the body of work involving photo-crosslinkable starch
hydrogels are fairly limited and sporadic work involving methacry-
lamide and sodium benzoate modification are only supplemented
by few works based on gamma radiation and Irgacure 2959
[85,160]. A list of selected works on this topic has been included
in Table 1. Considering the potentials of starch due to its water sol-
ubility, abundancy, and similar properties to soft tissues, there is
still a huge gap which should be thoroughly investigated and
addressed to obtain long-waited promising results for photo-
crosslinkable starch-based hydrogels.
5.1.3. Cellulose
Cellulose is an inexpensive, biocompatible and enzymatically
biodegradable linear glucose homopolymer polysaccharide with
tunable water solubility, and chemical and physical homogeneity
10 H. Samadian et al. / Coordination Chemistry Reviews 420 (2020) 213432
Table 1
The specifications of photo-crosslinked starch-based hydrogels fabricated for various biomedical applications.
Hydrogel type Type of photoinitiator
Modified starch hydrogel Irgacure 2959
Gelatin and starch hydrogel Irgacure 2959
Wheat starch based films SB
Acryloylated starch and 3-Dimethyl(methacryloyloxyethyl)
‘‘zwitterionic” monomer ammonium propane sulfonate
hydrogel
Starch-based films SB
Thermoplastic starch sheets SB
Starch based blends SB
Abbreviations: AdMSC: Adipose-derived mesenchymal stem cells, SB: Sodium benzoate.
[161–163]. Generally, cellulose can be obtained from plant and
bacterial sources with the same chemical structure [164]. How-
ever, bacterial cellulose is purer than the plant cellulose both have
promising applications in diverse filed of biomedicine [165].
Although its pure form has been successfully used in a variety of
biomedical applications, it is predominantly used as a precursor
for ester-based derivatives such as carboxymethyl cellulose, and
cellulose nitrate derivatives [161,166]. Alternatively, it can also
be used as composite or blend component, serving as a natural
constituent of a structure, which improves the mechanical and bio-
logical properties of said structure through its versatile and easily
manipulatable composition [167,168]. Different physical forms of
cellulose with various micro- and macro-morphology can used,
which include but are not limited to cellulose nanofibers,
cellulose-based hydrogels, and cellulose-based membranes [161].
Amongst the various formats of cellulose structures, cellulose-
based hydrogels were the most-investigated for applications in
biomaterial-guided tissue regeneration [169], three dimensional
cell culture [170,171], drug delivery [172,173], and wound healing
[87,88] amongst other potential and previously investigated appli-
cations. Such hydrogels can be categorized into native cellulose
hydrogels, cellulose derivatives hydrogels, and composite hydro-
gels containing a cellulose component [161,174]. Each category
presents various advantages and deficiencies and requires unique
and efficient fabrication strategies to engineer physical and chem-
ical properties of the hydrogels in addition to modulating the cell-
or tissue-substrate biological interactions [174,175]. For instance,
composite hydrogels containing a cellulose component provide
the opportunity can be potentially blended with natural polymers
to form a composite hydrogel scaffold for an inexpensive and
relatively-simple strategy for tissue regeneration and controlled
drug delivery due to improved biodegradability and tunability by
change in composition ratios and overcoming the cellulose hydro-
gel fabrication challenges, such as dissolving in solvents to obtain a
homogenous structure [161,176].
The fabrication strategy is undoubtedly the most deterministic
factor for obtaining a hydrogel structure with desired mechanical,
swelling, morphological, chemical and biological outcomes [175].
Photo-crosslinking has been proposed and implemented as one
of most reliable, versatile and effective method for obtaining
hydrogels with well-defined geometries as an alternative for tradi-
tional functionalized crosslinkers. This technique often involves UV
radiation in the presence of a photo-sensitive component such as
methacrylate groups which creates free radicals and help covalent
crosslinking of the polymer backbone [177,178]. Such methods
provide a platform for various applications such as in situ crosslink-
ing of injectable polymers, which have gained considerable atten-
tion in recent years. A summary of light-induced cellulose
hydrogels has been provided in Table 2.
Applied light (nm), duration In vitor/in vivo Potential biomedical Refs.
(min) and intensity (W cm
2) model applications
254, 2 In vitro drug Ophthalmologic drug [84]
release profiles delivery
250–450, various, 0.01 AdMSC Adipogenesis, osteogenesis [85]
and cell encapsulation
365, various, 0.034 – – [156]
365, 10, 8 – – [157]
365, various, 0.034 & 0.1 – – [158]
254, various, various – – [159]
365, 120, 0.034 – – [160]
Amongst widely used methods for photo-crosslinkable
cellulose-based hydrogel fabrication, modification with functional
groups have been constantly used and optimized throughout the
literature. Methacrylate is the most widely used functional group
for the functionalization of cellulose backbone to obtain photosen-
sitive polymer solutions. Early work on methacrylate modification
of cellulose and cellulose-derivative hydrogels involved methacry-
late modification of carboxymethylcellulose [179] cinnamoyl-
isopentyl cellulose [180], and methylcellulose [181], which mostly
relied on photo-crosslinking as the main step of hydrogel rein-
forcement/fabrication. Building upon previous work on methacry-
late modified carboxymethyl cellulose, Hossen et al. reported on
the fabrication of methacrylate functionalized carboxymethyl cel-
lulose and cellulose nanofibrils hydrogels [181]. The authors
adopted an interesting approach that revolved around preparing
mechanically robust composite of cellulose nanofibrils and
methacrylate modified carboxymethyl cellulose, followed by
lyophilization and rewetting. Shrinkage and swelling were con-
trolled by tuning the ratio of carboxymethyl cellulose and cellulose
nanofibrils, showing that a higher fraction of carboxymethyl cellu-
lose induces more swelling while more cellulose nanofibrils pro-
tected the hydrogel against excessive swelling [181].
5.1.4. Chitosan
Chitosan is an aminated linear and natural polysaccharide
obtained through the deacetylation of chitin via chemical or enzy-
matic hydrolysis under severe alkaline conditions or in the pres-
ence of particular enzymes (e.g., chitin deacetylase) [186,187].
Chitin is the second most abundant natural polymer worldwide
after cellulose and is found in the exoskeleton of insects (e.g., Bee-
tle cocoon, Cuticle, and Ovipositors), the cell walls of fungi (e.g.,
Aspergillis nidulans and Mucor rouxi), shell of crustaceans (e.g., Crab
and Shrimp), and Centric Diatoms (e.g., Algae and Thalassiosira flu-
viatilis) [188]. The rigid structure and poor solubility in aqueous
solutions, as well as high levels of acetylated groups are hindered
chitin applicability, while the deacetylation process enhances the
amount of amine groups, solubility, biocompatibility, and
biodegradability. Chitosan is composed of the deacetylated unit
(D-glucosamine) and the acetylated unit (N-acetyl-D-
glucosamine) linked by b-(1 ? 4) glycosidic linkages. Chitosan
has found a wide range of industrial and biomedical applications
due to its various physicochemical and biological properties. Chi-
tosan is biocompatible, biodegradable, mucoadhesive, antibacte-
rial, antifungal, and analgesic [189].
Among different structures, chitosan-based hydrogels have
promising properties suitable for various biomedical applications
such as drug delivery, TE, cell therapy, and single-cell analysis
[190,191]. Abundant hydroxyl (–OH) and amine (–NH2) functional
groups in the structure of chitosan can be utilized to crosslink the
 H. Samadian et al. / Coordination Chemistry Reviews 420 (2020) 213432 11

Table 2
The specifications of photo-crosslinked Cellulose-based hydrogels fabricated for various biomedical applications.

Hydrogel type
CMC
CMC
CMC
Multilayered assembly of
cellulose derivatives
Methylcellulose hydrogels
Cellulose nanofibrils based
CMC
Bacterialcellulose/acrylic
acid
Bacterial cellulose/acrylic
acid
Hydroxypropylcellulose
CMCand glycol chitosan
bacterial cellulose/acrylic
acid
Type of photoinitiator Applied light (nm), duration In vitro/in vivo model Potential biomedical Refs.
(min) and intensity (W cm
2) applications
Irgacure 2959 368, 10, 1.2 MSCs Nucleus pulposus [177]
replacement therapies
Irgacure 2959 368, 10, 1.2 hMSCs Nucleus pulposus [178]
replacement therapies
Irgacure 2959 368, 10, 1.2 Nucleus pulposus cells Cartilaginous TE [179]
Benzophenone and 4,40 -bis 254/360, 50/150 – – [180]
(diethylamino)-benzophenone)
Irgacure 2959 368, 10, 1.2 hDFs Soft tissue [181]
reconstruction
Irgacure 2959 320–390, 40, 35 – – [182]
– c 60Co, 10 or 1 kGy/h Biodegradability Biomedical devices [183]
– c 60Co, , 35 or 50 kGy – Drug delivery [172]
Irgacure 2959 c 60Co, 35 and50 kGy Mouse fibroblast Wound healing and TE [86]
Cinnamoyl 245, -, 60 Swiss albino mouse embryo TE applications [184]
fibroblast cells (RCB1642)
o-Nitrobenzyl alcohol 405, –, 0,02 L-929 fibroblast SD rats Anti-adhesion barrier [185]
for wound isolation
– 35 kGy Keratinocytes and fibroblasts Wound dressing and [89]
cells Male athymic mice cell carrier

Abbreviations: CMC: Carboxymethylcellulose, MSCs: Marrow-derived stromal cells, hMSCs: Human mesenchymal stem cells, hDFs: Human dermal fibroblasts, SD rate:
Sprague–Dawley rats, SB: Sodium benzoate.

polymer chains to form a robust hydrogel. Interestingly, below pH
6.3 ammonium groups can be obtained from the amine groups to
produce pH-responsive hydrogel [192]. Chitosan-based structures
are biodegradable through the enzyme’s activity such as lysozyme
which is nonspecific and ubiquitous in all mammalian tissues. The
byproducts of the degradation are oligosaccharides, which are
either used for glycoproteins and glycosaminoglycans or easily
excreted from the body. Moreover, chitosan can open the tight
junctions of epithelial cells and facilitate drug penetration and
delivery [193]. Either native chitosan or in combination with other
natural/synthetic polymers can be crosslinked to form a hydrogel.
Various approaches have been reported to produce chitosan hydro-
gel such as self-crosslinking in the elevated pH or by dissolving in a
non-solvent [194], freeze-thawing [149], electrostatic interactions
[195], and chemical crosslinking through the addition reactions,
condensation reactions, and free-radical polymerization [193].
Photo-crosslinked chitosan hydrogels have been developed in
various fileds. Qiao et al. [90] conjugated photo-sensitive 4-
azidophenylacetic acid (AZ) to C-2-amino of hydroxyethyl chitosan
(HECTS) to form photo-crosslinked chitosan hydrogels as the car-
rier of heparin for treatment of glaucoma surgery. They first pro-
duced AZ from 4-aminophenylacetic acid (AA) and then the
obtained AZ was conjugated to HECTS through EDC/NHS coupling
chemistry. The resulted HECTS-AZ crosslinked via UV radiation
for 30 s to form a hydrogel. They reported that the heparin loaded
HECTS-AZ hydrogel exhibited prolonged-period drug release and
provide maintained filtration bleb and decreased intraocular pres-
sure (IOP) after glaucoma filtration surgery (GFS). In another sce-
nario, Zhou et al. [96] fabricated (methacryloyloxy)ethyl
carboxyethyl chitosan (MAOECECS) from chitosan and ethylene
glycol methacrylate through Michael-addition reaction. They used
Irgacure 2959 as the photoinitiator and the resulted solution
exposed to UV light for 15 min to form a hydrogel. They reported
that the fabricated hydrogel was biocompatible with adjustable
swelling and degradation rate. Qi et al. [196] fabricated chitosan
grafted methyl acryloyl glycine (MAG) photo-crosslinkable hydro-
gel. They demonstrated that the grafting reduced the crystallinity
and thermal stability compared with pure chitosan, while the
porosity was favorable and dependent on the concentration of
the photoinitiator.
It is known that the biological properties such as biocompatibil-
ity, degradation, and swelling rates are associated with the
crosslinking parameters. In this regard, Hu et al. [95] compared
the effects of three different blue light initiators (riboflavin (RF),
fluorescein (FR), and camphorquinone (CQ)) as well as the irradia-
tion time on the properties of methacrylated glycol chitosan
(MeGC) hydrogel. They observed that MeGC hydrogel initiated
with RF was more biocompatible and exhibited proper mechanical
properties. Although the longer light exposure produced strong
hydrogel, the biocompatibility was compromised. Ma et al. [94]
used photo-crosslinking approach to fabricate injectable hydrogel
based on (methacryloyloxy) ethyl carboxyethyl chitosan
(EGAMA-CS), N,N-dimethylacrylamide (DMMA), and polyethylene
glycol dimethacrylate (PEGDA) as the bone TE scaffold. They
reported that the fabricated hydrogel was biocompatible and effec-
tively support bone cell attachment and proliferation. In the same
scenario, Yuan et al. [197] fabricated thermo-responsive glycidyl
methacrylate-modified hydroxypropyl chitin (GM-HPCH) as the
TE matrix based on photo-crosslinking technique. They used amino
groups instead of hydroxyl groups in HPCH to react with the epoxy
group in GM. They observed that the reversible thermo-sensitive
sol–gel transition was at lower temperatures compare with HPCH,
which can be attributed to the hydrophobicity of the methacrylate
groups. Moreover, some properties (e.g., swelling, degradation rate,
and stability) were tunable with the varying the concentration of
methacrylate groups and UV exposure time.
In another study, thiol-terminated poly(vinyl alcohol) (T-PVA)
was grafted to maleic chitosan (MCS) to enhance mechanical
strength and reduce the gelation time of photo-crosslinked inject-
able hydrogel. The authors utilized thiol-ene photo-polymerization
for the conjugation due to its low or even no oxygen inhibition
effect, fast process, and producing networks with proper mechan-
ical and physical properties. They reported relatively fast gelation
time (<120 s), enhanced compressive strength (0.285 ± 0.014 MP
a), and stiff (G’= ~5500 Pa), which have a direct correlation with
the amount of T-PVA. Moreover, the fabricated hydrogel was able
to support L929 cells attachment and proliferation critical for tis-
sue engineering applications [93].
In addition to TE and drug delivery, chitosan-based hydrogels
can be utilized for enzymes immobilization applications. Monier
12 H. Samadian et al. / Coordination Chemistry Reviews 420 (2020) 213432

et al. [92] modified chitosan with cinnamoyl chloride to immobi-
lize b-galactosidase via the entrapment technique. They reported
that the crosslinking was conducted through the cycloaddition
reaction [2p + 2p] between the grafted cinnamate moieties
induced by UV irradiation. The results showed that the entrapped
enzyme preserved around 80% of its initial activity and was stable
against pH and temperate changes. In another innovative study,
glucose oxidase (GOx) was immobilized onto the methacrylated
chitosan photo-crosslinked hydrogel to fabricate a glucose-
responsive DDS for diabetic’s periodontitis therapy. First off,
methacrylic anhydride was grafted on chitosan polymer and cross-
linked via UV irradiation to form hydrogel film. The fabricated
hydrogel was surface-activated by glutaraldehyde (1% v/v) and
GOx attached to the hydrogel. They proposed that the hydrogen
ions (H+) generated during oxidation of ambient glucose to glu-
curonide by immobilized GOx can alter the structure of pH-
responsive hydrogels and trigger the release of the loaded drugs.
The authors loaded metronidazole into the enzyme immobilized
hydrogel and the antibacterial activity was assessed against Por-
phyromonas gingivalis. They reported that the fabricated hydrogel
exhibited good mechanical properties and the bonding capacity
and activity of immobilized GOx preserved. Moreover, it was
shown that the fabricated hydrogel was glucose-responsive and
the presence of glucose increased the release of metronidazole
and exhibited significant antibacterial ability in high glucose con-
centration solution [91]. Table 3 summarized the studies con-
ducted on light-induced chitosan hydrogels.
5.1.5. Hyaluronic acid
Hyaluronic acid (HA, also known as hyaluronan) is a natural,
non-sulfated, linear polyanion glycosaminoglycan that consists of
repeating disaccharide units of D-glucuronic acid and N-
acetylglucosamine connected by b-1,4 and b-1,3 glycosidic bonds
[200]. It is a biopolymer found abundantly throughout the body,
which synthesized primarily in fibroblasts and then extruded into
ECM. HA-based biomaterials have used for multifarious biomedical
applications owing to its inherent characteristics comprising high
hydrophilicity, unique rheological behavior, biodegradability, bio-
compatibility, non-toxicity, non-immunogenicity, and non-
inflammatory [201,202]. HA contains many free active sites in its
native chemical structure (acetamide, carboxyl, hydroxyl, and ter-
minus aldehyde), which provide a multitude of functionalization
strategies to create crosslinkable HA hydrogels. Applying these
strategies is imperative because the use of un-crosslinked soluble
HA has restricted by the poor mechanical properties, rapid
in vivo degradation, and clearance [203,204]. Therefore, to obviate
these limitations, HA can be crosslinked through physical, chemi-
cal, and enzymatic methods either with a bi-functional reagent
or with the synthesized highly reactive derivatives of HA. A num-
ber of prevalent crosslinker agents and derivatives of HA are shown
in Scheme 5.
Photo-polymerization has been widely exploited to render
mechanically strong and stable HA hydrogels either in vitro or
in vivo [205–207]. In this regard, photo-crosslinkable hydrogels
have developed by modification or grafting of HA with photoactive
moieties and by mixing HA with other natural/synthetic polymers.
HA has been extensively derivatized with photoactive moieties,
including methacrylate [208], cinnamic acid [209], tyramine
[210], coumarin and hexamethylenediamine [211] (Scheme 5).
The HA-methacrylate hydrogels are the most common deriva-
tive of HA used in photo-polymerization, and can be made by mod-
ifying HA with glycidyl methacrylate [212,213], methacrylic
anhydride [104] and N-3-aminopropyl methacrylamide [214].
The synthesis, characterization and in vitro/in vivo studies of HA-
methacrylate hydrogels for a broad range of biomedical applica-
tions have been extensively performed (reviewed in [208,215–
217]).
Coumarin, as a photocleavable group, has grafted onto HA
chains to forming photo/thermo-responsive nanogels containing
paclitaxel for cancer chemotherapy [218]. The coumarin methacry-
late modified HA was able to self-assemble into nanogels (hydro-
dynamic radius of ~ 110 nm) with high stability and prolonged
blood circulation time due to strong hydrophobic interactions
and p–p stacking that resulted to efficient internalization in cancer
cells and tumor tissues [218]. Another study by Beninatto et al.
demonstrated that HA-coumarin solidified upon near-UV irradia-
tion via a clean [2 + 2] photo-induced cycloaddition reaction with-
out initiator [101]. Such hydrogels provided the porous structure
with good permeability and were also capable of supporting the
survival and proliferation of encapsulated fibroblasts.
Tyramine (Tyr), a phenolic photoactive moiety, has also shown
great efficacy to the fabrication of light-mediated HA hydrogels.

