Coordination Chemistry Reviews: Hadi Samadian, Hassan Maleki, Zahra Allahyari, Mehdi Jaymand

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

(ECM) environment of the host in the case of soft tissues. There-
Demand for biomaterials has grown continuously during the fore, hydrogels are extensively used in various areas of regenera-
last decade and several new strategies for developing more effi- tive medicine and TE (the mentioned concepts are referred to
cient biomaterials have been developed. This intense interest orig- regeneration or replacement of failed tissue/organ, respectively)
inated from their wide range of applications in the healthcare and [17–19]. This types of biomaterials can be fabricated through var-
medical industries including, wound healing therapies, plastic ious approaches, including ester or amide formation, radical poly-
surgeries, regenerative medicine, orthopedic disorders, diagnoses, merization, Michael addition, ‘‘Schiff-base”, and disulfide
implantable devices, tissue engineering (TE), and drug delivery crosslinking [13,17,19]. Amongst, the light-induced radical poly-
systems (DDSs) [1–6]. A biomaterial should possess general merization (known as photo-polymerization) for the fabrication
biological features such as non-toxicity, non-carcinogenicity, of natural polymers-based hydrogels has been received consider-
non-allergenicity, non-inflammatory, biocompatibility, and able interest due to its some advantages over other aforemen-
biodegradability in the case of in vivo applications [7,8]. Generally, tioned approaches [20–22].
biomaterials are divided into metallic (used in orthopedics and den- According to the above-mentioned facts, the naturally occurring
tal applications), ceramic and glasses (used in dental restorations polymers-based hydrogels have huge potential to translate into
and bone repair), polymeric, and composite classes [9,10]. Accord- clinical applications in the near future. Therefore, in this review,
ing to the consensus in the field, the most important issues that we focus on natural polymers-based light-induced hydrogels as
should be addressed in the case of any biomaterial are as follows: promising biomaterials for medical applications. To the best of
our knowledge, numerous reviews are available regarding the
a) Relationships between the molecular structures, physico- introduction and fundamentals of hydrogels as well as their vari-
chemical as well as biological features of biomaterial ous application fields. However, this is the first up-to-date compre-
b) Effect of interfacial interactions between biological systems hensive overview on the recent developments in the fabrication as
and biomaterial on its function well as biomedical applications of natural polymers-based light-
c) Controlled conversion of biomacromolecules into a hierar- induced hydrogels. Furthermore, the fundamentals of hydrogels
chical structure and natural polymers and various fabrication methodologies are
d) Engineering of biomaterials for stimulating specific cellular also briefly highlighted.
response
e) Tuning of cell/tissue bioadhesive property
2. Hydrogels
It should be pointed out that the recent advances in materials
science (e.g., new synthetic and semi-synthetic strategies), as well Hydrogel is a three-dimensional (3D) crosslinked network that
as the advent of nanotechnology, can address some of the above- can imbibe large quantities of water or any other biological fluid
mentioned issues [5,9,11]. with maintaining owns 3D architecture, mainly due to the pres-
Among the biomaterials, a great deal of research activities has ence of hydrophilic moieties (e.g., carboxyl, hydroxyl, ether, and
attempted to develop polymeric biomaterials mainly due to their amino groups) in its polymeric backbone [23–25]. As known,
abundances and superior physicochemical, as well as biological, hydrogels are swollen and distended due to the absorbing of any
features that capable of addressing most of the above-mentioned fluid and become soft and rubbery, which leads to low interfacial
issues. The most important advantages of polymeric biomaterials tension with water and other biological fluids. Another advantage
are biocompatibility, sterilizability, adequate mechanical and of swollen is reducing mechanical friction between tissues and
physical properties, excellent processability in most cases, and implanted hydrogel mainly due to its elastomeric consistency in
manufacturability [1–4]. These types of biomaterials are divided the case of in vivo purposes [26,27].