Table 3
The specifications of photo-crosslinked chitosan-based hydrogels fabricated for various biomedical applications.

Hydrogel type Type of Applied light (nm), duration In vitro/in vivo model Potential biomedical applications Ref
photoinitiator (min) and intensity (W cm
2)
Chitosan and methyl 4-Azidophenylacetic N/A, 0.5, N/A Sprague Dawley rats DDS for the treatment of ocular diseases [90]
acroloyl glycine acid (AZ)
hydrogel
Water-soluble chitosan- 2-Hydroxyethyl 320–480, up to 15, 0.01 L929 cells TE scaffolds [96]
based hydrogel methacrylate (HEMA)
Chitosan-MAG Irgacure D-2959 N/A, up to 15, 0.02 – TE applications [196]
Chitosan-MeGC RF, FR, and CQ 400–500, N/A and 0.5 Chondrocytes Cartilage TEscaffolds [95]
Injectable EGAMA- Irgacure D-2959 320–480, up to 15, 0.03 Human bone Bone TE matrix [94]
Chitosan/PEGDMA/ sarcoma cell
DMMA (SW1353)
MCS/TPVA Irgacure D-2959 N/A, 15, 0.06 L929 cells TE scaffolds [93]
Chitosan-cinnamate Cinnamte moieties 360, N/A, N/A – Biomaterial for various biotechnological and [92]
membrane pharmaceutical fields
Chitosan hydrogel film Irgacure 2959 254, 30, N/A MC3T3 cells, P. Diabetic’s periodontitis therapy [91]
gingivalis
Chitosan/PVP membranes – 250–550, 0–8, 1000 – Biomedical materials and removal of alcohol [198]
and water from organic materials
M
HGC thermogel Irgacure D-2959 220–260, 5–30, 0.02 – Injectable delivery systems and 3D cell [199]
culture systems

Abbreviations: MAG: Methyl acroloyl glycine, MeGC: Methacrylated glycol chitosan, RF: Riboflavin, FR: Fluorescein, CQ: Camphorquinone, EGAMA: Methacryloyloxy ethyl
carboxyethyl, PEGDMA: Polyethylene glycol dimethacrylate, DMMA: N,N-Dimethylacrylamide, MCS: Maleic chitosan, T-PVA: Thiol-terminated poly(vinyl alcohol), PVP: Poly
(vinylpyrrolidone), M
HGC: Methacrylated hexanoyl glycol chitosan.
 H. Samadian et al. / Coordination Chemistry Reviews 420 (2020) 213432 13

Hyaluronic acid (C14H21O11)n Blue: glucuronic acid

Green: N-Acetylglucosamine
Red: bi-functional reagents

1,4-butanediol
Adipic diglycidyl ether
3-aminopropyl cinnamate
dihydrazide Glycidyl Hexamethylenedi
methacrylate amine
H2N Coumarin H 2N
Thiopropionyl Glutaral O
NH hydrazide -dehyde Tyramide O
O O OH
HS Divinyl sulfone O
Bromoacetate
Methacrylate O O Br
O S O O O
O HO
O
O O O HO
HN
HN
O O O O O O
NH NH NH O NH
NH
O O O O O O
O O O O O
O OH HO
O O HO O HO O HO O HO
O
O O O O O O O
O O O O
O NH NH
NH HO NH O HO HO
HO HO
HO NH
O O O O O NH2 O O O O
O O
O
OH
O n
O
N
O O
Cyanide HO
O
Epoxide
O
Benzyl ester
NO2
O Cinnamic
Bis(4-nitrophenyl Ethylene glycol acid Aminoethyl
carbonate) diglycidyl ether methacrylate

Scheme 5. The chemical structures of crosslinker agents and derivatives of HA that are introduced to active groups of HA.

The synthesis of Try-substituted HA hydrogels was reported with a lable physicomechanical properties have been fabricated to mimic
photochemical process initiated by riboflavin through the forma- the ECM of breast tumors [105]. Cellular and animal studies dis-
tion of dityramines, which revealed it could be used to repairing played significantly increased migration/invasion abilities and
the damaged surface of articular cartilage [99]. The same group tumor-forming capability of MCF-7 cells in the 3D hydrogels.
developed photo-crosslinked Tyr-HA hydrogels with tunable Collagen is considered as a major component of ECM and can be
mechanical properties as stable interface for articular cartilage incorporated in HA-based hydrogels to benefit from its synergistic
repair [100]. The dityramine crosslinking of HA hydrogels occurred effects. A semi-IPN hydrogel containing photo-crosslinkable
by the formation of phenoxy radicals catalyzed by riboflavin, methacrylated HA and semi-IPN collagen components was created,
which then dimerizes to form the dityramines. Besides, Loebel which provided synergistically greater mechanical strength and
et al. reported the encapsulation of hMSCs in HA-Try hydrogels high encapsulated cell viability [106]. Also, collagen-riboflavin
prepared with visible light illumination [219]. Visible light (480– hydrogels combined with HA were able to accelerate the synthesis
550 nm) was able to form HA hydrogels through di-Tyr bonds with of ECM components for meniscus regeneration [225]. Moreover,
spatial and temporal control over polymerization and matrix stiff- tonsil derived mesenchymal stem cells have been encapsulated
ening. In a work by the same group, visible light (500 nm) was also in photo-crosslinked collagen-HA hydrogel to differentiate the
utilized to form covalent HA-Tyr networks for study of stem cell stem cells to meniscus tissue [102]. In another study, photo-
behavior that compared with enzymatically formed HA hydrogels crosslinked acrylated HA hydrogels embedded with collagen fibrils
[210]. and sulfated HA were developed for repair of damaged vascular-
Cinnamic acid, as a photo-crosslinkable residue, undergoes ized tissues [226]. More recently, a hydrogel composed of
photo-dimerization upon UV irradiation through [2 + 2] cycloaddi- HA-methacrylic anhydride and collagen-glycidyl methacrylate
tion reactions with the formation of cyclobutane rings [220,221]. encapsulating bone marrow mesenchymal stem cells was fabri-
The attachment of cinnamic acid groups to HA to produce photo- cated through UV crosslinking [227]. The resulted hydrogel pro-
crosslinked hydrogel films were originally reported by Matsuda vided a suitable microenvironment for adhesion, proliferation,
et al. for preventing the formation of postsurgical adhesion [222]. and osteogenic differentiation of bone marrow mesenchymal stem
Further, the photo-crosslinked-HA was developed for the fabrica- cells.
tion of contact lenses in which cinnamic acid is introduced into a Chitosan contains many positively charged amino groups that
hydroxyl group of HA [223]. Miyamoto and co-workers used a cin- allow the formation of ionic complexes with anionic polymers such
namic acid-modified HA to obtain a photo-polymerizable deriva- as HA. In this regard, methacrylated glycol chitosan/HA hydrogels
tive without an initiator, which resulted in a water-insoluble were made by blue light crosslinking that they were capable of
hydrogels with good biocompatibility in guinea pigs [209]. increasing the proliferation and accumulation of cartilaginous
Poly(N-e-acryloyl L-lysine) modified HA hydrogels were con- ECM by encapsulated chondrocytes [103]. The utilize of solution
structed by hydrazone bond crosslinking and photo-crosslinking blending of either 6% w/v methacrylated glycol chitosan or 6% w/
for bone TE [224]. The obtained hydrogels showed better elastic v methacrylated HA with the 20% w/v chondroitin sulfate has been
behavior and higher compressive modulus than HA hydrogels led to produce the hydrogels with high (>100 kPa) modulus, low
along with proper in vitro and in vivo biocompatibility. A double- swelling degree and high chondrocyte viability for use in load-
network of poly(N-e-acryloyl L-lysine)/HA hydrogel with control- bearing soft TE [103]. In an osteoarthritis treatment study by Xia
14 H. Samadian et al. / Coordination Chemistry Reviews 420 (2020) 213432
Fig. 2. Chlorhexidine (CHX)-loaded nanogels (CLNs) incorporated into PEG-HA hydrogels intended for controlling of bleeding and wound healing. Reproduced with
permission from reference [232].
et al., the photo-crosslinked methacrylated HA hydrogel was
applied as a vehicle to facilitate intra-articular injection of chitosan
microspheres encapsulating cordycepin [97]. This combination
resulted in synergistically preventing the progression of degenera-
tive changes in induced osteoarthritis. In a similar study, the
photo-crosslinked gelatin methacrylate/methacrylated HA (5:2
w/v) hydrogels combined with crizotinib-loaded chitosan micro-
spheres demonstrated retarding the progression of osteoarthritis
and ameliorated cartilage matrix degradation [98].
The photo-dimerizable hydrogels composed of cinnamoyl-
modified HA and alginate containing basic fibroblast growth factor
was made that demonstrated sustained release kinetics [228].
Blends of methacrylated gelatin, alginate and HA biopolymers
reported as the stable, non-toxic and biocompatible hydrogel scaf-
folds for heart tissue regeneration [229]. Furthermore, the photo-
crosslinked alginate hydrogel containing interpenetrating HA
chains was used for encapsulating MSCs, which led to robust chon-
drogenic differentiation and high cell viability [78].
PEG can be also combined/conjugated with HA-based hydrogels
to specifically tune physicochemical properties and cellular inter-
action/behavior. In this respect, a PEG-peptide was conjugated
onto glycidyl methacrylate-modified HA. They found that the
stable hydrogels were formed via UV photo-crosslinking with tun-
able material properties and high peptide conjugation efficiencies
[207]. The same researchers have reported the bovine serum
albumin-containing poly(lactic-co-glycolic acid) (PLGA) micro-
spheres embedded into glycidyl methacrylate HA–PEG hydrogel
scaffolds for controlled release of proteins in TE applications
[230]. Besides, integrating a PEG diacrylate into hydroxyapatite
NPs-reinforced HA hydrogels revealed that mechanical perfor-
mances enhanced because of the presence of the second PEG
network and the NPs [231]. In 2018, Zhu et al. developed a
photo-crosslinking hydrogel dressing for controlling bleeding and
wound repairing composed of aminoethyl methacrylate HA and
methylether methacrylate mPEG hydrogel that incorporated with
chlorhexidine-loaded nanogels (Fig. 2) [232]. The nanogels-
loaded hydrogel provided the enhanced mechanical properties
due to higher crosslinking density, stable antibacterial effects, the
rapid hemostasis capacity and accelerated wound healing.
Ultimately, the main characteristics of the photo-crosslinked
HA and HA-based hydrogels are shown in Table 4.
5.1.6. Dextran
Dextran, a non-ionic hydrophilic homopolysaccharide, is com-
posed mainly of linear a-1,6 linked D-glucopyranose residues with
about 5–10% a-1,3 linked side chains [234]. Dextran is broadly
applicable in biomedical applications owing to its biocompatibility,
biodegradability, low toxicity, high natural abundance, and simple
modification [235,236]. It contains plenty of hydroxyl functional
groups, which turns it suitable for derivatization and crosslinking
process (Scheme 6) [237]. Dextran and its derivatives can easily
transform to organized 3D hydrogel structures, in which network
formation is established by either physical crosslinking (e.g.,
ionic/hydrophobic interactions, hydrogen bonding, and crystalliza-
tion) [238] or chemical crosslinking (e.g., radical polymerization,
photo-polymerization, and enzymatically or chemically reaction
of complementary groups) [237].
Dextran can be modified by photoactive moieties to incorporate
functional groups into the structure. In this way, the photo-
crosslinked dextran-based hydrogels were first developed by Kim
et al. via UV crosslinking of vinyl groups that incorporated in dex-
tran by substitution of maleic anhydride [239], acrylate [240] and
methacrylate [240] moieties (Scheme 6). Dextran/poly(D,L-lactic
acid) hydrogels have been made from hydrophilic dextran acrylate
and hydrophobic poly(D,L-lactic acid) diacrylate macromere by UV
crosslinking to generate hydrogels with controlled swelling prop-
erties [241,242]. The hydrogels formed by photo-crosslinking of
unsaturated vinyl groups introduced onto the polymers backbones
and mixing the hydrophilic/hydrophobic segments.
Table 4
The characteristics of photo-crosslinked HA-based hydrogels fabricated for various biomedical applications.

Hydrogel type Type of photoinitiator Applied light (nm), duration (min) and In vitro/in vivo model Potential biomedical applications Refs.
intensity (W cm
2)
HA-glycidyl methacrylate DMPA and 1-vinyl-2- 315–400, 10, NA NIH/3T3 cells As potential candidates for vocal fold regeneration. [212]
pyrrolidinone
Methacrylated HA Irgacure 2959 UV light, 10, ~1.9 MSCs A 3D scaffolds for chondrogenesis [104]
Mice
HA-coumarin 2,2-Azobis(2-methylpropionitrile) UV light, 30, 50 Vero and HeLa cell As delivery systems for anticancer chemotherapy [218]
HeLa tumor bearing
mice
HA-coumarin – 365, 3 or 5, 120 BJ cell Hydrogels for regenerative medicine (e.g., muscular [101]

H. Samadian et al. / Coordination Chemistry Reviews 420 (2020) 213432

regeneration or cartilage repair)
Tyramine-HA Riboflavin and Irgacure 2959 365, 12, 5 Chondrocytes For repairing surface damaged articular cartilage [99]
Tyramine-HA Riboflavin 365, 2.5 to 120, 4 TC-28a2 chondrocytes As an interface for articular cartilage repair [100]
Tyramine-HA Rose bengal and eosin Y 480–550, 60, NA hMSCs Hydrogels for TE and regenerative medicine [219]
Poly(N-e-acryloyl L-lysine)/HA Irgacure 2959 365, 0.5, NA MC3T3-E1 cells, SD rats A promising candidate in bone TE [224]
Poly(N-e-acryloyl L-lysine)/HA Irgacure 2959 UV light, 1.5, 400 MCF-7 A 3D microenvironment for MCF-7 cells [105]
cells
BALB/c nude mice
Collagen/methacrylatedHA semi-IPN Irgacure 2959 UV light, 3, 200 NIH-3T3 For 3D cell-culture applications [106]
Collagen/acrylated HA Lithium phenyl-2,4,6-trimethyl- 365, 10, 0.17 PAE/KDR cells For repair of damaged vascularized tissues [226]
benzoylphosphinate
Collagen/hexamethylenediamene HA Riboflavin UV light, 3, 0.0035 T-MSC For meniscus tissue repairs [102]
BALB/c mice
Collagen-glycidyl methacrylate/HA-methacrylic Irgacure 2959 365, 7, 65 BMSCs As a 3D scaffold for bone injury repair [227]
anhydride
Methacrylated glycol chitosan/HA Riboflavin 400–500, 0.183 , 300 Chondrocytes For the treatment of cartilage damage [103]
Methacrylated glycol chitosan/methacrylated Irgacure 320–390, 1, 10 Chondrocytes Potential for use in load-bearing soft tissue engineering. [233]
HA/chondroitin sulfate 2959
Cordycepin-loaded chitosan microspheres/ Irgacure 2959 320–500, 2, 0.007 Chondrocytes, Mouse As a therapeutic target for osteoarthritis prevention and [97]
methacrylated HA treatment
Crizotinib -loaded chitosan microspheres/ Irgacure 2959 320–500, 2, 0.007 Knee joints and mouse A therapeutic approach for osteoarthritis treatment. [98]
methacrylated HA chondrocytes
Cinnamoyl- modified HA-alginate Irgacure 2959 UV light, NA, 18 NA Scaffolds for incorporating growth factors [228]
Methacrylated alginate/HA VA-086 365, 5, 0.000002 MSCs As a delivery mechanism for cell-based cartilage repair [78]
therapies
Glycidyl methacrylate HA-PEG peptides Irgacure 2959 365, 1, 22 NA Scaffolding biomaterial for soft TE applications [207]
Glycidyl methacrylate HA-PEG Irgacure 2959 365, 1, 22 NA For delivering stable proteins from scaffolding in TE [230]
applications
PEG diacrylate/hydroxyapatite NPs-reinforced Irgacure 2959 365, 5, 16 NA As load-bearing materials for biomedical applications [231]
maleated HA
Aminoethyl methacrylate HA-mPEG hydrogel NA UV light, 20, NA L929 fibroblast cell, As hemostasis and anti-infection materials for the [232]
loaded with chlorhexidine C57BL/6 mice wound dressing application

Abbreviations: HA: hyaluronic acid, NA: Not applied, MDPA: 2,2-Dimethoxy-2-phenylacetophenone, MSCs: Mesenchymal stem cells, SD rats: Sprague Dawley rats, T-MSC: Tonsil-derived mesenchymal stem cells, BMSCs: Bone
marrow stromal cells, mPEG: Methoxy poly(ethylene glycol).

15
16 H. Samadian et al. / Coordination Chemistry Reviews 420 (2020) 213432
Scheme 6. Chemical structure of the building blocks of various photo-crosslinked dextran-based hydrogels.
Pitarresi and colleagues reported the use of a poly(aspartamide)
derivatized with glycidyl methacrylate copolymer for the prepara-
tion of dextran hydrogels containing methacrylate groups by UV
irradiation [107]. They showed that the hydrogels were formed
by intramolecular and/or intermolecular crosslinking of the
methacrylate residues as well as a co-crosslinking reaction
between the two polymers. The similar hydrogels loaded with
beclomethasone dipropionate have been used for treating inflam-
matory bowel diseases, resulted in the biocompatible hydrogels
with a prolonged drug release and negligible hydrolysis in simu-
lated gastric/intestinal fluids [243]. Moreover, it has been reported
the synthesis and photo-patterning in microfluidic channels of
dextran-glycidyl methacrylate hydrogel (Scheme 6) along with a
crosslinker, N,Ń-methylene-bisacrylamide [244]. This photo-
patternable hydrogel could reduce the duration of photo-
crosslinking process and degrade via enzymatic breakdown. In
another study, an injectable and pH-sensitive hydrogel made up
of binary mixtures of dextran methacrylate and a carboxylated
derivative of scleroglucan was submitted to UV irradiation to
improve rheological properties and be crosslinked in situ [245].
One other of dextran derivatives having methacrylated PEG moi-
eties (Scheme 6) has been applied to produce hydrogels with
higher elasticity and degradability, aiming to improve the extreme
fragility and lack of typical hardness of gels made of dextran
methacrylate [246].
In another strategy, a copolymeric dextran-based hydrogel was
fabricated by photo-crosslinking of precursor blend solutions of
urethane methacrylated dextran and 2-hydroxyethyl methacrylate
(HEMA) intended for in situ curing tissue adhesives. The copoly-
merization of HEMA and the modified dextran remarkably
increased the adhesion strength to 86 times that of Tisseel (a com-
mercial fibrin adhesive) and resulted in less cytotoxicity to L929
cells [247].
Dextran-based hydrogels have also used as delivery vehicles for
loading and controlled release of bioactive molecules such as
drugs, proteins/peptides, and nucleic acids. Doxorubicin has been
incorporated into photo-crosslinked dextran-methacrylate hydro-
gels that revealed a delayed and controlled release profile [248].
 H. Samadian et al. / Coordination Chemistry Reviews 420 (2020) 213432
Besides, 2-phenylpropionic acid functionalized with methacrylic
groups bound to dextran methacrylate has been used for the
preparation of photo-crosslinked hydrogels without initiator
[249]. The hydrogels were able to retain the drug in acid solution
simulating the conditions of the gastric tract and provided a sus-
tained release system. Also, vancomycin has been incorporated
into photo-crosslinking hydrogels composed of methacrylated
dextran/poly(L-glutamic acid)-g-hydroxyethyl methacrylate
intended for enhanced drug loading and long-term antibacterial
effects [108].
Dextran-based IPN and semi-IPN hydrogel systems are other
feasible approaches to fabricate the photo-crosslinked dextran-
based hydrogels for biomedical applications. Pescosolido et al.
developed photo-crosslinked IPN/semi-IPN hydrogels based on cal-
cium alginate and dextran methacrylate derivative, in which drugs
or proteins can be dispersed/delivered [108,250]. Upon UV irradia-
tion the methacrylate moieties crosslinked and alginate chains are
interspersed within the chemical hydrogel network, leading to
injectable hydrogels with improved mechanical strength. The same
authors also developed another IPN hydrogels made from dextran-
HEMA and calcium alginate with tailorable degradation and
mechanical characteristics suitable as protein delivery systems
[251,252]. Besides, they developed 3D printed semi-IPNs hydrogels
made from HA/dextran-HEMA encapsulated with the chondrocyte
cells for bioprinting applications in TE [253].
The biocompatible thermo-sensitive hybrid hydrogel comprised
of dextran-allyl isocyanate (Dex-AI) and N-isopropylacrylamide
(NIPAAm) was created by Zhang and colleagues through UV
photo-crosslinking [254,255]. Hydrogel formation was accom-
plished by the molecular crosslinking NIPAAm to Dex-AI and
Dex-AI to Dex-AI through the unsaturated functional groups
(>C = C < ) as well as urethane linkage in the ally isocyanate groups
located in Dex-AI. In a similar study, dextran was substituted with
maleic anhydride and photo-polymerized with NIPAAm that
formed hydrogels responsive to the temperature and pH, by
crosslinking carboxylic acid groups and doubles bonds in the
maleic acid segments [256]. Dextran hydrogels based on dextran-
allyl isocyanate-ethylamine and PEG-diacrylate have been also
prepared through UV photo-crosslinking to form hybrid biodegrad-
able hydrogels having pH sensitivity with improved protein release
[257].
Tanna et al. developed glucose-responsive UV-polymerized
dextran-based hydrogels using acrylic derivatives of dextran and
concanavalin A (Con A), a sugar-binding lectin with a reversible
strong affinity to glucose for the design of a self-regulating/
closed-loop insulin delivery system [109,110]. They revealed that
covalently crosslinking of the acrylated monomers occurred, in
addition to physical entanglements, therefore the crosslinked
hydrogels have been able to keep the activity of reversible binding
to glucose as well as controlled insulin diffusion as a function of
glucose content. In a similar study, a glucose-sensitive hydrogel
composed of methacrylate modified dextran–Con A and PEG
dimethacrylate have been synthesized by UV polymerization. The
findings showed the hydrogels could prevent component loss
and maintained glucose sensitivity to a certain extent [258].
Visible light and electron-beam irradiation have also applied for
the fabrication of dextran-based hydrogels. In this regard, visible
light irradiation was used to fabricating the dextran-
methacrylate hydrogel by riboflavin and l-arginine (as
photoinitiator/co-initiator) to avoid UV crosslinking limitations
[259]. During the visible light irradiation, generation of radical-
anionic riboflavin and radical-cationic L-arginine occurred, which
initiates the polymerization reaction by covalent bonding of the
amine species to the dextran methacrylate hydrogel backbone.
Additionally, HEMA-coupled dextran precursor was applied to syn-
thesize hydrogels by visible light in the presence of cam-
17
phorquinone photoinitiator in combination with tertiary amines,
as co-initiators to enhance the efficiency of the photo-curing
[260]. The free radicals, excited camphorquinone and co-
initiators, are generated by electron transfer and hydrogen
abstraction that can initiate a radical polymerization to form the
biocompatible hydrogels. Synthesis of the methacrylate-modified
dextran hydrogels can also be achieved by electron-beam irradia-
tion without any additives, that resulted in the formation of
crosslinked structures through unsaturated carbon double bonds
of methacrylate substituents, which showed non-cytotoxic effects
on mouse fibroblasts L929 cells [261].
As a promising strategy, small interfering RNA (siRNA) have
incorporated in dextran-based hydrogels to inhibiting/promoting
the aberrant expression of disease-causing genes. In this way,
dextran-HEMA microgel has been loaded with atto647-siRNA aim-
ing for better control over the intensity of gene silencing effect and
release of encapsulated siRNA [113]. The same group developed
the anti-luciferase siRNA loaded cationic dextran-HEMA nanogels
to enhance endosomal escape that found it able to silence the luci-
ferase gene in hepatoma cells without relevant cytotoxicity [114].
In another work, the photo-crosslinked hydrogels composed of
methacrylated dextran and methacrylated linear poly(ethylene
imine) were developed [112]. Such hydrogels were capable of
forming electrostatic interactions with siRNA and provided con-
trolled/sustained delivery of siRNA with extended deGFP silencing.
Dextran-mono(2-acryloyloxyethyl) succinate hydrogels incorpo-
rated with RGD peptide and siNoggin siRNA have also been
reported to induce human mesenchymal stem cells (hMSCs) osteo-
genesis. The hydrogels allowed prolonged siNoggin release over
7 weeks with tunable cell adhesion that increased osteogenic dif-
ferentiation in encapsulated hMSCs [111].
In the other strategy, dextran-based hydrogels have combined
with cells and growth factors/cytokines to provide sufficient cell
growth and enhance TE performance. In this respect, photo-
crosslinkable epoxy benzophenone-modified carboxymethyl dex-
tran hydrogels incorporated with silica NPs were either com-
pounded with cytokines (stromal-derived-growth factor and
bone morphogenic protein) [262,263] or with osteoblasts and
endothelial cells [264]. The findings indicated the cytokines further
enhanced cell proliferation, migration, and angiogenesis as well as
the cells significantly induced the bone formation in mice calvarial
defects.
Some of the main characteristics of the photo-crosslinked
dextran-based hydrogels in above-mentioned studies are shown
in Table 5. Overall, the results of these studies have shown unique
features of dextran-based hydrogels fabricated with photo-
polymerization techniques for biomedical purposes such as drug
delivery and TE. Physico-mechanical properties of the hydrogels
can be modulated by inserting proper photoactive molecules to
dextran chains. These structures demonstrated significant out-
comes, especially when combined with growth factors, siRNA
and cells. However, definitely further studies required to perform
in vivo investigations.
5.2. Polypeptide-based photo-polymerizable hydrogels
5.2.1. Collagen
Collagen is a protein-based polymer, which naturally synthe-
sized in most mammals (25% of protein) and is the main protein
of the ECM. Collagen has mainly a structural role in the tissues
and its orientation, packing, and density determine the mechanical
properties in various tissues [266,267]. Collagen family has at least
16 members, but types I, II, and III comprise 80–90% of the collagen
in the body. These types pack together to form long thin fibrils
structure, while there are other forms such as two-dimensional
reticulum, type IV. Due to its biocompatibility, degradability, low
 18
Table 5
The specifications of photo-crosslinked dextran-based hydrogels fabricated for various biomedical applications.

Hydrogel type Type of Applied light (nm), duration (min) In vitro/in vivo model Potential biomedical applications Refs.
photoinitiator and intensity (Wcm
2)
Dextran-maleic acid DMPA 360, 40, NA NA NA [239]
Acrylated dextran DMPA 360, 60, NA NA NA [240]
Dextran–methacrylate DMPA 365, 120, NA NA NA [265]
Dextran/poly(D,L-lactic acid) DMPA 365, 60–180, 8 NA As a vehicle for the controlled delivery of drugs [241,242]
Theophylline incorporated dextran–methacrylate NA 365, 360, 400 NA For a controlled delivery of theophylline [107]
Beclomethasone dipropionate incorporated dextran– NA 313, 90, 8 Caco-2 cells Potential use for the treatment of inflammatory bowel [243]
methacrylate diseases

H. Samadian et al. / Coordination Chemistry Reviews 420 (2020) 213432

Glycidyl methacrylate derivatized dextran DMPA 365, 22.5, 0.0078 NA NA [244]
Dextran methacrylate/carboxylated scleroglucan Irgacure 2959 UV light, 5, 125 NA For TE and delivery of biomolecules application [245]
Dextran/PEG methacrylate Irgacure 2959 UV light, 10, 125 NA As possible drug carrier of proteins [246]
Urethane methacrylated dextran/HEMA Irgacure 2959 320–480, 5–30, 50 L929 cells Could be used as tissue adhesives in medical area (44)
Calcium alginate/methacrylated dextran Irgacure 2959 UV light, 5, 120 NA The novel system as a drug delivery system [250]
Oxidized alginate/dextran-HEMA Irgacure 2959 350–450, 10, 20 NA As in situ forming protein releasing hydrogels [251]
Calcium alginate/dextran-HEMA Irgacure 2959 350–450, 5, 400 Chondrocytes As injectable in situ forming hydrogels for protein [252]
delivery and tissue engineering applications
HA/dextran-HEMA Irgacure 2959 350–450, 10, 20 Chondrocytes Bioprinted constructs for TE [253]
Doxorubicin-incorporated dextran-methacrylate DMPA 365, 120, NA NA As a drug carrier [248]
2-Phenylpropionic acid entrapped dextran methacrylate NA 313, 60, 12 NA As colon-specific delivery systems [249]
Vancomycin-loaded methacrylated dextran/poly(L- Irgacure 2959 365, 10. 4.5 Methicillin-Resistant S. aureus As scaffolds or coatings for local antibacterial drug [108]
glutamic acid)-g-hydroxyethyl methacrylate release in TE
Dextran-AI/NIPAAm DMPA 365, 540, 8 NA NA [254]
Dextran-AI/NIPAAm DMPA 365, 22 h, 8 NA NA [255]
Dextran-allyl isocyanate-ethylamine/polyethylene Irgacure 2959 365, 1200, 16 NA For protein delivery applications [257]
glycol- diacrylate
Dextran–maleic anhydride/NIPAAm DMPA 365, 22 h, 8 NA NA [256]
Dextran methacrylate/Con A methacrylamide Irgacure 2959 365, 50, 10 mJ cm
2 NA A promising system for self-regulated insulin delivery [109,110]
Methacrylate modified dextran–Con A and PEG Irgacure 2959 365, 3, 0.03 NA As glucose biosensor and intelligent insulin delivery [258]
diamethacrylate carrier
Dextran-methacrylate Riboflavin/L- Visible light, 15–40, 17 NA NA [259]
Arginine
Dextran-HEMA Camphorquinone 430–490, 2, 1000 NA As a drug delivery system in dental applications [260]
Dextran-methacrylate NA Electron beam, 0.5 – 100 kGy, Fibroblast L929 cells Applications in regeneration medicine [261]
Dextran-HEMA loaded with siRNA Irgacure 2959 UV light, 7.5, HUH7 cells For time-controlled delivery of siRNA [113]
Cationic dextran-based nanogels Irgacure 2959 365, 15, NA HuH-7 human hepatoma cells As a siRNA carrier [114]
Dextran-HEMA/linear polyethyleneimine methacrylate Irgacure 2959 320–500, 2, 0.0035 HEK293 cells As a sustained siRNA delivery hydrogel system [112]
Mono(2-acryloyloxyethyl) succinate-dextran Irgacure 2959 320–500, 85 s, 0.0025 hMSCs A platform for the prolonged delivery of genetic [111]
molecules
Epoxy benzophenone-modified carboxymethyl dextran NA 365, 60, 17 J cm
2 Fibroblast L929 cells Osteoblasts As biomaterials for bone regeneration [263]
cells Endothelial cells
Epoxy benzophenone-modified carboxymethyl dextran NA 254, 60, 10.4 J cm
2 Mouse As biomaterials for bone regeneration [264]
0
Abbreviations: DMPA: 2,2 -dimethoxy-2-phenyl acetophenone , NA: Not available, PEG: Poly(ethylene glycol), HEMA: Hydroxyethylmethacrylate, AI: Allyl isocyanate, NIPAAm: N-isopropylacrylamide.
 H. Samadian et al. / Coordination Chemistry Reviews 420 (2020) 213432 19

immunogenicity, as well as biological properties such as cell
attachment, migration, and differentiation regulation, collagen
has been widely used in various fields of biomedical [267,268].
Despite these properties, collagen suffers from low structural sta-
bility and mechanical strength upon hydration, which hinders its
clinical applications. In this regard, intermolecular crosslinking
through different physical and chemical approaches can enhance
mechanical strength and stability. Among the various forms of col-
lagen, hydrogel structure has gained tremendous attention in
biomedical applications due to mimicking ECM structure, high
water retention capacity, and high swelling ratio, as well as the
above-mentioned properties [269]. Collagen can be chemically
crosslinked by EDC/NHS, glutaraldehyde, and Genipin to form
hydrogel structure. Despite their high efficacy, using these
crosslinking agents induce cytotoxicity and cells are restricted
being seeded on the surface of the hydrogels rather than encapsu-
lated into the hydrogel. On the other hand, photo-chemically
crosslinking using biocompatible photoinitiator, a minimal amount
of UV exposure and visible light circumvent the previous
approaches issues and provide encapsulation of cells within the
3D structure of hydrogel. Various scientists have developed
photo-chemically crosslinked collagen hydrogels using different
photoinitiators and crosslinking lights for drug/cell/gene delivery,
TE, enzyme immobilization, and so on.
Nagaraj et al. [270] fabricated crosslinked collagen through vis-
ible light irradiation using erythrosine B (EB) and methylene blue
(MB) as the photosensitizer in the presence of ammonium persul-
phate (APS). This crosslinking method was based on free radical
mechanism and APS was used as the electron acceptor to facilitate
oxygen-free radicals formation upon irradiation. In this scenario,
the photosensitizers, EB and MB, excited by visible radiation and
convert to short-lived singlet excited state following intersystem
crossing to form a longer-lived triplet state then reach to the
ground state via energy transfer and free radical formation. The
absorbed energy can be transferred to molecular oxygen which
subsequently generates ROS such as sulfate radical anion SO42
,
singlet oxygen (1O2), superoxide anion (O2), and hydroxyl radicals
(OH) under interaction with APS. The SO2
4 as well as the excited
state sensitizer can oxidize aromatic amino acids such as trypto-
phan, tyrosine, and cytosine residues in the side chain backbone
of collagen. In the crosslinking process, Tyr-Tyr bridge forms
through the reaction between two tyrosyl radicals in the side chain
of collagen. The authors reported that, although the radiation oxi-
dized some amino acids in the structure of collagen, the triple-
helical conformation was preserved confirmed by SEM, Raman
spectroscopy, circular dichroism (CD) FTIR spectral studies.
Nguyen et al. [271] evaluated the effects of photoinitiator type
(i.e., I2959 and VA086) and concentration (i.e., 0.02% and 0.1%) as
well as crosslinking time (1 min and 10 min) on compressive
strength, gel morphology, and stability of methacrylated collagen.
They reported that the photo-chemical crosslinking reduced the
porosity and subsequently water retention ability of collagen
hydrogel compared with un-crosslinked hydrogels. They also
observed that increasing the concentration of the photoinitiators
and crosslinking time enhanced the compressive modulus and
the stability of hydrogel. Moreover, they pointed out that VA086
was more biocompatible than I2959 and cell-mediated mineraliza-
tion was significantly higher on VA086 crosslinked hydrogels com-
pared with I2959.
Yang et al. [272] fabricated photo-crosslinked methacrylamide-
modified collagen hydrogel to control actin traction and subse-
quent contraction of the collagen matrix and differentiation of
BMSCs toward chondrogenic lineage. The authors proposed that
the collagen hydrogel can induce chondrogenic differentiation,
while its low mechanical properties cannot withstand agents the
traction of cells which results in collagen matrix contraction. This
collagen matrix contraction is a non-physiological mechanical
stimulus, which disrupts the actin cytoskeleton and subsequently
compromises cell viability and also dedifferentiates the differenti-
ated chondrocytes. They used collagen type I extracted from calf-
skin modified with methacrylamide and crosslinked via UV
radiation to provide a robust 3D structure. They reported that, as