into three main categories known as synthetic, semi-synthetic, Hydrogels can be categorized into various classes based on
and natural polymers [1,2]. However, numerous drawbacks have polymeric composition (homo-polymeric, co-polymeric or multi-
limited their applications in biomedical fields. The most important polymeric), source (natural, synthetic or hybrid), crosslinking
drawbacks, as well as the modification strategies, of natural and (chemical, physical, and enzymatic), configuration (crystalline,
synthetic polymeric biomaterials have been described in our previ- semi-crystalline or amorphous), physical appearance (matrix, film
ous work [1]. In brief, naturally occurring polymeric biomaterials or microsphere), and network electric charge (ionic, neutral,
do not typically offer the cytotoxicity issues in comparison with amphoteric electrolyte or zwitterionic) [28–30]. The physicochem-
synthetic polymers. Besides, they have specific protein binding ical, as well as biological properties of a hydrogel, strongly depend
sites as well as other biochemical signals that play pivotal roles on the chemical composition, type and number of functional
in many biomedical processes [1,12]. groups, fabrication method, molecular weight of each polymeric
Among the various type of polymer-based biomaterials, consid- chain, the rigidity, and intermolecular and intramolecular forces
erable efforts are being made to develop hydrogels mainly due to strengths [13,27].
their inherent physicochemical, as well as biological features From the source’s point-of-view, the natural hydrogels have
[13–16], which will be described extensively in the corresponding some superior physicochemical as well as biological features over
H. Samadian et al. / Coordination Chemistry Reviews 420 (2020) 213432 3
synthetic hydrogels. The most important advantages of natural these types of hydrogels have higher absorbance potential and
hydrogels are low immunogenicity, excellent biocompatibility mechanical strength [37,39,45].
and cytocompatibility, biodegradability, specific cellular/tissue Among the above-mentioned approaches, radical polymeriza-
response (due to functional groups within their structures), anti- tion can be achieved using both conventional free radical polymer-
genicity, adequate stability, superior structural design, variable/- ization and photo-polymerization reactions through external
controllable solubility, and 3D geometry [31,32]. However, the radiation sources such as near-infrared (NIR), visible light, and
most important drawbacks of these hydrogels are difficult to con- ultraviolet (UV) in the presence of a photoinitiator [45–47]. The
trol reproducibly due to their natural origin, weak mechanical fundamentals and challenges of this polymerization approach
properties (in most cases), poor processability (e.g., cellulose and toward the fabrication of hydrogels are discussed in the following
chitosan), source limitations as well as high production costs in section.
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]. 4. Photo-polymerization: fundamentals, current status,
In contrast, synthetic hydrogels can be produced in a large scale challenges, and recent progress
with low costs, more reproducible, more flexibility for tuning the
chemical composition and mechanical properties, and tuning capa- Photo-polymerization is a versatile and powerful tool for the
bility to be hydrolyzed or biodegrade over variable periods. Despite rapid fabrication of a hydrogel. In this strategy, the spatiotemporal
these advantages, the main concern regarding the synthetic hydro- formation of the hydrogel and its network features such as the
gels is their biological aspects (e.g., biocompatibility and crosslinking density and matrix stiffness can be controlled using
biodegradability), because each foreign material without proper light intensity, exposure time, and the illuminated area. The con-
biological aspects is inherently thrombogenic in vivo. The main ventional photo-polymerization method is based on the chain-
reason for this phenomenon is the denaturation of proteins, prop- growth mechanism. The most important drawbacks of this
agation of thrombi, activation of coagulation factors, provocation approach are lack of control over the crosslinking kinetics, oxygen
of inflammatory responses, and accumulation of debris [1,33,34]. inhibition, and the generation of heterogeneities within the hydro-
In general, hydrogels can be applied in various fields, including gel network, which significantly affect the mechanical integrity
agriculture, hygienic products, food additives, sensing, separation, and swelling behavior of the resultant hydrogel [48–50].
as well as biomedical applications (e.g., DDSs, TE, wound dressing, The oxygen inhibition is one of the most important drawbacks
and diagnostics) [13,20,24,33,34]. Among the wide verity of appli- of this approach due to the production of peroxy radicals and the
cations, this review highlights the biomedical purposes of light- significant contribution of these radicals to the polymerization
induced natural polymers-based hydrogels. reaction that reduces both polymerization rate and final conver-
sion ratio, which lead to the production of undesirable and highly
viscous substances [51,52].