Fig. 3. The interplay between the actin cytoskeleton of BMSCs and different hydrogel matrix at different days, highlighted by phalloidin/DAPI staining. COL: native collagen,
CD: BMSCs laden collagen cultured in medium supplemented with cytochalasin D, CMA: BMSCs laden photo-crosslinked collagen hydrogel in normal medium, and MD:
BMSCs laden photo-crosslinked collagen hydrogel in medium supplemented with cytochalasin D. F-actin cytoskeleton, cell nucleus, and collagen fibers were stained red, blue,
and green, respectively. (Scale bars, 20 mm). Reproduced with permission from reference [272].
20 H. Samadian et al. / Coordination Chemistry Reviews 420 (2020) 213432
shown in Fig. 3, BMSCs possessed round shapes in the first attach-
ment with the collagen matrix. The cells exhibited spread shape,
actin microfilaments expressed, and the collagen fibers bunched
up around the cells in collagen one day after cell seeding in the col-
lagen group. Interestingly, in this group on day 2, BMSCs lost the
cytoskeleton filaments and changed back to the round shapes. Con-
versely, in CMA group, the cells demonstrated high actin expres-
sion and spreading forms with robust cytoskeleton structure.
Moreover, dispersive fibers distribution without aggregation was
observed around the cells in this group. It is apparent in CD and
MD groups that the addition of cytochalasin D inhibited the actin
polymerization and subsequently, the arrangement and distribu-
tion of collagen fibers remained constant over time. They con-
cluded that the observed aggregation of collagen fibers is related
to the traction of the actin cytoskeleton in the low strength hydro-
gel. On the other hand, photo-crosslinked hydrogel withstands
against the actin pulling induced contraction and induced powerful
expression of the cytoskeleton as illustrated in CMA group. In CD
and MD groups, cytochalasin D inhibited the interplay of cell and
matrix. This study critically demonstrated that proper mechanical
strength is vital for cell viability, proliferation, and differentiation.
Some studies combined collagen-based hydrogels with a 3D
printing technique to construct well-designed cell-laden architec-
ture. In a study, Stratesteffen et al. [130] blended collagen with
methacrylated gelatin (GelMA) and tailored the mechanical and
rheological properties to obtain desired 3D drop-on-demand print-
ing characteristics. Firstly, gelatin was methacrylated, cells (HUVEC
and hMSC), collagen type I, and photoinitiator added to the solu-
tion. The resulted solution was printed using a custom-built 3D
drop-on-demand bioprinter. The authors reported that the combi-
nation of collagen with GelMA provided a bioink with improved
printing properties suitable for microvalve-based bioprinting
device, sufficiently low viscosities. The fabricated bioink exhibited
acceptable elastic shear modulus and gelation time suitable for
cell-laden bioprinting approaches. Moreover, they showed that
the fabricated construct was biocompatible and the interconnected
architecture, as well as cell attachment sites of GelMA-collagen,
enabled HUVEC and hMSC to rearrange into tubular formations
and subsequently provide angiogenesis. Using collagen as the
bioink for nozzle-based 3D printing techniques may encounter
clotting the nozzle. Hence, some researchers conducted studies
to develop a nozzle-free fabrication method with acceptable reso-
lution. In this regard, Drzewiecki et al. [129] modified collagen type
I with methacrylamide (CMA) and utilized as the bioink for free-
form fabrication of TE scaffold. They fabricated fibril hydrogel
through the self-assembly of CMA, utilized a patterned photomask
to photo-crosslinking into the intended pattern, and finally cooled
the hydrogel to remove unphoto-crosslinked regions through the
cold-melting process. The beneficial feature of collagen for this
nozzle-less hydrogel patterning is based on its ability to form a fib-
rillar hydrogel at temperatures above ~ 20 °C. The authors reported
the resolution on the order of ~ 350 lm for this method, which can
be conducted with or without cells. They in vitro and in vivo studies
demonstrated that the fabricated photo-crosslinked CMA hydrogel
was biocompatible.
5.2.2. Gelatin
Gelatin is a biopolymer with fascinating physicochemical and
biological properties such as adjustable biodegradability, excellent
biocompatibility, non-carcinogenicity, low antigenicity, and
immunogenicity [273–275]. Generally, gelatin is obtained from
hydrolysis and denaturation of collagen and possesses collagenˈs
natural properties, including matrix metallopeptidase (MMP) sen-
sitive sites and Arg-Gly-Asp (RGD) adhesive motifs, which modu-
late cell-mediated matrix degradation and cell attachment,
respectively [276]. Moreover, it is more processible than its par-
enteral component, collagen, and has grabbed considerable atten-
tion in the biomedical and food processing applications. Despite
its brilliant properties, gelatin suffers from low mechanical
strength and should be crosslinked to retain desired structures
during the handling and also in the site of action. However, gelatin
can be physically crosslinked, it’s physical network is also unstable
at higher temperatures and breaks down. Therefore, it’s mechani-
cal and thermal stability should be improved for long-term
biomedical applications at 37 °C [127,277,278].
Photo-crosslinking is a rapid, effective, convenient, and safe
crosslinking approach that avoids the applications of some toxic
chemical crosslinking agents. In this regard, gelatin should be func-
tionalized by photo-reactive side groups, such as acrylates and
methacrylates, or blended/grafted with other polymers containing
the photo-reactive side groups [279]. Various studies have been
conducted in this concept and magnificent breakthrough achieved.
Gelatin-methacrylate (GelMA) is an attractive photo-crosslinkable
derivative of gelatin, which obtains by conjugating the primary
amino groups of gelatin with methacrylate pendant groups. GelMA
retains the unique properties of gelatin but exhibits desirable
activities of photo-crosslinkable hydrogels such as mild gelation
conditions and biocompatibility [279]. Moreover, it is possible to
simply adjust the mechanical strength, thermal stability, degrada-
tion rat, and biological activities of GelMA by varying the polymer
crosslinking density through changing the methacryloyl modifica-
tion degree. GelMA has extensively used in various fields of biome-
dicine such as drug delivery and TE [280,281].
Parthiban et al. [282] covalently conjugated VEGF-mimicking
peptide (AcQK) to GelMA to induce microvascular network forma-
tion within GelMA by encapsulated cells. They used the acrylated
peptide to conduct the conjugation process. They observed that
the conjugation significantly compromised the mechanical
strength of the hydrogel which was attributed to the interference
of the peptide with the crosslinking process. They proposed that,
with the presence of acrylated peptide, the generated free radicals
attack both the methacrylate groups of GelMA and acrylate groups
in the peptide. Hence, the free radical propagation reaction is ham-
pered in comparison with pure GelMA polymer. Moreover, they
observed that there is a direct correlation between the concentra-
tion of acrylated peptide and the compliance of the hydrogel
matrix (Young’s modulus) since generated free radicals are con-
sumed by peptides to form a covalent linkage. Interestingly, the
incorporation of the peptide increased the pore size as the function
of loosening the network. The authors also utilized human umbil-
ical vein endothelial cells (HUVECs) as the model to assess the bio-
logical effects of conjugated AcQK. They observed that, apart from
the biological activities of AcQK, their effect on the hydrogel matrix
compliance (reduction) and pore size (increasing) improved the
vascular network formation. They conducted that the cell migra-
tion possibilities (determines by mechanical properties of hydro-
gel) are as critical as the presence of vasculature, inducing
biological cues. In conclusion, they proposed that the incorporation
of acrylated peptide provides additional possibilities to tailor the
mechanical properties, as well as induce desired biological
activities.
In an innovative approach, Smith et al. [116] applied GelMA
hydrogel to construct biologically based replacement teeth as the
alternative over the currently used dental implants. They encapsu-
lated HUVECs, porcine dental mesenchymal (pDM) progenitor
cells, and post-natal porcine dental epithelial (pDE) within GelMA
and implanted subcutaneously onto the backs of female Rowett
Nude rats. Mechanical measurement using force volume–atomic
force microscopy (FV-AFM) illustrated that increasing concentra-
tion of GelMA and the photoinitiator enhanced the elastic moduli.
Moreover, cells-laden hydrogel indicated as Gel 3 with the compo-
sition of GelMA (5% w/v) and photoinitiator (0.1% w/V) exhibited
 H. Samadian et al. / Coordination Chemistry Reviews 420 (2020) 213432
the elastic moduli similar to the natural dental pulp tissue. In vivo
studies revealed that GelMA constructs consisting of pDM-HUVECs
in 5% GelMA and pDE–HUVECS within 3% GelMA supported differ-
entiation dental cell and formation of vascular mineralized dental
tissue. The authors concluded that, the fabricated 3D biomimetic
tooth bud model can be eventually considered as a bioengineered
tooth replacement.
Photo-crosslinkable gelatin-based biomaterials have been con-
sidered as the akin and wound care constructs in the form of skin
substitute or wound dressing materials [115,280]. Sun et al. [117]
combined electrospinning with photo-crosslinking of GelMA to
fabricate 3D fibrous scaffolds for improved vascularization process.
Nanofibrous GelMA was fabricated by the electrospinning method
and then, crosslinked under UV radiation. The physicochemical
properties, as well as biological activities of the prepared GelMA
nanofibers were compared with electrospun gelatin nanofibers
chemically crosslinked by glutaraldehyde. They observed that
GelMA fibers had a better water swelling property than pure gela-
tin and formed highly porous matrix architecture. Mechanical per-
formance comparison illustrated that GelMA fibers were more
flexible/compliant than gelatin fibers. The in vitro studies showed
that the fabricated nanofibrous GelMA support proliferation, and
migration of human dermal fibroblasts (HDFs) and HUVECs into
the scaffolds, which facilitates vascularization. Moreover, the
in vivo study confirmed the results of the in vitro results by a higher
flap survival rate and more microvascular formation than control
groups. The authors suggested that the combination of electrospin-
ning with photo-crosslinking of GelMA can provide sophisticated
3D scaffolds desired for the complex engineered tissues.
In a similar study, Kim et al. [115] fabricated a bi-layer hybrid
scaffold based on chitosan/human hair keratin nanofibrous mat
and GelMA hydrogel as the skin graft. They fabricated chitosan/
keratin nanofibers via the electrospinning method and set as the
top layer and GelMA hydrogel considered as the bottom layer. To
mimic the native skin tissue, they encapsulated fibroblasts in the
hydrogel matrix and HaCaT cells on the nanofibrous layer. They
reported that the incorporation of chitosan improved the mechan-
ical properties and preserved the porous structures in the wet
form. Moreover, the combination of the nanofibrous mat with
GelMA hydrogel circumvents fastidious handling and suturablity
of the hydrogel and improves its handling during the implementa-
tion. They concluded that the fabricated bi-layer scaffold mimics
the dermis and epidermis of skin tissue and supports the prolifer-
ation and functions of HaCaT and NHDFs cells.
Oktay et al. [283] fabricated a smart electro-responsive trans-
dermal drug delivery system for skin disease treatment, which
can release a specific amount of the drug at pre-determined time
points. They encapsulated poly(styrene sulfonate)/poly(3,4-ethyle
nedioxy thiophene) (PSS/PEDOT) into GelMA hydrogel and used
5-fluorouracil (5-FU) as the model drug. They simply dispersed a
proper amount of PSS/PEDOT into GelMA sole and irradiated with
UV light to induce photo-crosslinking. They applied electric field
(1.5 V) perpendicularly to the hydrogel to assess the effect of the
electrical stimulation on drug release from the hydrogel. The
authors reported that the electrical stimulation increased the
amount of drug released from 18.2 to 23.3%, which is related to
de-swelling effect of the electrical stimulation. Upon the electrical
stimulation the network size is changed, hydrogel shrinks, and the
encapsulated drugs squeeze out from the hydrogel. The authors
suggested that the fabricated electro-responsive hydrogel-based
DDS enables non-invasive, reliable, remote, and repeatable drug
delivery with accurate dosage, timing, and duration.
Despite the wide applications of GelMA, it’s thermal instability
is a concerning issue in the biofabrication applications. Kolesky
et al. [284] have shown that the shear moduli and viscosity of
GelMA significantly changed at around 25 °C. The viscosity of the
21
materials is a critical parameter in the most of the biofabrication
systems, for instance, the viscosity in the range of 3.5 and
12 MPa is applicable in inkjet bioprinting and higher viscosity
results in non-uniform structures and or clogging the nozzle.
Therefore, precise temperature control during the biofabrication
process of thermally unstable substances is needed which on the
other hand increase the cost and complexity of biofabrication sys-
tems. An alternative approach is to develop thermally stable mate-
rials. Wang et al. [285] produced cold soluble gelatin as the source
material for GelMA hydrogel with low viscosity and thermal stabil-
ity at room temperature. They reported that GelMA prepared from
a cold soluble gelatin exhibited similar biological properties to por-
cine skin gelatin-based GelMA while it had improved thermal sta-
bility and partially low viscosity at room temperature. They
concluded that the fabricated cold soluble gelatin-based GelMA
can be considered as the promising alternative bioink for biofabri-
cation applications applicable in regenerative medicine and TE.
In an innovative approach, Wang et al. [286] combined a flow-
focusing droplet microfluidic system with GelMA photo-
crosslinking concept to produce cell-laden, solid-like, and core–
shell microgels for micro-TE applications (Fig. 4a). They used min-
eral oil, GelMA, and methyl cellulose (MC) for the continuous flow,
core and shell, respectively. They showed that the flow rates and
the concentration of the polymers determined the overall size
and the stability of the microgels, as well as the shell thickness
and the core diameter. They observed a direct correlation between
core and shell flow rates with the core and shell diameter, respec-
tively. The authors indicated that the overall size, core diameter,
and shell thickness are easily adjustable using the flow rates while
the core-shell structure is preserved (Fig. 4b). They also assessed
the biocompatibility of the microgels using HepG2 and HUVECs
cells in a co-culture method. They encapsulated the cells within
the core and observed the proliferation of both cells. Moreover,
they reported that the production of albumin and urea increased
as the function of the biological activities of the cells in the co-
culture method due to the cell–cell interactions. Interestingly, they
observed increasing the core size with the proliferation of the cells,
which revealed the flexibility of the microgels against cells-
induced remolding of the microgels. The authors concluded that
the fabricated core-shell microgel can be considered as the promis-
ing microcarriers for the culture of heterogenous cells with poten-
tial applications in the fabrication of organoids, microtissues, and
stimuli-responsive materials. Table 6 summarized the studies con-
ducted on photo-crosslinked gelatin-based hydrogels.
In conclusion, the studies revealed and documented the gelatin-
based photo-crosslinkable materials not only exhibit fascinating
biological properties but also offer tunable mechanical and mor-
phological performances, as well as effective integrability with a
wide range of biofabrication methods. In this concept, the integra-
tion of gelatin-based photo-crosslinkable materials with the elec-
trospinning, rapid prototyping, and microfluidic methods resulted
in fascinating and sophisticated structures applicable in a wide
range of biomedical applications.
5.2.3. Silk
Silk is defined as highly oriented spun protein fibers, which are
produced by some creatures mainly silkworms, comprised of two
fibroin strands wrapped with the glue-like sericin protein [299].
Sericin constitutes 25–30 wt% of total silkworm cocoon and should
be removed by proper de-gumming processes [300]. The silk
fibroin (SF) is built of a heavy chain (Mw ~ 325 kDa, 85%, w/w)
and a light chain (Mw ~ 26, kDa, 15%) linked together by a
disulfide bond as well as a glycoprotein, P25, with a 6:6:1 M ratio
[301–303]. SF is a large hydrophobic protein made up of (Gly-Ala-
Gly-Ala-Gly-Ser) six amino acid repeat units, which can form anti-
parallel b-sheet structures that intra/inter-connected by hydrogen
22 H. Samadian et al. / Coordination Chemistry Reviews 420 (2020) 213432

Fig. 4. Morphology of the core–shell microgels. (A) Schematic diagram of the core–shell microgels formation. The core, MC solution, was stained with fluorescent polystyrene
NPs L3280 and the shell, the GelMA solution, stained with fluorescent polystyrene NPs L4655. (B) The effects of flow rates (continuous flow rate- shell flow rate- core flow rate
lL min
1) on the core–shell microgels visualized by CLSM. (C) SEM micrograph of the freeze-dried microgels. (D) The size distribution of the core–shell. Microgels. Scale bar:
100 lm. Reproduced with permission from reference [286].

bonds, Van der Waals and hydrophobic interactions [304]. The
unique structure, ease of processing, high mechanical strength,
excellent biocompatibility, absent or minimal immunogenicity,
tunable degradation, and facile modification possessing, make SF
as a suitable biomaterial for multifarious biomedical applications,
such as TE, drug delivery and regenerative medicine [305–307].
By tailoring the preparation conditions, the various morphologies
can be generated from SF [304].
Amongst different SF forms, SF hydrogels are 3D crosslinked
hydrated matrices that their structural conformation and physico-
chemical properties can be modulated. The hydrogel formation can
be achieved by shearing forces (overtaxing or sonication), changing
temperature, pH or ionic concentration, as well as exposure to sol-
vents, gases and surfactants [308]. The sol-gel transition (from ran-
dom coil to antiparallel b-sheet structures) of SF occurs during the
process of gelation, which may be affected by many factors such as
SF concentration, temperature, pH, and crosslinking agent [309].
Further, SF hydrogels can be blended with other natural/synthetic
polymers [308] and/or chemically/physically crosslinked [310] to
form hydrogels with improved strength properties. However, SF
hydrogels suffer from poor mechanical properties with low repro-
ducibility and difficulty in the maintenance of homogeneous reac-
tion conditions in the SF solution [310,311].
In the same way, photo-crosslinking methods have been
applied for the fabrication of SF-based hydrogels. The first strategy
includes the photo-polymerization of SF in the presence of reduc-
ing agents accompanied by covalent bond formation between
active photo-reaction groups of SF mainly tyrosine residues. Whit-
taker et al. suggested the facile ruthenium-catalyzed photo-
crosslinking method for the fabrication of photo-crosslinkable SF
hydrogel with impressive modulus values (~71 MPa). Under visible
light and tris(2,2-bipyridyl) dichloro ruthenium (II) hexahydrate
2þ
(RuðIIÞðbpyÞ3 ) as a catalyst in SF solution, tyrosine radicals can
be formed, thereby allowing tautomerization of the tyrosine resi-
dues and the formation of SF hydrogel through di-tyrosine links
(Scheme 7) [125]. A similar method has been also used to photo-
chemically crosslink of the recombinant spider silk protein,
eADF4(C16) hydrogels [312] and regenerated silk fibroin (RSF)/
poly(N-vinylcaprolactam) hydrogels [313]. Such the photo-
crosslinking method was utilized for a co-crosslinked hybrid
hydrogel combining Rec1-resilin and RSF hydrogels to improve
water uptake ability and elasticity [314]. This study also confirmed
the formation of inter/intra-molecular dityrosine crosslinks as well
as b-turn conformations much more than the random coil and b-
sheet structures. Subsequently, the structural evolution of photo-
crosslinked RSF and RSF hybrid hydrogels exhibited crosslinked
network structure with hydrophobic domains (dominated by b-
sheets in 2–3 nm length scale), hydrophilic domains (dominated
by turns and random coil in 4–20 nm length scale) and intercon-
nected pores in the microscale. While the nanoscale size of
Table 6
The specifications of photo-crosslinked gelatin-based hydrogels fabricated for various biomedical applications.

Hydrogel type Type of photoinitiator Applied light (nm), duration (min) In vitro/in vivo studies Potential biomedical applications Refs.
and intensity (Wcm2)
GelMA Irgacure 2959 UV, 30 s, 7 mW.cm
2 HUVECs Vasculatured 3D cell-laden scaffold for TE applications [282]
GelMA Irgacure 2959 UV, 30 s, 9.16 W.cm
2 pDE cells Bioengineered 3D GelMA tooth buds [116]
HUVECs
pDM
immunocompromised 5-month-old
female
Rowett Nude rats
GelMA Irgacure 2959 UV (365 nm), 30 min, NA HUVECs Vasculatured 3D cell-laden scaffold for TE applications [117]
HDFs
Rat
GelChMA Irgacure 2959 UV (254 nm), 10 min
4.78 mW.cm
2 (6 W)
GelMA/SF Irgacure 2959 UV (320–500 nm),30 s, 7.0 mW.cm
2 MC3T3-E1 Robust and tunable load-bearing cell-laden soft tissue engineering scaffold [127]

H. Samadian et al. / Coordination Chemistry Reviews 420 (2020) 213432

GelMA/Collagen LAP UV (365 nm), 5 min, 3.4 mW.cm
2 MDA-MB-231 human breast cancer Cell/tissue-specific scaffold with tunable mechanical range and fibrous [279]
cells nature
GelMA/PSS/PEDOT Irgacure 2959 UV (365 nm), 25 min, NA L929 cell line Electro-responsive transdermal drug delivery system for skin disease [283]
treatment
GelChMA Irgacure 2959 UV (254 nm), 10 min, 4.78 mW.cm
2 HEK293T Biocompatible and tunable hybrid hydrogels for wound healing and skin [280]
(6 W) tissue repair applications
GelMA Irgacure 2959 UV, 3 min, 7.0 mW.cm
2 C2C12 Micropatterned hydrogel containing biological cue applicable in muscle TE [281]
and regeneration, drug screening and biorobotics

2
HK/Ch/GelMA LAP UV (365 nm), 5 min, 5 mW.cm HaCaT cell Bi-layer cell bearing scaffold as the skin graft [115]
NHDFs cell
GelMA Irgacure 2959 UV, 50 s, 16 mW.cm
2 HaCaT 3D skin model [287]
fibroblasts
GelMA Eosin Y Blue-green visible light (450– Primary rat CMs male Sprague-Dawley Injectable hydrogel as the regenerative treatment following MI [123]
550 nm), 100 mW.cm
2 rat (2 + months of age and 250–275 g)
GelMA/pectin-g-PCL Irgacure 2959 UV (360–480 nm), 240 s, 7.7 mW. MC3T3-E1 Interpenetrating polymer network (IPN) hydrogel as the bone TE scaffold [288]
cm
2 preosteoblasts
GelMA/Ch Irgacure 2959 UV (365 nm), 30 s, 1.5 W.cm
2 BMSCs Composite IPN GelMA/Ch hydrogel with tunable mechanical properties as [289]
the multifunctional biomaterial
GelMA Irgacure 2959 UV (365 nm), 1 min, 0.120 Joule. Human keratocytes Transparent keratocytes-laden GelMA hydrogel for the treatment of corneal [121]
cm
2 blindness
Cold soluble gelatin-based VA-086 UV (375 nm), 1.5 mW.cm
2 NIH-3 T3 fibroblast cells Thermally stable bioink applicable in biofabrication applications [285]
GelMA

2
MC/GelMA 2-Hydroxy-2- UV (365 nm), 20 s, 58.8 mW.cm HepG2 Protective, flexible, tunable, and biocompatible core-shell microgels [286]
methylpropiophenone HUVECs applicable in the construction of stimuli-responsive materials, organoids,
and microtissues
PCL/GelMA Irgacure 2959 UV (254–354 nm), NA NHDF Nanofibrous vascular graft [290]
GelMA Irgacure 2959 UV, 40 s, 800 mW, 8 cm PBMCs Immunomodulatory and anti-inflammatory scaffold for immune system [291]
adjustment
GelMA LAP DL, 5–20 s, 1650, 2300 and 3700 OD21 Visible light crosslinkable hydrogel as the dental TE scaffold [292]
mW.cm
2
GelMA VA-086 Vis (440 nm), 2 min, 10 mW.cm
2 MSCs 3D scaffold with tunable mechanical properties for osteogenic and [120]
endothelial differentiation of MSCs
CAR/GelMA Irgacure 2959 UV (365 nm), 30 min, 4 mW.cm
2 ASCs 3D bioactive with adjustable mechanical properties for adipose TE [122]
GelMA/NPx Irgacure 2959 UV (365 nm), 50 min MSCs Multifunctional thermo-responsive with tunable mechanical performances [293]
for a wide range of biomedical applications
Acrylamide-modified Irgacure 369 UV (365 nm), 4 h, 780 nm Ti- HDF 3D gelatin-based hydrogel with patterned topography on the surface to [273]
gelatin Sapphire laser emitting 100 fs direct the he polarization and the collagen production of HDF with a certain
pulses at 80 MHz directionality
150 mW
Acrylamide-modified Irgacure 369 780 nm Ti-Sapphire laser emitting NIH-3 T3 cells The microfabricated photo-actuable gelatin as the dynamic caging culture [119]

(continued on next page)

23
 24
Table 6 (continued)

Hydrogel type Type of photoinitiator Applied light (nm), duration (min) In vitro/in vivo studies Potential biomedical applications Refs.
and intensity (Wcm2)
gelatin 100 fs pulses at 80 MHz systems for stem cell niches simulation
150 mW
gelatin/Dex-MA Darocur 2959 UV (365 nm), 30 min L929 cells Nanofibrous scaffold for TE applications [276]
GelHA Irgacure 2959 UV, 2 min, 7.0 mW.cm
2 ASCs Bioactive cell-laden hydrogel-based scaffold for intervertebral disc repair [294]
AMSA/AG Irgacure 2959 UV (365 nm), 15 min, 1 mW.cm
2 L929 cells Hydrogel-based scaffold with tunable mechanical properties for TE [136]
applications
GELMA Irgacure 2959 UV, 30 s, 100 mWcm
2 —— GelMA hydrogel scaffold as a microphysiological tissue model [295]
GELMA/PEG Eosin Y Green visible light (530 nm), 10 min, MSCs, A549, RAW264.7, and Jurkat Gelation based polymer cell coating as the effective TE-based therapy for [296]
30 mW.cm
2 cells. acute myocardial infarction
Male C57BL/6 wt and C57BL/6-Tg(CAG-
EGFP)131Osb/LeySopJ mice aged 6–
10 weeks
GelMA/HAMA LAP UV (365 nm), 20 s, 10 mW.cm
2 Embryonic Medullary Reticular Cells HA-modified GelMA hydrogel as the scaffold for embryonic neurons for [118]
nerve cell growth induction and maintenance

2

H. Samadian et al. / Coordination Chemistry Reviews 420 (2020) 213432

GelMA/HAMA LAP UV, 30 s, 5.69 mW.cm HUVECs Tricultured GelMA/HAMA hydrogel as the model to assess the interactions [297]
NHLFs between GBM cells and vascular networks in the brain
U87-MG cells
GMA-functionalized gelatin Irgacure 2959 UV (350–370 nm) L929 Cell-laden gelatin-based microcapsules for cell immobilization and delivery [298]
30 s to 3 min in TE
GelNB Eosin Y Vis (400 – 700 nm), 5 min, 10 mW. HepaRG Visible light curable hydrogel for liver regeneration [278]
cm
2

Abbreviations: GelMA: Gelatin-methacrylate, HUVECs: Human umbilical vein endothelial cells, HDFs: Human dermal fibroblasts, SF: Silk fibroin, MC3T3-E1: Mouse pre-osteoblast cells, LAP: Lithium phenyl-2,4,6-trimethylben-
zoylphosphinate, GelChMA: Gelatin/methacrylamide chitosan, HEK293T: Human embryonic kidney cell line, C2C12: Murine skeletal muscle myoblasts, CMs: Primary cardiomyocytes, BMSCs: Bone mesenchymal stem cells, MC:
Methyl cellulose, NHDF: Normal human dermal fibroblasts cells, PCL: poly(caprolactone), PBMCs: Human primary peripheral blood mononuclear cells, OD21: Odontoblast-like cells, DL: Dental curing light, MSCs: Human bone
marrow mesenchymal stem cells, ASCs: Human adipose-tissue-derived stem cells, NPx: N-isopropylacrylamide (NIPAAm)/poly(ethylenglycol) dimethacrylate (PEGDMA), Dex: Dextran, MA: Maleic anhydride, GelHA: Gelatin
hyaluronic acid methacrylate, AMSA: Methacrylate sodium alginate, AG: Amino gelatin, GELMA: Gelatin methacrylamide, A549: Human epithelial lung carcinoma, RAW264.7: Mouse macrophage cell line, Jurkat: T lymphocyte
cells, HAMA: Hyaluronic acid methacrylate, GMA: Glycidylmethacrylate, GelNB: Gelatin-norbornene, HepaRG: Bi-potent hepatoblasts.
 H. Samadian et al. / Coordination Chemistry Reviews 420 (2020) 213432
HO Ru(III) Nearby
O O
-H+ . H
Tyr
-Ru(II)
SF 1 SF 1
Tyr radical Intermeduate
Ru(II)(bpy)32+
Scheme 7. The suggested reaction mechanism for photo-crosslinking of SF chains by dityrosine crosslinks tyrosine groups in the presence of RuðIIÞðbpyÞ3 photoinitiator.
Reproduced with permission from reference [16].
hydrophilic and hydrophobic domains increased and the homo-
geneity of pore size distribution in the microscale decreased by
adding Rec1-resilin or poly(N-vinylcaprolactam) [315].
The other study was suggested flavin-mononucleotide pho-
toinitiator, a nontoxic water-soluble variant of riboflavin, could
be used for SF hydrogel fabrication, which can make possible to
use for abnormal corneal diseases [316]. The mechanism of SF-
riboflavin photo-crosslinking described as forming inter-covalent
bond formation between tyrosine groups under visible light. Incor-
poration of graphene oxide into RSF matrix has been reported to
improve the mechanical and adhesive properties of RSF-based
hydrogels by a ruthenium mediated photo-crosslinking method
[317]. The photo-crosslinked hydrogel formed tacky hydrogels
with high toughness (~2.4 MJm
3), which could be attributed to
increasing b-sheet content and formation of tyrosine oxidation
products of a proportion of tyrosine amino acids in RSF during
photo-crosslinking in the presence of graphene oxide.
The second strategy comprises techniques involving chemical
modification of SF chains which transform reactive amino acid
residues into reactive olefinic functional groups such as methacry-
late and further subjected to photo-polymerization. Kim et al.
reported the synthesis of SF-methacrylate hydrogel using a con-
trolled UV photo-crosslinking method, which resulted in hydrogel
formation by chain-growth radical polymerization of methacrylate
and also provides good water-solubility, higher elasticity and thix-
otropic property [310]. Likewise, the fabrication of dually-
crosslinked SF hydrogel scaffolds has been accomplished by the
methacrylated derivative of SF in the presence of diphenyl(2,4,6-tri
methylbenzoyl) phosphine oxide photoinitiator for bone TE [318].
An SF hydrogel as a bioink for digital light processing 3D printing,
which consists of SF covalently immobilized with glycidyl
methacrylate, has been shown to printability and support NIH/3T3
cell processes within the hydrogel [319]. The hydrogel formation is
driven by vinyl double bonds formation with each other intra-
chain or between chains depending on LAP and modified SF con-
centration, and also with physical entanglement of SF chains.
The third strategy for the fabrication of photo-crosslinked SF-
based hydrogels is combination/blending with other photo-
crosslinkable materials. An in situ assemblies of SF-based hydrogel
composed of calcium phosphate-coated SF microfibers (CaP@mSF)
and HA dually linked with acrylamide and bisphosphonate groups
(Am-HA-BP) as binder developed and implanted into rat cranial
defects with 8 mm of diameter. The dually crosslinked hydrogels
containing both Ca2+BP coordination bonds and photo-
crosslinkages between acrylate groups provided excellent stability,
enhanced stem cell proliferation, and osteogenesis in vivo [124]. In
a study by Kundu et al. an SF/PVA methacrylate semi-IPN hydrogel
was photo-crosslinked in the presence of Irgacure (I-2959) to tai-
loring structural and releasing properties. Upon photo-
polymerization, the vinyl groups of PVA chains crosslinked and
25
HO HO HO HO
HO H
. H
Tautomerization .
SF 1 SF 1 SF 2 SF 1 SF 2
SF 2
Light
Ru(III)(bpy)33+ + SO42- + SO41-
452 nm
2þ
the formed crystalline beta-sheets of fibroin chains entangled
within the PVA 3D network [320]. According to Zhou et al. report,
maleilated chitosan (MCS)/methacrylated silk fibroin (MSF)
micro/nanocomposite hydrogels were prepared for cartilage repair
as TE scaffolds. The photo-crosslinking resulted in hydrogel forma-
tion through vinyl groups linkages on the side chains of MCS and
MSF, as well as the hydrogels loaded with transforming growth
factor-1 improved cytocompatibility and cell proliferation toward
to mouse articular chondrocytes [126].
Recently, using a combination of sonication and photo-
crosslinking methods, a cell-encapsulated IPN hydrogel based on
GelMA and SF has been made, which was able to apply as a 3D cell
scaffold for load-bearing soft TE [127]. The sonication process
induced the formation of SF b-sheet structures, followed by the
photo-initiated radical polymerization of GelMA to form the hybrid
hydrogels incorporating MC3T3-E1 pre-osteoblasts.
A summary table of the above-mentioned photo-crosslinking
methods applied for making SF-based hydrogels is provided herein
(Table 7). This table represents an overview of types of SF hydro-
gels formed by different photo-initiated crosslinking methods,
biomedical studies, and proposed applications.
Collectively, the photo-crosslinked SF-based hydrogels have
been constructed by three strategies that they are elucidated along
with the principles of their formations. These photo-crosslinking
processes can provide the hydrogels with high applicability and
tunability that endowed unique structural characteristic properties
and high performance (e.g., transparency, resiliency, and injectabil-
ity). Additionally, cells and/or bioactive factors can be encapsu-
lated/delivered in a minimally invasive manner with highly
in vitro/in vivo compatibility, highlighting their potential suitability
for designing advanced silk-based hydrogel material in biomedical
applications.
6. Conclusions and future remarks
Despite the significant progress in the field of biomaterials, the
design and development of more efficient biomaterials for biomed-
ical applications are still on demand. In general, biomaterials are
categorized into metallic, ceramic, and glasses, polymeric, and
composite. Among these, polymer-based biomaterials have
received a great deal of interest mainly due to their inherent
physicochemical as well as biological features. The most important
advantages of polymeric biomaterials are biocompatibility, steriliz-
ability, adequate mechanical and physical properties, excellent
processability in most cases, and manufacturability.
Despite the unprecedented physicochemical and biological
properties of natural polymer-based hydrogels, they suffer from
some critical drawbacks, as mentioned in the hydrogel section.
Therefore, new synthetic, semi-synthetic, and bioengineering
strategies should be developed to address the above-mentioned
26 H. Samadian et al. / Coordination Chemistry Reviews 420 (2020) 213432

Abbreviations: SF: Silk fibroin, RSF: Regenerated silk fibroin, PVA: Poly(vinyl alcohol), Am: Acrylamide, HA: Hyaluronic acid, BP: Bisphosphonates, HaCaT: Human keratinocyte cell line, CaP@mSF: Calcium phosphonate coated silk
issues through the physical, chemical, or biological modification

[125]
[316]

[317]

[124]

[126]

[319]

[318]

[127]
[320]

[310]
Refs.

approaches of natural polymers-based hydrogels. Various strate-

gies, including ester or amide formation, radical polymerization,
Michael addition, ‘‘Schiff-base”, disulfide crosslinking ‘‘click chem-
istry”, and ‘‘native chemical ligation” have been applied for the

A promising material for 3D printing ink, cell culture matrix, injectable

Applications in biomedical (such as load-bearing tissue bioelectronics,
synthesis of chemical hydrogels. Among these, radical polymeriza-
tion can be achieved using both conventional free radical polymer-
ization, as well as photo-polymerization reactions through

microfibers, LAP: Lithium phenyl-2,4,6-trimethylbenzoylphosphinate, MCS: Maleilated chitosan, MSF: Methacrylated silk fibroin, GelMA: Gelatin methacryloyl: IPN: Interpenetrating polymer networks.
external radiation sources such as near-infrared (NIR), visible light,
Cell culture matrix for TE of chondrocyte progenitor cells

and ultraviolet (UV) in the presence of a photoinitiator. Photo-

A promising injectable scaffold for bone regeneration

polymerization is a versatile and powerful tool due to some advan-

biochemical filters and energy storage engineering)
A promising material for use in ocular prostheses

tages, including easy and rapid network formation, solvent-free,

energy-efficient, fast process (taking usually only seconds to min-
utes), spatial and temporal control, and in situ gelling viscoelastic
systems in vivo with a minimally invasive manner. Furthermore,
For delivery of macromolecular drugs

in this approach crosslinking density and matrix stiffness can be

As TE scaffolds for cartilage repair
Potential biomedical applications

As load-bearing soft TE scaffold

controlled using light intensity, exposure time, and the illuminated
area. Moreover, the photo-crosslinking approach can be integrated
hydrogel, and surgical glue.

As a candidate for bone TE

with a wide range of biofabrication techniques such as microflu-

A bioink for TE printing

idics, electrospinning, and rapid prototyping methods. In this con-

cept, it is possible to precisely design the internal architecture and
subsequently obtain improved performance beneficial for biomed-
ical applications. However, the most important drawbacks of
photo-polymerization are lack of control over the crosslinking
kinetics, oxygen inhibition, and the generation of heterogeneities
within the hydrogel network, which significantly affect the
mechanical integrity and swelling behavior of the resultant
NIH/3T3 mouse fibroblast

hydrogel.
enucleated porcine eyes

3 T3 murine fibroblasts
In vitro/in vivo model

Despite the most application ranges of UV-light-induced photo-

Corneal adhesion to

h-MSCs Wistar rat

polymerization approach, the low penetration depth and loss of

Mouse articular

power with the square of the distance due to great absorption by

chondrocytes
ATDC5 cell

biological systems, potentially harmful side effects of UV light irra-

MC3T3-E1

diation, cytotoxicity and poor solubility of the UV-light-sensitive

HaCaT

cells
NA*

photoinitiators, and local inflammation due to un-reacted mono-

NA

mers or double bonds are the most important drawbacks of this

method. It is well documented that the UV and visible lights
The specifications of photo-crosslinked SF-based hydrogels fabricated for various biomedical applications.