3. Synthetic strategies The emergence of ‘‘thiol-ene” reaction circumvents some of the
above-mentioned problems mainly due to its step-growth mecha-
Hydrogels can be synthesized through in situ crosslinking or nism. This strategy can produce structurally uniform hydrogels
post-crosslinking approaches. In situ crosslinking can be achieved with minimal network defects. Despite this, the main drawback
through two main strategies of physical and chemical crosslinking of this strategy is poor shelf-life that makes it difficult to provide
methods. This approach involves the polymerization and simulta- room temperature stable one-component systems [53,54].
neous crosslinking of multifunctional monomer(s) or mono- In general, photo-polymerization is divided into three main cat-
functional monomer(s) in the presence of bi-functional or multi- egories known as free radical photo-polymerization (FRP), cationic
functional crosslinking agents [35–37]. In contrast, the post- photo-polymerization (CP), and hybrid initiating system (FRCP). It
crosslinking approach involves two or more phases, including the should be pointed out that the FRP is the most common approach
synthesis of a polymer chain with reactive functional groups in in this category of polymerization technique [22,50]. In general,
its backbone followed by reticulation using specific crosslinking three different systems can be designed toward the synthesis of
agents [37–39]. hydrogels using a photo-polymerization approach as follows:
Generally, in physical hydrogels ionic interactions, hydrogen
bonding, hydrophobic forces, host–guest interactions, as well as a) Use of hydrophilic reactive monomers and bi-functional
combinations of these plays the main role in forming the network. crosslinkers
These types of hydrogels are often reversible and may be dissolved b) Use of polyfunctional cross-linkers with or without reactive
through the change in environmental conditions such as ionic monomers
strength, pH, and temperature [40–44]. c) Use of non-functionalized polymer chains [55–57].
In contrast, chemical hydrogels are more stable and polymeric
chains are joining through covalent bonds. Some synthetic This type of polymerization allows rapid network formation
approaches, including ester or amide formation, radical polymer- under physiological conditions, with efficient temporal and spatial
ization, Michael addition, ‘‘Schiff-base”, and disulfide crosslinking control. Other advantages of this approach are solvent-free,
have used for the synthesis chemical hydrogels. Additionally, ‘‘click energy-efficient, fast process (taking usually only seconds to min-
chemistry”, and ‘‘native chemical ligation” approaches are intro- utes), spatial and temporal control, and economical. In addition,
duced as efficient and novel strategies mainly due to their ease due to the irradiation capacity of various types of light (UV, visible
of use and high conversion. or NIR), this approach can be applied for the preparation of in situ
Another synthetic strategy that may be achieved using the gelling viscoelastic systems in vivo with a minimally invasive man-
above-mentioned approaches is Interpenetrating (IPNs) or Semi- ner [57,58].
Interpenetrating Networks (Semi-IPNs). In these approaches, a In general, photo-polymerization is initiated through the
pre-polymerized hydrogel is placed into a solution of monomers decomposition of the photoinitiator upon exposure to light (UV,
and a polymerization initiator with (IPNs) or without (Semi-IPNs) visible or NIR) with suitable wavelength, leading to the generation
crosslinking agent. In comparison with homo-polymeric hydrogels, of radicals. Afterward, a hydrogel can be fabricated through one of
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]. trast, LAP has good absorption at both 365 and 405 nm light, and
low cytotoxicity [61].
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 4.2. Visible-light-induced photo-polymerization
and poor solubility of the UV-light-sensitive photoinitiators are
the most important drawbacks of this method. In this context, 1- This type of photo-polymerization is proposed in the 1970s and
[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1-propane-1- then extensively employed for curing dental composites [20,63].
one (Irgacure 2959), lithium (phenyl-2,4,6-trimethylbenzoylpho The photoinitiator systems for visible-light-induced photo-
sphinate) (LAP), and 2,2-azobis[2-methyl-N-(2-hydroxyethyl) polymerization are classified into three main categories known
propionamide]) (VA-086) are the most popular water-soluble type as free radical initiating, ionic initiating and hybrid initiating sys-
I initiators for the fabrication of cell encapsulated hydrogels mainly tems. Among these approaches, the free radical initiating systems
due to their superior initiation efficiency as well as cytocompatibil- are the most commonly used approach. In this type of photo-
ity. However, low absorption at wavelengths > 370 nm is the main induced polymerization method, the most popular light sources
drawback of Irgacure 2959 that leads to long cure times. In con- are as follows:
a) Laser diodes with the light intensity of 100 mWcm2 at 457, ing systems have been extensively discussed recently [50,65,66].