Applied light (nm), duration (min)

365, variable based on layer type,

strongly interact with biological systems (e.g., proteins and nucleo-

tides) and do not efficiently penetrate tissues, which limit their
in vivo applications such as transdermal induction of polymeriza-
and intensity (W cm
2)

tion. In contrast, NIR light is less harmful to biological systems

UV-light, 10 min, NA

and can interact with tissues deeper, and few molecules directly
320–500, 30, 0.007
UV light, 30, 0.06

UV light, 10, NA

interact with it to generate radicals. Therefore, NIR light-induced

450, 20, 0.0187

365, 15, 0.01

365, 5, 0.005

photo-polymerization is a suitable strategy for forming hydrogels

452, 2, 250

452, 2, 50

in vivo. Moreover, if some improvements achieved in the case of

NIR-light-induced photo-polymerization approach in terms of pho-
0.03

toinitiator system (improving the solubility of photosensitizer and

radical initiator (RI) in a high viscous monomeric substrate) and
light sources, this method can be considered as the first choice
trimethylbenzoyl)phosphine

for the fabrication of hydrogels in the biomedical purposes both

Flavin-mononucleotide

in vivo and in vitro due to its less side effect to the biological
Type of photoinitiator

systems.
Irgacure (I-2959)

Diphenyl-(2,4,6-

Stimuli-responsive natural polymers based-hydrogels can be

Irgacure 2959

Irgacure 2959
Darocur 2959

fabricated using photo-polymerization approach for the develop-

Ru(II) (bpy)

Ru(II) (bpy)

ment of on demand DDSs or other biomedical devices with remote

triggers that will enable the patients with chronic diseases to con-
oxide
LAP

LAP

trol the frequency and dosage of cargo. Fabrication of hydrogel

nanoparticles (define as nanogels) is a relatively new strategy. In
nanocomposite hydrogels

3D-printed SF-methacrylate

Methacrylated SF hydrogel

comparison with bulk hydrogels, the nanosized hydrogels have

SF-methacrylate hydrogel

SF-GelMA IPN hydrogels

numerous advantages, including good internalized into cells to

SF/PVA methacrylate
Am-HA-BPCaP@mSF

MCS/MSF hydrogels

deliver pharmaceutical agents (in the case of DDSs) and excellent

RSF/graphene oxide

cell-matrix interaction (in the case of TE and regenerative medi-

Hydrogel type

cine). The most interesting achievement with photo-

SF hydrogels

hydrogel

hydrogel
SF hydrogel

polymerization technique in recent years is controlled radical

photo-polymerization using ATRP and RFAT polymerization in
Table 7

the synthesis of macromolecules with narrow dispersity, and

well-defined architecture. The physicochemical, as well as biolog-
 H. Samadian et al. / Coordination Chemistry Reviews 420 (2020) 213432
ical properties of hydrogels are strongly dependent on chemical
composition, type and number of functional groups, fabrication
method, molecular weight of each polymeric chain, the rigidity,
as well as intermolecular and intramolecular forces strengths.
Therefore, molecular modeling could be used as a powerful tool
to address some issues before experimental approaches.
The fabrication strategy is undoubtedly the most deterministic
factor for obtaining a hydrogel structure with desired mechanical,
swelling, morphological, chemical, and biological outcomes. Thiol-
ene photo-polymerization approach is advantageous due to its
some features, including, fast process, low or even no oxygen inhi-
bition effect, and producing networks with proper mechanical and
physical properties. However, this technique under-exploited for
the fabrication of natural polymers-based hydrogels. In conclusion,
it seems that the development of efficient photo-polymerization
systems in terms of light sources and photo-initiators is one of
the great forthcoming challenges.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgments
The authors gratefully acknowledge the partial financial sup-
port from Kermanshah University of Medical Sciences, Kerman-
shah, Iran.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.ccr.2020.213432.
References
[1] M. Abbasian, B. Massoumi, R. Mohammad-Rezaei, H. Samadian, M. Jaymand,
Int. J. Biol. Macromol. 134 (2019) 673–694.
[2] M.P. Lutolf, J.A. Hubbell, Nat. Biotechnol. 23 (2005) 47–55.
[3] B. Massoumi, M. Hatamzadeh, N. Firouzi, M. Jaymand, Mater. Sci. Eng., C 98
(2019) 300–310.
[4] L.S. Nair, C.T. Laurencin, Progr. Polym. Sci. (Oxford) 32 (2007) 762–798.
[5] B.D. Ratner, S.J. Bryant, Annu. Rev. Biomed. Eng. (2004) 41–75.
[6] S. Vandghanooni, M. Eskandani, Int. J. Biol. Macromol. (2019).
[7] R. Zhang, M.M. Billingsley, M.J. Mitchell, J. Control. Release 292 (2018) 256–
276.
[8] G. Cheng, Z. Davoudi, X. Xing, X. Yu, X. Cheng, Z. Li, H. Deng, Q. Wang, ACS
Biomater. Sci. Eng. 4 (2018) 2704–2715.
[9] P. Zarrintaj, B. Bakhshandeh, M.R. Saeb, F. Sefat, I. Rezaeian, M.R. Ganjali, S.
Ramakrishna, M. Mozafari, Acta Biomater. 72 (2018) 16–34.
[10] P. Zarrintaj, S. Manouchehri, Z. Ahmadi, M.R. Saeb, A.M. Urbanska, D.L. Kaplan,
M. Mozafari, Carbohydr. Polym. 187 (2018) 66–84.
[11] C. Qi, J. Lin, L.H. Fu, P. Huang, Chem. Soc. Rev. 47 (2018) 357–403.
[12] E.R. Ruskowitz, C.A. Deforest, Nat. Rev. Mater. 3 (2018).
[13] T.R. Hoare, D.S. Kohane, Polymer 49 (2008) 1993–2007.
[14] N. Bhattarai, J. Gunn, M. Zhang, Adv. Drug Deliv. Rev. 62 (2010) 83–99.
[15] Z. Mozaffari, M. Hatamzadeh, B. Massoumi, M. Jaymand, J. Appl. Polym. Sci.
135 (2018).
[16] N. Poorgholy, B. Massoumi, M. Ghorbani, M. Jaymand, H. Hamishehkar, Drug
Dev. Ind. Pharm. 44 (2018) 1254–1261.
[17] D. Stern, H. Cui, Adv. Healthcare Mater. 8 (2019).
[18] B.W. Walker, R. Portillo Lara, E. Mogadam, C. Hsiang Yu, W. Kimball, N.
Annabi, Prog. Polym. Sci. 92 (2019) 135–157.
[19] B. Massoumi, Z. Mozaffari, M. Jaymand, Int. J. Biol. Macromol. 117 (2018)
418–426.
[20] M.L. Gómez, A. Gallastegui, M.B. Spesia, H.A. Montejano, R.J. Williams, C.M.
Previtali, Polym. Adv. Technol. 28 (2017) 435–442.
[21] M.L. Gómez, V. Avila, H.A. Montejano, C.M. Previtali, Polymer 44 (2003) 2875–
2881.
[22] H. Yao, J. Wang, S. Mi, Polymers 10 (2017).
[23] T.E. Brown, K.S. Anseth, Chem. Soc. Rev. 46 (2017) 6532–6552.
[24] C. Fan, D.A. Wang, Tissue Eng. - Part B: Reviews 23 (2017) 451–461.
27
[25] D.A. Gyles, L.D. Castro, J.O.C. Silva Jr., R.M. Ribeiro-Costa, Eur. Polym. J. 88
(2017) 373–392.
[26] B. Xue, V. Kozlovskaya, E. Kharlampieva, J. Mater. Chem. B 5 (2017) 9–35.
[27] D.L. Taylor, M. in het Panhuis, Adv. Mater. 28 (2016) 9060–9093.
[28] L. Voorhaar, R. Hoogenboom, Chem. Soc. Rev. 45 (2016) 4013–4031.
[29] W.S. Toh, X.J. Loh, Mater. Sci. Eng., C 45 (2015) 690–697.
[30] P. Thoniyot, M.J. Tan, A.A. Karim, D.J. Young, X.J. Loh, Adv. Sci. 2 (2015).
[31] Z. Shi, X. Gao, M.W. Ullah, S. Li, Q. Wang, G. Yang, Biomaterials 111 (2016) 40–
54.
[32] X. Xu, A.K. Jha, D.A. Harrington, M.C. Farach-Carson, X. Jia, Soft Matter 8
(2012) 3280–3294.
[33] J.R. Choi, K.W. Yong, J.Y. Choi, A.C. Cowie, Biotechniques 66 (2019) 40–53.
[34] M. Gajendiran, J.S. Rhee, K. Kim, Tissue Eng. - Part B: Rev. 24 (2018) 66–74.
[35] L. Lu, S. Yuan, J. Wang, Y. Shen, S. Deng, L. Xie, Q. Yang, Curr. Stem Cell Res.
Ther. 13 (2018) 490–496.
[36] K. Yue, G. Trujillo-de Santiago, M.M. Alvarez, A. Tamayol, N. Annabi, A.
Khademhosseini, Biomaterials 73 (2015) 254–271.
[37] M.K. Nguyen, E. Alsberg, Prog. Polym. Sci. 39 (2014) 1235–1265.
[38] A.S. Hoffman, Adv. Drug Deliv. Rev. 64 (2012) 18–23.
[39] G.D. Nicodemus, S.J. Bryant, Tissue Eng. - Part B: Rev. 14 (2008) 149–165.
[40] M. Yang, R. Xing, G. Shen, C. Yuan, X. Yan, Colloids Surf., A 572 (2019) 259–
265.
[41] E. Mei, S. Li, J. Song, R. Xing, Z. Li, X. Yan, Colloids Surf., A 577 (2019) 570–575.
[42] X. Ren, Q. Zou, C. Yuan, R. Chang, R. Xing, X. Yan, Angew. Chem. Int. Ed. 58
(2019) 5872–5876.
[43] Y. Zhang, H. Zhang, Q. Zou, R. Xing, T. Jiao, X. Yan, J. Mater. Chem. B 6 (2018)
7335–7342.
[44] R. Xing, S. Li, N. Zhang, G. Shen, H. Möhwald, X. Yan, Biomacromolecules 18
(2017) 3514–3523.
[45] L.B. Xing, S.F. Hou, J. Zhou, S. Li, T. Zhu, Z. Li, W. Si, S. Zhuo, J. Phys. Chem. C
118 (2014) 25924–25930.
[46] P. Matricardi, C. Di Meo, T. Coviello, W.E. Hennink, F. Alhaique, Adv. Drug
Deliv. Rev. 65 (2013) 1172–1187.
[47] T.V.C. McOscar, W.M. Gramlich, Cellulose 25 (2018) 6531–6545.
[48] R.F. Pereira, P.J. Bártolo, J. Appl. Polym. Sci. 132 (2015).
[49] P. Kissel, D.J. Murray, W.J. Wulftange, V.J. Catalano, B.T. King, Nat. Chem. 6
(2014) 774–778.
[50] P. Xiao, J. Zhang, F. Dumur, M.A. Tehfe, F. Morlet-Savary, B. Graff, D. Gigmes, J.
P. Fouassier, J. Lalevée, Prog. Polym. Sci. 41 (2015) 32–66.
[51] M. Straub, M. Gu, Opt. Lett. 27 (2002) 1824–1826.
[52] R. Msaadi, G. Yilmaz, A. Allushi, S. Hamadi, S. Ammar, M.M. Chehimi, Y. Yagci,
Polymers 11 (2019).
[53] C. Dietlin, S. Schweizer, P. Xiao, J. Zhang, F. Morlet-Savary, B. Graff, J.P.
Fouassier, J. Lalevée, Polym. Chem. 6 (2015) 3895–3912.
[54] M. Jaymand, M. Lotfi, M. Abbasian, Mater. Res. Express 5 (2018).
[55] D. Debroy, K.D. Li-Oakey, J. Oakey, Colloids Surf., B 180 (2019) 371–375.
[56] K.A. Smeds, M.W. Grinstaff, J. Biomed. Mater. Res. 54 (2001) 115–121.
[57] B.D. Polizzotti, B.D. Fairbanks, K.S. Anseth, Biomacromolecules 9 (2008)
1084–1087.
[58] R. Censi, T. Vermonden, M.J. van Steenbergen, H. Deschout, K. Braeckmans, S.
C. De Smedt, C.F. van Nostrum, P. di Martino, W.E. Hennink, J. Control. Release
140 (2009) 230–236.
[59] J.D. Cho, H.T. Ju, J.W. Hong, J. Polym. Sci. A: Polym. Chem. 43 (2005) 658–670.
[60] M.K. Darani, S. Bastani, M. Ghahari, P. Kardar, E. Mohajerani, Prog. Org. Coat.
104 (2017) 97–103.
[61] J. Deng, L. Wang, L. Liu, W. Yang, Progr. Polym. Sci. (Oxford) 34 (2009) 156–
193.
[62] A. Saad, I. Bakas, J.Y. Piquemal, S. Nowak, M. Abderrabba, M.M. Chehimi, Appl.
Surf. Sci. 367 (2016) 181–189.
[63] M. Ciftci, M.A. Tasdelen, Y. Yagci, Polym. Int. 65 (2016) 1001–1014.
[64] J. Zhang, P. Xiao, C. Dietlin, D. Campolo, F. Dumur, D. Gigmes, F. Morlet-
Savary, J.P. Fouassier, J. Lalevée, Macromol. Chem. Phys. 217 (2016) 1214–
1227.
[65] N. Zivic, M. Bouzrati-Zerelli, A. Kermagoret, F. Dumur, J.P. Fouassier, D.
Gigmes, J. Lalevée, ChemCatChem 8 (2016) 1617–1631.
[66] J. Shao, Y. Huang, Q. Fan, Polym. Chem. 5 (2014) 4195–4210.
[67] Q. Xiao, Y. Ji, Z. Xiao, Y. Zhang, H. Lin, Q. Wang, Chem. Commun. 49 (2013)
1527–1529.
[68] C. Mendes-Felipe, J. Oliveira, I. Etxebarria, J.L. Vilas-Vilela, S. Lanceros-
Mendez, Adv. Mater. Technol. 4 (2019) 1800618.
[69] A. Gupta, P. Avci, T. Dai, Y.-Y. Huang, M.R. Hamblin, Adv. Wound Care 2 (2013)
422–437.
[70] W. Teshima, Y. Nomura, N. Tanaka, H. Urabe, M. Okazaki, Y. Nahara,
Biomaterials 24 (2003) 2097–2103.
[71] C.-C. Lin, A. Raza, H. Shih, Biomaterials 32 (2011) 9685–9695.
[72] H. Shih, C.C. Lin, Macromol. Rapid Commun. 34 (2013) 269–273.
[73] Z. Chen, W. Sun, H.J. Butt, S. Wu, Chem.–A, Eur. J. 21 (2015) 9165–9170.
[74] Z. Chen, X. Wang, S. Li, S. Liu, H. Miao, S. Wu, ChemPhotoChem 3 (2019)
1077–1083.
[75] H. Samadian, H. Maleki, A. Fathollahi, M. Salehi, S. Gholizadeh, H.
Derakhshankhah, Z. Allahyari, M. Jaymand, Int. J. Biol. Macromol. (2020).
[76] J.N. Etter, M. Karasinski, J. Ware, R.A. Oldinski, J. Mater. Sci. - Mater. Med. 29
(2018) 143.
[77] A. Boddupalli, K.M. Bratlie, Biomater. Sci. 7 (2019) 1188–1199.
[78] E.E. Coates, C.N. Riggin, J.P. Fisher, J. Biomed. Mater. Res. Part A 101 (2013)
1962–1970.
28 H. Samadian et al. / Coordination Chemistry Reviews 420 (2020) 213432
[79] O. Jeon, C. Powell, S.M. Ahmed, E. Alsberg, Tissue Eng. Part A 16 (2010) 2915–
2925.
[80] O. Jeon, K.H. Bouhadir, J.M. Mansour, E. Alsberg, Biomater. 30 (2009) 2724–
2734.
[81] O. Jeon, C. Powell, L.D. Solorio, M.D. Krebs, E. Alsberg, J. Control. Release 154
(2011) 258–266.
[82] S.I. Somo, K. Langert, C.-Y. Yang, M.K. Vaicik, V. Ibarra, A.A. Appel, B. Akar, M.-
H. Cheng, E.M. Brey, Acta Biomater. 65 (2018) 53–65.
[83] D. Lu, C. Xiao, S. Xu, eXPRESS Polym. Lett. 3 (2009) 366–375.
[84] A. Vieira, P. Ferreira, J. Coelho, M. Gil, Int. J. Biol. Macromol. 43 (2008) 325–
332.
[85] I. Van Nieuwenhove, S. Van Vlierberghe, A. Salamon, K. Peters, H. Thienpont,
P. Dubruel, J. Mater. Sci. - Mater. Med. 26 (2015) 104.
[86] N. Mohamad, M.C.I.M. Amin, M. Pandey, N. Ahmad, N.F. Rajab, Carbohydr.
Polym. 114 (2014) 312–320.
[87] S.-P. Lin, H.-N. Kung, Y.-S. Tsai, T.-N. Tseng, K.-D. Hsu, K.-C. Cheng, Cellulose
24 (2017) 4927–4937.
[88] Z. Di, Z. Shi, M.W. Ullah, S. Li, G. Yang, Int. J. Biol. Macromol. 105 (2017) 638–
644.
[89] N. Mohamad, E.Y.X. Loh, M.B. Fauzi, M.H. Ng, M.C.I.M. Amin, Drug Deliv.
Transl. Res. 9 (2019) 444–452.
[90] X. Qiao, X. Peng, J. Qiao, Z. Jiang, B. Han, C. Yang, W. Liu, J. Mater. Sci. - Mater.
Med. 28 (2017) 149.
[91] J. Liu, Y. Xiao, X. Wang, L. Huang, Y. Chen, C. Bao, Int. J. Biol. Macromol. 122
(2019) 19–28.
[92] M. Monier, I. Youssef, D. Abdel-Latif, React. Funct. Polym. 124 (2018) 129–
138.
[93] Y. Zhou, S. Zhao, C. Zhang, K. Liang, J. Li, H. Yang, S. Gu, Z. Bai, D. Ye, W. Xu,
Carbohydr. Polym. 184 (2018) 383–389.
[94] G. Ma, D. Yang, Q. Li, K. Wang, B. Chen, J.F. Kennedy, J. Nie, Carbohydr. Polym.
79 (2010) 620–627.
[95] J. Hu, Y. Hou, H. Park, B. Choi, S. Hou, A. Chung, M. Lee, Acta Biomater. 8 (2012)
1730–1738.
[96] Y. Zhou, G. Ma, S. Shi, D. Yang, J. Nie, Int. J. Biol. Macromol. 48 (2011) 408–413.
[97] C. Xia, P. Chen, S. Mei, L. Ning, C. Lei, J. Wang, J. Zhang, J. Ma, S. Fan, Oncotarget
8 (2017) 2835.
[98] P. Chen, S. Mei, C. Xia, R. Zhu, Y. Pang, J. Wang, J. Zhang, F. Shao, S. Fan,
Oncotarget 8 (2017) 30235.
[99] S. Grenier, P.E. Donnelly, J. Gittens, P.A. Torzilli, J. Biomech. 48 (2015) 122–
129.
[100] P.E. Donnelly, T. Chen, A. Finch, C. Brial, S.A. Maher, P.A. Torzilli, J. Biomater.
Sci. Polym. Ed. 28 (2017) 582–600.
[101] R. Beninatto, C. Barbera, O. De Lucchi, G. Borsato, E. Serena, C. Guarise, M.
Pavan, C. Luni, S. Martewicz, D. Galesso, Mater. Sci. Eng., C 96 (2019) 625–
634.
[102] R.H. Koh, Y. Jin, B.-J. Kang, N.S. Hwang, Acta Biomater. 53 (2017) 318–328.
[103] H. Park, B. Choi, J. Hu, M. Lee, Acta Biomater. 9 (2013) 4779–4786.
[104] C. Chung, J.A. Burdick, Tissue Eng. Part A 15 (2008) 243–254.
[105] W. Xu, J. Qian, Y. Zhang, A. Suo, N. Cui, J. Wang, Y. Yao, H. Wang, Acta
Biomater. 33 (2016) 131–141.
[106] M.D. Brigham, A. Bick, E. Lo, A. Bendali, J.A. Burdick, A. Khademhosseini,
Tissue Eng. Part A 15 (2008) 1645–1653.
[107] G. Pitarresi, F. Palumbo, G. Giammona, M. Casadei, F.M. Moracci, Biomaterials
24 (2003) 4301–4313.
[108] J.-Z. Zhang, C.-S. Xiao, J.-C. Wang, X.-L. Zhuang, X.-S. Chen, Chin. J. Polym. Sci.
31 (2013) 1697–1705.
[109] S. Tanna, M.J. Taylor, T.S. Sahota, K. Sawicka, Biomaterials 27 (2006) 1586–
1597.
[110] S. Tanna, T.S. Sahota, K. Sawicka, M.J. Taylor, Biomaterials 27 (2006) 4498–
4507.
[111] M.K. Nguyen, A. McMillan, C.T. Huynh, D.S. Schapira, E. Alsberg, J. Mater.
Chem. B 5 (2017) 485–495.
[112] K. Nguyen, P.N. Dang, E. Alsberg, Acta Biomater. 9 (2013) 4487–4495.
[113] K. Raemdonck, T.G. Van Thienen, R.E. Vandenbroucke, N.N. Sanders, J.
Demeester, S.C. De Smedt, Adv. Funct. Mater. 18 (2008) 993–1001.
[114] K. Raemdonck, B. Naeye, K. Buyens, R.E. Vandenbroucke, A. Høgset, J.
Demeester, S.C. De Smedt, Adv. Funct. Mater. 19 (2009) 1406–1415.
[115] J.W. Kim, M.J. Kim, C.S. Ki, H.J. Kim, Y.H. Park, Int. J. Biol. Macromol. 105
(2017) 541–548.
[116] E.E. Smith, W. Zhang, N.R. Schiele, A. Khademhosseini, C.K. Kuo, P.C. Yelick, J.
Tissue Eng. Regener. Med. 11 (2017) 3326–3336.
[117] X. Sun, Q. Lang, H. Zhang, L. Cheng, Y. Zhang, G. Pan, X. Zhao, H. Yang, Y.
Zhang, H.A. Santos, Adv. Funct. Mater. 27 (2017) 1604617.
[118] A.M. Magariños, S. Pedron, M. Creixell, M. Kilinc, I. Tabansky, D.W. Pfaff, B.A.
Harley, Front. Mater. 5 (2018) 40.
[119] F.A. Pennacchio, C. Fedele, S. De Martino, S. Cavalli, R. Vecchione, P.A. Netti,
ACS Appl. Mater. Interfaces 10 (2017) 91–97.
[120] C.H. Lin, J.J.M. Su, S.Y. Lee, Y.M. Lin, J. Tissue Eng. Regener. Med. 12 (2018)
2099–2111.
[121] C. Kilic Bektas, V. Hasirci, J. Tissue Eng. Regener. Med. 12 (2018) e1899–
e1910.
[122] L. Tytgat, M. Vagenende, H. Declercq, J. Martins, H. Thienpont, H. Ottevaere, P.
Dubruel, S. Van Vlierberghe, Carbohydr. Polym. 189 (2018) 1–9.
[123] I. Noshadi, S. Hong, K.E. Sullivan, E.S. Sani, R. Portillo-Lara, A. Tamayol, S.R.
Shin, A.E. Gao, W.L. Stoppel, L.D. Black III, Biomater. Sci. 5 (2017) 2093–2105.
[124] L. Shi, F. Wang, W. Zhu, Z. Xu, S. Fuchs, J. Hilborn, L. Zhu, Q. Ma, Y. Wang, X.
Weng, Adv. Funct. Mater. 27 (2017) 1700591.
[125] J.L. Whittaker, N.R. Choudhury, N.K. Dutta, A. Zannettino, J. Mater. Chem. B 2
(2014) 6259–6270.
[126] Y. Zhou, K. Liang, S. Zhao, C. Zhang, J. Li, H. Yang, X. Liu, X. Yin, D. Chen, W. Xu,
Int. J. Biol. Macromol. 108 (2018) 383–390.
[127] W. Xiao, J. Li, X. Qu, L. Wang, Y. Tan, K. Li, H. Li, X. Yue, B. Li, X. Liao, Mater. Sci.
Eng., C 99 (2019) 57–67.
[128] F. Yu, X. Han, K. Zhang, B. Dai, S. Shen, X. Gao, H. Teng, X. Wang, L. Li, H. Ju, J.
Biomed. Mater. Res. Part A 106 (2018) 2944–2954.
[129] K.E. Drzewiecki, J.N. Malavade, I. Ahmed, C.J. Lowe, D.I. Shreiber, Technology
5 (2017) 185–195.
[130] H. Stratesteffen, M. Köpf, F. Kreimendahl, A. Blaeser, S. Jockenhoevel, H.
Fischer, Biofabrication 9 (2017) 045002.
[131] O. Jeon, Y. Lee, T. Hinton, A. Feinberg, E. Alsberg, Mater. Today Chem. 12
(2019) 61–70.
[132] A. Ehterami, M. Salehi, S. Farzamfar, H. Samadian, A. Vaez, H. Sahrapeyma, S.
Ghorbani, Biomed. Eng. Lett. (2020) 1–11.
[133] R. Jahanban-Esfahlan, H. Derakhshankhah, B. Haghshenas, B. Massoumi, M.
Abbasian, M. Jaymand, Int. J. Biol. Macromol. (2020).
[134] J. Maitra, V.K. Shukla, Am. J. Polym. Sci 4 (2014) 25–31.
[135] M. Farokhi, F. Jonidi Shariatzadeh, A. Solouk, H. Mirzadeh, International
Journal of Polymeric Materials and Polymeric Biomaterials, (2019) 1-18.
[136] L. Yuan, Y. Wu, Q.-S. Gu, H. El-Hamshary, M. El-Newehy, X. Mo, Int. J. Biol.
Macromol. 96 (2017) 569–577.
[137] R.R. McCarthy, M.W. Ullah, P. Booth, E. Pei, G. Yang, Biotechnol. Adv. (2019)
107448.
[138] W. Aljohani, M.W. Ullah, X. Zhang, G. Yang, Int. J. Biol. Macromol. 107 (2018)
261–275.
[139] B. Biduski, W.M.F. da Silva, R. Colussi, S.L.d.M. El Halal, L.-T. Lim, Á.R.G. Dias, E.
da Rosa Zavareze, Int. J. Biol. Macromol. 113 (2018) 443–449.
[140] A. Pereira, A. Paulino, A. Rubira, E. Muniz, eXPRESS Polym. Lett. 4 (2010).
[141] L. Szabó, S. Imanishi, F. Tetsuo, M. Nishio, D. Hirose, T. Tsukegi, K. Taki, K.
Ninomiya, K. Takahashi, Compos. A Appl. Sci. Manuf. 121 (2019) 386–396.
[142] S. Sethi, B.S. Kaith, M. Kaur, N. Sharma, S. Khullar, J. Biomater. Sci. Polym. Ed.
30 (2019) 1687–1708.
[143] J. Yang, F. Li, M. Li, S. Zhang, J. Liu, C. Liang, Q. Sun, L. Xiong, Carbohydr. Polym.
173 (2017) 223–232.
[144] H. Sá-Lima, S.G. Caridade, J.F. Mano, R.L. Reis, Soft Matter 6 (2010) 5184–
5195.
[145] T. Hemamalini, V.R.G. Dev, Int. J. Biol. Macromol. 106 (2018) 712–718.
[146] R. Ashraf, H.S. Sofi, A. Malik, M.A. Beigh, R. Hamid, F.A. Sheikh, Appl. Biochem.
Biotechnol. 187 (2019) 47–74.
[147] K. Pal, A. Banthia, D. Majumdar, Trends Biomater. Artif. Organs 20 (2006) 59–
67.
[148] A. Hassan, M.B.K. Niazi, A. Hussain, S. Farrukh, T. Ahmad, J. Polym. Environ. 26
(2018) 235–243.
[149] S. Baghaie, M.T. Khorasani, A. Zarrabi, J. Moshtaghian, J. Biomater. Sci. Polym.
Ed. 28 (2017) 2220–2241.
[150] D. Dong, J. Li, M. Cui, J. Wang, Y. Zhou, L. Luo, Y. Wei, L. Ye, H. Sun, F. Yao, ACS
Appl. Mater. Interfaces 8 (2016) 4442–4455.
[151] S. Piluso, M. Labet, C. Zhou, J.W. Seo, W. Thielemans, J. Patterson,
Biomacromolecules 20 (2019) 3819–3830.
[152] C. Lan, L. Yu, P. Chen, L. Chen, W. Zou, G. Simon, X. Zhang, Macromol. Mater.
Eng. 295 (2010) 1025–1030.
[153] Y. Li, C. Liu, Y. Tan, K. Xu, C. Lu, P. Wang, Carbohydr. Polym. 110 (2014) 87–94.