473, 532, and 635 nm The chemical structures of the most commonly used visible-
b) Laser diode with the light intensity of 2–10 mWcm2 at light-sensitive photoinitiators are shown in Scheme 3.
405 nm
c) Halogen lamp with the light intensity of 12 mWcm2
d) Light-emitting diode (LEDs) with the light intensity of 10 4.3. NIR-light-induced photo-polymerization
mWcm2 at 462, 514, 591, and 630 nm [50,63].
Generally, in the NIR-initiated photo-polymerization the pho-
Among the numerous photoinitiator systems, metal-based (e.g., toinitiator system involves a cyanine as photosensitizer (Sens)
copper, zinc, germanium, ruthenium or iridium) photoinitiators and an iodonium salt as a radical initiator. It is an indisputable fact
have received a great deal of interest mainly due to excited-state that the NIR-initiated photo-polymerization has not received sig-
visible light absorptions and high excited-state energy levels nificant attention due to poor solubility of Sens and radical initiator
and/or lower oxidation potentials. However, this type of photoini- (RI) in a high viscous monomeric substrate. The most commonly
tiator system is expensive [64]. In this context, incorporation of used light sources in the NIR-light-induced photo-polymerization
organic dyes (any molecule that absorb light between 380 and approach are NIR laser with emission at either 808 or 830 nm as
700 nm wavelength) can be considered as an alternative candidate well as NIR LEDs with emission at 750, 790, 850, and 940 nm.
mainly due to their cost benefits and commercial availability, The chemical structures of the most commonly used NIR sensitiz-
proper biocompatibility, good stability, and solubility, as well as ers are shown in Scheme 4. In comparison with visible-light-
easier extractability [50]. Amongst these organic dyes, cam- induced photo-polymerization and especially UV-initiated
phorquinone, benzophenone, anthraquinone, pyrene, carbazole, approaches the NIR-initiated photo-polymerization has very low
and thioxanthone derivatives are the most important and widely harmful side effects on the cells/tissues that discussed in the next
used members. The developed visible-light-sensitive photoinitiat- 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.
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 chemical properties thanks to controlling over the spatiotemporal
formation and network features of the hydrogels [33,48,50].
The naturally occurring polymers-based hydrogels have Photo-crosslinked alginate-based hydrogels were engineered to
emerged immense potential in dealing with a range of multifarious produce tunable constructs for TE and other regenerative medicine
biomedical problems/applications, specially intended for thera- applications [76–82]. Many of the features required for these appli-
peutics agent delivery, wound healing/dressing, cell encapsulation cations are provided by these structures such as tunable biodegra-
and TE [6,75]. Such structures have got attention due to their dation rate and mechanical properties with controlled cell
inherent physicochemical and biological properties, the mentioned adhesivity for encapsulation and delivery of cells and bioactive
special benefits of hydrogels, versatile fabrication approaches and growth factors. However, in order to achieve appropriate stability,
so on [23,25,31,35,38]. In particular, photo-crosslinkable hydrogels alginate has been modified that it seems to be necessary. Photo-
are developed as exclusive constructs with tunable mechanical and crosslinked starch-based hydrogels have not developed enough
possibility due to its undesirable characteristics [83]. The 2- 5.1. Polysaccharide-based photo-polymerizable hydrogels
isocyanatoethyl methacrylate-modified starch was developed to
ophthalmic applications as a sustained DDS [84]. Moreover, the 5.1.1. Alginate
starch-based IPN hydrogel systems modified with methacrylic Alginate is an important member of polysaccharide-based
and pentenoic anhydride for stem cell engineering was fabricated biopolymers and widely used in industry as well as medicine. It
to support the adhesion and the proliferation of adipose-derived is an anionic biopolymer with the linear structure composed of
mesenchymal stem cells (AdMSCs) [85]. b-(1 ? 4)-linked D-mannuronic acid (M) and a-(1 ? 4)-linked L-
The most use of photo-crosslinked cellulose-based hydrogels guluronic acid (G) residues. It is typically extracted from brown
was seen in the field of wound healing/dressing. The studies sug- seaweed cell walls [132]. The industrial applications of alginate
gested this type of hydrogels is a promising material that can be are due to its high water retention capacity, the viscosifying fea-
applicable to heal wound injuries [86,87]. Also, the hydrogels could ture, gelling form, relatively low cost, and stabilizing activity.