[154] J. Ngoenkam, A. Faikrua, S. Yasothornsrikul, J. Viyoch, Int. J. Pharm. 391
(2010) 115–124.
[155] M. Jaymand, ACS Biomater. Sci. Eng. (2019).
[156] J. Delville, C. Joly, P. Dole, C. Bliard, Carbohydr. Polym. 53 (2003) 373–381.
[157] J.M. Li, L.M. Zhang, Starch-Stärke 59 (2007) 418–422.
[158] J. Delville, C. Joly, P. Dole, C. Bliard, Carbohydr. Polym. 49 (2002) 71–81.
[159] J. Zhou, Y. Ma, J. Zhang, J. Tong, J. Appl. Polym. Sci. 112 (2009) 99–106.
[160] N. Follain, C. Joly, P. Dole, C. Bliard, Carbohydr. Polym. 60 (2005) 185–192.
[161] C. Chang, L. Zhang, Carbohydr. Polym. 84 (2011) 40–53.
[162] A. Sannino, C. Demitri, M. Madaghiele, Materials 2 (2009) 353–373.
[163] M. Abbasian, M. Bakhshi, M. Jaymand, S.G. Karaj-Abad, J. Elastomers Plast. 51
(2019) 473–489.
[164] S. Khan, M. Ul-Islam, M. Ikram, S.U. Islam, M.W. Ullah, M. Israr, J.H. Jang, S.
Yoon, J.K. Park, Int. J. Biol. Macromol. 117 (2018) 1200–1210.
[165] Y. Kim, M.W. Ullah, M. Ul-Islam, S. Khan, J.H. Jang, J.K. Park, Biochem. Eng. J.
142 (2019) 135–144.
[166] K. Khoshnevisan, H. Maleki, H. Samadian, M. Doostan, M.R. Khorramizadeh,
Int. J. Biol. Macromol. 140 (2019) 1260–1268.
[167] S. Khorshidi, A. Solouk, A. Karkhaneh, H. Mirzadeh, S. Sharifi, S. Mazinani, J.
Appl. Polym. Sci. 133 (2016).
[168] O. Grigoray, H. Wondraczek, E. Heikkilä, P. Fardim, T. Heinze, Carbohydr.
Polym. 111 (2014) 280–287.
[169] J. Fricain, P. Granja, M. Barbosa, B. De Jéso, N. Barthe, C. Baquey, Biomaterials
23 (2002) 971–980.
[170] M. Bhattacharya, M.M. Malinen, P. Lauren, Y.-R. Lou, S.W. Kuisma, L.
Kanninen, M. Lille, A. Corlu, C. GuGuen-Guillouzo, O. Ikkala, J. Control.
Release 164 (2012) 291–298.
[171] S. Khan, M. Ul-Islam, M. Ikram, M.W. Ullah, M. Israr, F. Subhan, Y. Kim, J.H.
Jang, S. Yoon, J.K. Park, RSC Adv. 6 (2016) 110840–110849.
 H. Samadian et al. / Coordination Chemistry Reviews 420 (2020) 213432
[172] M.C.I.M. Amin, N. Ahmad, N. Halib, I. Ahmad, Carbohydr. Polym. 88 (2012)
465–473.
[173] S. Li, A. Jasim, W. Zhao, L. Fu, M. Ullah, Z. Shi, G. Yang, E.S. Mater, Manuf 1
(2018) 41–49.
[174] L. Vlaia, G. Coneac, I. Olariu, V. Vlaia, D. Lupuleasa, Emerging Concepts in
Analysis and Applications of Hydrogels 176 (2016).
[175] H. Tan, K.G. Marra, Materials 3 (2010) 1746–1767.
[176] F. Zhao, D. Yao, R. Guo, L. Deng, A. Dong, J. Zhang, Nanomaterials 5 (2015)
2054–2130.
[177] M.S. Gupta, E.S. Cooper, S.B. Nicoll, Tissue Eng. Part A 17 (2011) 2903–2910.
[178] H.A. Lin, M.S. Gupta, D.M. Varma, M.L. Gilchrist, S.B. Nicoll, J. Biomed. Mater.
Res. Part A 104 (2016) 165–177.
[179] A.T. Reza, S.B. Nicoll, Acta Biomater. 6 (2010) 179–186.
[180] C. Woo, B. Schiewe, G. Wegner, Macromol. Chem. Phys. 207 (2006) 148–159.
[181] S.S. Stalling, S.O. Akintoye, S.B. Nicoll, Acta Biomater. 5 (2009) 1911–1918.
[182] M.R. Hossen, N. Dadoo, D.G. Holomakoff, A. Co, W.M. Gramlich, M.D. Mason,
Polymer 151 (2018) 231–241.
[183] R.A. Wach, H. Mitomo, F. Yoshii, T. Kume, J. Appl. Polym. Sci. 81 (2001) 3030–
3037.
[184] S. Yano, T. Iwase, N. Teramoto, T. Shimasaki, M. Shibata, Carbohydr. Polym.
184 (2018) 418–426.
[185] Y. Yang, X. Liu, Y. Li, Y. Wang, C. Bao, Y. Chen, Q. Lin, L. Zhu, Acta Biomater. 62
(2017) 199–209.
[186] J. Xu, L. Ma, Y. Liu, F. Xu, J. Nie, G. Ma, Int. J. Biol. Macromol. 50 (2012) 438–
443.
[187] A. Ehterami, M. Salehi, S. Farzamfar, H. Samadian, A. Vaez, S. Ghorbani, J. Ai,
H. Sahrapeyma, J. Drug Deliv. Sci. Technol. 51 (2019) 204–213.
[188] P.I. Soares, A.I. Sousa, J.C. Silva, I.M. Ferreira, C.M. Novo, J.P. Borges, Carbohydr.
Polym. 147 (2016) 304–312.
[189] M.A. Pujana, L. Pérez-Álvarez, L.C.C. Iturbe, I. Katime, Carbohydr. Polym. 94
(2013) 836–842.
[190] M. Ul-Islam, F. Subhan, S.U. Islam, S. Khan, N. Shah, S. Manan, M.W. Ullah, G.
Yang, Int. J. Biol. Macromol. 137 (2019) 1050–1059.
[191] X. Li, X. Ji, K. Chen, M.W. Ullah, X. Yuan, Z. Lei, J. Cao, J. Xiao, G. Yang,
Biomaterials science, (2020).
[192] C. Xiao, R. You, Y. Fan, Y. Zhang, Int. J. Biol. Macromol. 85 (2016) 386–390.
[193] M.C. Pella, M.K. Lima-Tenório, E.T. Tenorio-Neto, M.R. Guilherme, E.C. Muniz,
A.F. Rubira, Carbohydr. Polym. 196 (2018) 233–245.
[194] N.A. Peppas, J.Z. Hilt, A. Khademhosseini, R. Langer, Adv. Mater. 18 (2006)
1345–1360.
[195] R.R. Mohamed, M.H.A. Elella, M.W. Sabaa, Int. J. Biol. Macromol. 98 (2017)
302–313.
[196] Z. Qi, J. Xu, Z. Wang, J. Nie, G. Ma, Int. J. Biol. Macromol. 53 (2013) 144–149.
[197] M. Yuan, B. Bi, J. Huang, R. Zhuo, X. Jiang, Carbohydr. Polym. 192 (2018) 10–
18.
[198] Q.G. Zhang, W.W. Hu, A.M. Zhu, Q.L. Liu, RSC Adv. 3 (2013) 1855–1861.
[199] I.S. Cho, M.O. Cho, Z. Li, M. Nurunnabi, S.Y. Park, S.-W. Kang, K.M. Huh,
Carbohydr. Polym. 144 (2016) 59–67.
[200] G. Kogan, L. Šoltés, R. Stern, P. Gemeiner, Biotechnol. Lett. 29 (2007) 17–25.
[201] K.T. Dicker, L.A. Gurski, S. Pradhan-Bhatt, R.L. Witt, M.C. Farach-Carson, X. Jia,
Acta Biomater. 10 (2014) 1558–1570.
[202] S. Tiwari, P. Bahadur, Int. J. Biol. Macromol. (2018).
[203] T. Segura, B.C. Anderson, P.H. Chung, R.E. Webber, K.R. Shull, L.D. Shea,
Biomaterials 26 (2005) 359–371.
[204] G. Pitarresi, P. Pierro, F.S. Palumbo, G. Tripodo, G. Giammona,
Biomacromolecules 7 (2006) 1302–1310.
[205] A. Ramamurthi, I. Vesely, J. Biomed. Mater. Res. A 66 (2003) 317–329.
[206] K.S. Masters, D.N. Shah, G. Walker, L.A. Leinwand, K.S. Anseth, J. Biomed.
Mater. Res. A 71 (2004) 172–180.
[207] J.B. Leach, K.A. Bivens, C.N. Collins, C.E. Schmidt, J. Biomed. Mater. Res. A 70
(2004) 74–82.
[208] J.A. Burdick, G.D. Prestwich, Adv. Mater. 23 (2011) H41–H56.
[209] K. Miyamoto, M. Sasaki, Y. Minamisawa, Y. Kurahashi, H. Kano, S.i. Ishikawa, J.
Biomed. Mater. 70 (2004) 550–559.
[210] C. Loebel, S.E. Szczesny, B.D. Cosgrove, M. Alini, M. Zenobi-Wong, R.L. Mauck,
D. Eglin, Biomacromolecules 18 (2017) 855–864.
[211] J. Yeom, S.H. Bhang, B.-S. Kim, M.S. Seo, E.J. Hwang, I.H. Cho, J.K. Park, S.K.
Hahn, Bioconjug. Chem. 21 (2010) 240–247.
[212] X. Jia, J.A. Burdick, J. Kobler, R.J. Clifton, J.J. Rosowski, S.M. Zeitels, R. Langer,
Macromolecules 37 (2004) 3239–3248.
[213] S.A. Bencherif, A. Srinivasan, F. Horkay, J.O. Hollinger, K. Matyjaszewski, N.R.
Washburn, Biomaterials 29 (2008) 1739–1749.
[214] Y.D. Park, N. Tirelli, J.A. Hubbell, Biomaterials 24 (2003) 893–900.
[215] F.S. Palumbo, G. Pitarresi, C. Fiorica, G. Giammona, Hyaluronic Acid-g-
Copolymers: Synthesis, Properties, and Applications, in: Polysaccharide
Based Graft Copolymers, Springer, 2013, pp. 291-323.
[216] C.E. Schanté, G. Zuber, C. Herlin, T.F. Vandamme, Carbohydr. Polym. 85 (2011)
469–489.
[217] S. Khunmanee, Y. Jeong, H. Park, J. Tissue Eng. 8 (2017).
[218] T.F. Stefanello, B. Couturaud, A. Szarpak-Jankowska, D. Fournier, B. Louage, F.
P. Garcia, C.V. Nakamura, B.G. De Geest, P. Woisel, B. Van Der Sanden,
Nanoscale 9 (2017) 12150–12162.
[219] C. Loebel, N. Broguiere, M. Alini, M. Zenobi-Wong, D. Eglin,
Biomacromolecules 16 (2015) 2624–2630.
[220] T. Bobula, J. Běťák, R. Buffa, M. Moravcová, P. Klein, O. Židek, V. Chadimová, R.
Pospíšil, V. Velebný, Carbohydr. Polym. 125 (2015) 153–160.
29
[221] A.C. Fonseca, M.S. Lima, A.F. Sousa, A.J. Silvestre, J.F. Coelho, A.C. Serra, Polym.
Chem. 10 (2019) 1696–1723.
[222] T. Matsuda, M. Moghaddam, H. Miwa, K. Sakurai, F. Iida, ASAIO J. 38 (1992)
(1992) M154–M157.
[223] Y. Motani, S. Miyauchi, in, Google Patents, 1998.
[224] N. Cui, J. Qian, W. Xu, M. Xu, N. Zhao, T. Liu, H. Wang, Carbohydr. Polym. 136
(2016) 1017–1026.
[225] J. Heo, R.H. Koh, W. Shim, H.D. Kim, H.-G. Yim, N.S. Hwang, Drug Deliv. Transl.
Res. 6 (2016) 148–158.
[226] S. Rother, V.D. Galiazzo, D. Kilian, K.M. Fiebig, J. Becher, S. Moeller, U. Hempel,
M. Schnabelrauch, J. Waltenberger, D. Scharnweber, Macromol. Biosci. 17
(2017) 1700154.
[227] T. Zhang, H. Chen, Y. Zhang, Y. Zan, T. Ni, M. Liu, R. Pei, Colloids Surf., B 174
(2019) 528–535.
[228] H.S. Nam, J. An, D.J. Chung, J.-H. Kim, C.-P. Chung, Macromol. Res. 14 (2006)
530–538.
[229] L. Möller, A. Krause, J. Dahlmann, I. Gruh, A. Kirschning, G. Dräger, Int. J.
Artificial Organs 34 (2011) 93–102.
[230] J.B. Leach, C.E. Schmidt, Biomaterials 26 (2005) 125–135.
[231] A. Ronca, U. D’Amora, M. Raucci, H. Lin, Y. Fan, X. Zhang, L. Ambrosio,
Materials 11 (2018) 2454.
[232] J. Zhu, F. Li, X. Wang, J. Yu, D. Wu, ACS Appl. Mater. Interfaces 10 (2018)
13304–13316.
[233] J.W. Hayami, S.D. Waldman, B.G. Amsden, Eur. Polym. J. 72 (2015) 687–697.
[234] J.L. Ifkovits, J.A. Burdick, Tissue Eng. 13 (2007) 2369–2385.
[235] P. Nonsuwan, A. Matsugami, F. Hayashi, S.-H. Hyon, K. Matsumura,
Carbohydr. Polym. 204 (2019) 131–141.
[236] R. Mehvar, J. Control. Release 69 (2000) 1–25.
[237] S.R. Van Tomme, W.E. Hennink, Expert Rev. Med. Devices 4 (2007) 147–164.
[238] R. Stenekes, H. Talsma, W. Hennink, Biomaterials 22 (2001) 1891–1898.
[239] S.H. Kim, C.Y. Won, C.C. Chu, J. Biomed. Mater. Res. 46 (1999) 160–170.
[240] S. Kim, C. Won, C. Chu, Carbohydr. Polym. 40 (1999) 183–190.
[241] Y. Zhang, C.Y. Won, C.C. Chu, J. Polym. Sci., Part A: Polym. Chem. 37 (1999)
4554–4569.
[242] Y. Zhang, C.Y. Won, C.C. Chu, J. Polym. Sci., Part A: Polym. Chem. 38 (2000)
2392–2404.
[243] G. Pitarresi, M.A. Casadei, D. Mandracchia, P. Paolicelli, F.S. Palumbo, G.
Giammona, J. Control. Release 119 (2007) 328–338.
[244] C.W. Lo, H. Jiang, Polym. Eng. Sci. 50 (2010) 232–239.
[245] F. Corrente, H.M.A. Amara, S. Pacelli, P. Paolicelli, M.A. Casadei, Carbohydr.
Polym. 92 (2013) 1033–1039.
[246] S. Pacelli, P. Paolicelli, M.A. Casadei, Carbohydr. Polym. 126 (2015) 208–214.
[247] T. Wang, X. Mu, H. Li, W. Wu, J. Nie, D. Yang, Carbohydr. Polym. 92 (2013)
1423–1431.
[248] S.-H. Kim, C.-C. Chu, J. Biomater. Appl. 15 (2000) 23–46.
[249] M. Feeney, M. Giannuzzo, P. Paolicelli, M.A. Casadei, Drug Deliv. 14 (2007)
87–93.
[250] P. Matricardi, M. Pontoriero, T. Coviello, M.A. Casadei, F. Alhaique,
Biomacromolecules 9 (2008) 2014–2020.
[251] L. Pescosolido, T. Piro, T. Vermonden, T. Coviello, F. Alhaique, W.E. Hennink, P.
Matricardi, Carbohydr. Polym. 86 (2011) 208–213.
[252] L. Pescosolido, T. Vermonden, J. Malda, R. Censi, W.J. Dhert, F. Alhaique, W.E.
Hennink, P. Matricardi, Acta Biomater. 7 (2011) 1627–1633.
[253] L. Pescosolido, W. Schuurman, J. Malda, P. Matricardi, F. Alhaique, T. Coviello,
P.R. van Weeren, W.J. Dhert, W.E. Hennink, T. Vermonden,
Biomacromolecules 12 (2011) 1831–1838.
[254] X.Z. Zhang, D.Q. Wu, G.M. Sun, C.C. Chu, Macromol. Biosci. 3 (2003) 87–91.
[255] X.-Z. Zhang, G.-M. Sun, D.-Q. Wu, C.-C. Chu, J. Mater. Sci. - Mater. Med. 15
(2004) 865–875.
[256] X. Zhang, D. Wu, C.-C. Chu, Biomaterials 25 (2004) 4719–4730.
[257] G. Sun, C.-C. Chu, Carbohydr. Polym. 65 (2006) 273–287.
[258] R. Yin, K. Wang, J. Han, J. Nie, Carbohydr. Polym. 82 (2010) 412–418.
[259] S.-H. Kim, C.-C. Chu, Fibers Polym. 10 (2009) 14–20.
[260] E.A. Kamoun, H. Menzel, J. Appl. Polym. Sci. 117 (2010) 3128–3138.
[261] K. Szafulera, R.A. Wach, A.K. Olejnik, J.M. Rosiak, P. Ulański, Radiat. Phys.
Chem. 142 (2018) 115–120.
[262] U. Ritz, P. Kögler, I. Höfer, P. Frank, S. Klees, S. Gebhard, C. Brendel, K.
Kaufmann, A. Hofmann, P.M. Rommens, J. Mater. Chem. B 4 (2016) 6552–
6564.
[263] A. Brunsen, U. Ritz, A. Mateescu, I. Höfer, P. Frank, B. Menges, A. Hofmann, P.
Rommens, W. Knoll, U. Jonas, J. Mater. Chem. 22 (2012) 19590–19604.
[264] U. Ritz, M. Eberhardt, A. Klein, P. Frank, H. Götz, A. Hofmann, P. Rommens, U.
Jonas, Gels 4 (2018) 63.
[265] S.H. Kim, C.C. Chu, J. Biomed. Mater. Res. 49 (2000) 517–527.
[266] X. Yu, C. Tang, S. Xiong, Q. Yuan, Z. Gu, Z. Li, Y. Hu, Curr. Org. Chem. 20 (2016)
1797–1812.
[267] H. Samadian, A. Vaez, A. Ehterami, M. Salehi, S. Farzamfar, H. Sahrapeyma, P.
Norouzi, J. Mater. Sci. - Mater. Med. 30 (2019) 107.
[268] B. Sarker, J. Hum, S.N. Nazhat, A.R. Boccaccini, Adv. Healthcare Mater. 4
(2015) 176–194.
[269] K. Lin, D. Zhang, M.H. Macedo, W. Cui, B. Sarmento, G. Shen, Adv. Funct.
Mater. 29 (2019) 1804943.
[270] S. Nagaraj, S. Easwaramoorthi, J.R. Rao, P. Thanikaivelan, Int. J. Biol.
Macromol. 131 (2019) 779–786.
[271] T.U. Nguyen, K.E. Watkins, V. Kishore, Journal of Biomedical Materials
Research Part A, (2019).
30 H. Samadian et al. / Coordination Chemistry Reviews 420 (2020) 213432
[272] K. Yang, J. Sun, Z. Guo, J. Yang, D. Wei, Y. Tan, L. Guo, H. Luo, H. Fan, X. Zhang, J.
Mater. Chem. B 6 (2018) 7543–7555.
[273] F.A. Pennacchio, C. Casale, F. Urciuolo, G. Imparato, R. Vecchione, P.A. Netti,
Biomater. Sci. 6 (2018) 2084–2091.
[274] B. Massoumi, M. Abbasian, B. Khalilzadeh, R. Jahanban-Esfahlan, A. Rezaei, H.
Samadian, H. Derakhshankhah, M. Jaymand, Int. J. Polym. Mater. Polym.
Biomater. (2020) 1–10.
[275] H. Samadian, A. Ehterami, A. Sarrafzadeh, H. Khastar, M. Nikbakht, A. Rezaei,
L. Chegini, M. Salehi, Int. J. Biol. Macromol. 150 (2020) 380–388.
[276] X. Yang, D. Yang, X. Zhu, J. Nie, G. Ma, Eur. Polym. J. 113 (2019) 142–147.
[277] J.-Y. Lai, D.H.-K. Ma, Mater. Sci. Eng., C 72 (2017) 150–159.
[278] T. Greene, T.Y. Lin, O.M. Andrisani, C.C. Lin, J. Appl. Polym. Sci. 134 (2017).
[279] A.J. Berger, K.M. Linsmeier, P.K. Kreeger, K.S. Masters, Biomaterials 141 (2017)
125–135.
[280] I.C. Carvalho, H.S. Mansur, Mater. Sci. Eng., C 78 (2017) 690–705.
[281] M. Ebrahimi, S. Ostrovidov, S. Salehi, S.B. Kim, H. Bae, A. Khademhosseini, J.
Tissue Eng. Regener. Med. 12 (2018) 2151–2163.
[282] S.P. Parthiban, D. Rana, E. Jabbari, N. Benkirane-Jessel, M. Ramalingam, Acta
Biomater. 51 (2017) 330–340.
[283] S. Oktay, N. Alemdar, J. Appl. Polym. Sci. 136 (2019) 46914.
[284] D.B. Kolesky, R.L. Truby, A.S. Gladman, T.A. Busbee, K.A. Homan, J.A. Lewis,
Adv. Mater. 26 (2014) 3124–3130.
[285] Z. Wang, Z. Tian, F. Menard, K. Kim, Biofabrication 9 (2017) 044101.
[286] H. Wang, H. Liu, H. Liu, W. Su, W. Chen, J. Qin, Adv. Mater. Technol. 4 (2019)
1800632.
[287] B.S. Kwak, W. Choi, J.-W. Jeon, J.-I. Won, G.Y. Sung, B. Kim, J.H. Sung, J. Ind.
Eng. Chem. 66 (2018) 254–261.
[288] M.M. Fares, E.S. Sani, R.P. Lara, R.B. Oliveira, A. Khademhosseini, N. Annabi,
Biomater. Sci. 6 (2018) 2938–2950.
[289] H. Suo, D. Zhang, J. Yin, J. Qian, Z.L. Wu, J. Fu, Mater. Sci. Eng., C 92 (2018)
612–620.
[290] P. Ferreira, P. Santos, P. Alves, M.P. Carvalho, K.D. de Sá, S.P. Miguel, I.J.
Correia, P. Coimbra, Eur. Polym. J. 97 (2017) 210–219.
[291] A.R. Donaldson, C.E. Tanase, D. Awuah, P.V. Bathrinarayanan, L. Hall, M.
Nikkhah, A. Khademhosseini, F. Rose, C. Alexander, A.M. Ghaemmaghami,
Front. Bioeng. Biotechnol. 6 (2018).
[292] N. Monteiro, G. Thrivikraman, A. Athirasala, A. Tahayeri, C.M. França, J.L.
Ferracane, L.E. Bertassoni, Dent. Mater. 34 (2018) 389–399.
[293] A.A. Aldana, M.I. Rial-Hermida, G.A. Abraham, A. Concheiro, C. Alvarez-
Lorenzo, Soft Mater. 15 (2017) 341–349.
[294] P. Chen, L. Ning, P. Qiu, J. Mo, S. Mei, C. Xia, J. Zhang, X. Lin, S. Fan, J. Tissue
Eng. Regener. Med. 13 (2019) 682–693.
[295] S. Sivashankar, A.T. Young, P.D. Erb, F.S. Ligler, M.A. Daniele, in: 2017 IEEE
12th International Conference on Nano/Micro Engineered and Molecular
Systems (NEMS), IEEE, 2017, pp. 554-557.
[296] A. Gottipati, L. Chelvarajan, H. Peng, R. Kong, C.F. Cahall, C. Li, H. Tripathi, A.
Al-Darraji, S. Ye, E. Elsawalhy, Stem Cell Rev. Rep. 15 (2019) 404–414.
[297] M.T. Ngo, B.A. Harley, Adv. Healthcare Mater. 6 (2017) 1700687.
[298] A. Blocki, F. Löper, N. Chirico, A.T. Neffe, F. Jung, C. Stamm, A. Lendlein, Clin.
Hemorheol. Microcirc. 67 (2017) 251–259.
[299] J.G. Hardy, L.M. Römer, T.R. Scheibel, Polymer 49 (2008) 4309–4327.
[300] C. Vepari, D.L. Kaplan, Prog. Polym. Sci. 32 (2007) 991–1007.
[301] R. Valluzzi, S. Winkler, D. Wilson, D.L. Kaplan, Philos. Trans. Royal Soc. London
Series B: Biol. Sci. 357 (2002) 165–167.
[302] S. Inoue, K. Tanaka, F. Arisaka, S. Kimura, K. Ohtomo, S. Mizuno, J. Biol. Chem.
275 (2000) 40517–40528.
[303] W. Liu, Z. Zhou, S. Zhang, Z. Shi, J. Tabarini, W. Lee, Y. Zhang, S. Gilbert Corder,
X. Li, F. Dong, Adv. Sci. 4 (2017) 1700191.
[304] L.-D. Koh, Y. Cheng, C.-P. Teng, Y.-W. Khin, X.-J. Loh, S.-Y. Tee, M. Low, E. Ye,
H.-D. Yu, Y.-W. Zhang, Prog. Polym. Sci. 46 (2015) 86–110.
[305] B. Kundu, N.E. Kurland, S. Bano, C. Patra, F.B. Engel, V.K. Yadavalli, S.C. Kundu,
Prog. Polym. Sci. 39 (2014) 251–267.
[306] B. Kundu, R. Rajkhowa, S.C. Kundu, X. Wang, Adv. Drug Deliv. Rev. 65 (2013)
457–470.
[307] Q. Liu, H. Liu, Y. Fan, Microsc. Res. Tech. 80 (2017) 312–320.
[308] S. Kapoor, S.C. Kundu, Acta Biomater. 31 (2016) 17–32.
[309] A. Matsumoto, J. Chen, A.L. Collette, U.-J. Kim, G.H. Altman, P. Cebe, D.L.
Kaplan, J. Phys. Chem. B 110 (2006) 21630–21638.
[310] H. Kim, J. Kim, J. Choi, Y. Park, C. Ki, Polymer 153 (2018) 232–240.
[311] P.H.G. Chao, S. Yodmuang, X. Wang, L. Sun, D.L. Kaplan, G. Vunjak-Novakovic,
J. Biomed. Mater. Res. B: Appl. Biomater. 95 (2010) 84–90.
[312] K. Schacht, T. Scheibel, Biomacromolecules 12 (2011) 2488–2495.
[313] J.L. Whittaker, N.K. Dutta, A. Zannettino, N.R. Choudhury, J. Mater. Chem. B 4
(2016) 5519–5533.
[314] J. Whittaker, N. Dutta, C. Elvin, N. Choudhury, J. Mater. Chem. B 3 (2015)
6576–6579.
[315] J.L. Whittaker, R. Balu, R. Knott, L. de Campo, J.P. Mata, C. Rehm, A.J. Hill, N.K.
Dutta, N.R. Choudhury, Int. J. Biol. Macromol. 114 (2018) 998–1007.
[316] M.B. Applegate, B.P. Partlow, J. Coburn, B. Marelli, C. Pirie, R. Pineda, D.L.
Kaplan, F.G. Omenetto, Adv. Mater. 28 (2016) 2417–2420.
[317] R. Balu, S. Reeder, R. Knott, J. Mata, L. de Campo, N.K. Dutta, N.R. Choudhury,
Langmuir 34 (2018) 9238–9251.
[318] I.V. Bessonov, Y.A. Rochev, A.Y. Arkhipova, M.N. Kopitsyna, D.V. Bagrov, E.A.
Karpushkin, T.N. Bibikova, A.M. Moysenovich, A.S. Soldatenko, I.I. Nikishin,
Biomed. Mater. 14 (2019) 034102.
[319] S.H. Kim, Y.K. Yeon, J.M. Lee, J.R. Chao, Y.J. Lee, Y.B. Seo, M.T. Sultan, O.J. Lee, J.
S. Lee, S.-I. Yoon, Nat. Commun. 9 (2018) 1620.
[320] J. Kundu, L.A. Poole-Warren, P. Martens, S.C. Kundu, Acta Biomater. 8 (2012)
1720–1729.