be incorporated with Ag nanoparticles (NPs) intended for preven- Whereas, the biocompatibility, good scaffold-forming property,
tion of microbial infection [88], as well as could be incorporated mild gelation condition, biodegradability, along with the above-
with epithelial cells intended for wound healing acceleration by mentioned properties, have been mad alginate as a fascinating
promoting neovascularization, re-epithelialization, and prolifera- biomaterial in various biomedical fields. Different forms of
tion of fibroblasts [89]. Photo-crosslinked chitosan-based hydro- alginate-based biomaterials such as micro/nanofibers, film, and
gels have been more used for TE and therapeutics delivery. These hydrogel have been fabricated and employed in biomedical
structures have shown high potential as drug delivery devices for applications. The swollen feature and the structural similarity of
ocular diseases [90], periodontal antibacterial agents [91] and alginate hydrogels to ECM of living tissues introduce them as the
enzyme proteins [92]. In addition, they have been designed to pro- promising biomaterials for drug delivery, wound healing, cell ther-
mote cell attachment and proliferation and employed as hydrogel apy, and TE applications [133]. Different crosslinking approaches
matrices for bone and cartilage TE [93–96]. are available for the preparation of alginate-based hydrogels,
Among the photo-crosslinked hydrogels, hyaluronic acid (HA)- which generally categorized into physical and chemical methods.
based hydrogels have most widely used to create more desirable The chemical crosslinking produces more stable hydrogels than
structures for TE applications. Since HA is a native component of physical approaches. Hence, various chemical crosslinking tech-
cartilage, HA-based hydrogels have been mostly applied for pro- niques such as radical polymerization, enzymatic crosslinking,
motion of chondrogenesis and cartilage regeneration or repair and chemical reactions between complemented groups have been
[97–104]. Besides, HA-based hydrogels have been constructed to developed to alleviate the poor mechanical properties of physically
provide a 3D cell culture or microenvironment to fibroblasts crosslinked alginate-based hydrogels [134,135].
and tumor cell encapsulation [105,106]. Photo-crosslinked For the first time, Jeon et al. have fabricated the methacrylate
dextran-based hydrogels have presented great potential for effec- alginate to produce photo-crosslinked biodegradable alginate,
tive delivery of various therapeutic agents. The studies indicated and modulated the swelling ratio, degradation rate, and elastic
chemical drugs such as theophylline [107] and vancomycin moduli for cell encapsulation application. They also reported that
[108], and also protein components such as insulin [109,110] the concentration of alginate methacrylate adjusted the physical
could be reserved in the hydrogels and released in controlled properties [80]. In another study, Jeon et al. proposed that photo-
and self-regulated manner. Moreover, siRNAs can be entrapped crosslinking technique is beneficial for in situ crosslinking and fill-
in the dextran hydrogels to achieve localized and time- ing the irregular-shaped defects in a minimally invasive manner.
controlled release profile [111–114]. They fabricated heparin incorporated photo-crosslinked methacry-
Polypeptide-based photo-polymerizable hydrogels have used late alginate as a carrier for delivery of the growth factors (bone
less than polysaccharide-based hydrogels for biomedical applica- morphogenetic protein-2 (BMP-2) and vascular endothelial growth
tions. Among them, gelatin-based hydrogels mostly utilized for factor (VEGF)) and scaffold for bone TE [81]. They reported that the
designing innovative 3D biomimetic structures and applying them fabricated carrier provided a sustained and controlled delivery pro-
for cell encapsulation and TE. It was able to provide the microenvi- file without any burst effect. In addition to the in vitro studies, the
ronment and scaffolds for stem/progenitor/endothelial cells encap- in vivo evaluation of the osteogenesis potential of the fabricated
sulation, confinement, differentiation and proliferation, intended hydrogels confirmed by the new bone formation and calcium con-
for skin flap regeneration, tooth regeneration and neural TE tent assessments. In another successful study, E. Coates et al. fab-
[115–120]. Furthermore, several types of cells, including kerato- ricated HA incorporated photo-crosslinked alginate as the
cytes, adipose stem cells, and mesenchymal stem cells have been scaffold for mesenchymal stem cell (MSCs) differentiation and
loaded into photo-polymerizable gelatin-based hydrogels used to delivery. They observed that the fabricated hydrogel provided a
treat corneal blindness [121], adipose TE [122] and cardiac regen- suitable 3D microenvironment for MSCs viability and also, the
eration [123], which visualize a significant potential of such con- incorporation of HA induced the chondrogenic differentiation.
structs. Also, the photo-polymerizable hydrogels based on silk Moreover, proteins and genes related to the chondrogenic pheno-
fibroin have been developed as a promising biomaterial with type were enhanced during the study [78].
regard to TE applications for bone [124], cartilage [125,126] and Yuan et al. synthesized a double crosslinked network hydrogel
load-bearing soft tissues [127]. from aldehyde methacrylate sodium alginate (AMSA) and
Recently, cell-laden hydrogel (bioink) bioprinting provides a ethylenediamine modified gelatin (AG). The AMSA was synthe-
powerful tool that allows precise fabrication of customized and sized via a two-step process: oxidization to form an aldehyde
biomimetic 3D tissue constructs. In this context, photo- sodium alginate, and then functionalization with methacrylate
polymerizable hydrogels based on collagen, gelatin, and alginate groups. In the next step, AG was added to the AMSA and the pri-
have been used for 3D bioprinting that exhibited favorable mary network was formed through the reaction between amino
biological and rheological properties [128–131]. Thus, photo- groups in AG and aldehyde groups in AMSA via the ‘‘Schiff-base”
polymerizable hydrogels would be ideal building blocks to reaction. The hydrogel stricture with the double crosslinked net-
fabricate 3D printed cell-laden hydrogel constructs to forming work was formed through the radical reaction of methacrylate
complicated tissue constructs for TE and regenerative medicine groups in AMSA initiated by a 365 nm UV light. The results demon-
applications. strated that the double crosslinked hydrogels were stronger than
single ‘‘Schiff-base” networks hydrogels and exhibited controllable responsive, which swelled the most at the pH 9 condition com-
degradation rate, biocompatibility, and improved mechanical pared with the acidic conditions. The authors proposed that, since
properties [136]. In a similar study, Somo et al. [82] fabricated 2- chronic wound has an alkaline environment the prepared hydro-
aminoethyl methacrylate hydrochloride (AEMA)-modified alginate gels are beneficial for the drug delivery due to their excellent swel-
to fabricate dual crosslinked hydrogel. They reported that the UV ling at alkaline conditions.
crosslinked (dual crosslinked) alginate was more stable than the Visible light cross-linkable alginate hydrogels are more cell-
ionic crosslinked one. Jeon et al. covalently conjugated methacry- compatible than UV light ones and can circumvent the possible
lated alginate with RGD motif (Arg-Gly-Asp amino acid sequence) damage induced by UV light. Etter et al. [76] fabricated b-
to fabricated cell adhesive photo-crosslinkable hydrogel. They cyclodextrin (b-CD) conjugated methacrylated alginate hydrogel
reported that the conjugation had no adverse effects on the as the carrier for MSCs. They also utilized custom microfluidic
mechanical properties such as elastic moduli, degradation profiles, devices (MFDs) to optimize the fabrication process and adjust both
and swelling ratios. While the conjugation improved the chondro- the mechanical properties and size of the microspheres. They con-
genic differentiated function and the proliferation revealed by DNA jugated b-CD using a multistep process based on carbodiimide
content and glycosaminoglycans production assessments. They chemistry. They reported that the combination of alginate hydro-
proposed that the fabricated hydrogel is effective for insoluble gel crosslinking with proper MFDs provides additional options to
(e.g., cell adhesion ligands) and soluble (e.g., growth factors) factors control the desired properties such as size and mechanical fea-
delivery [79]. tures. They observed that increasing the continuous flow resulted
The in situ polymerization systems are highly applicable for in smaller droplets while increasing dispersion flow produced big-
suture-less closure of wounds and TE. The photo-polymerizable ger droplets. This study implied that MFDs provide the possibility
hydrogels can seal wounds, which are located at sites not easily to tune the size and mechanical properties of photo-crosslinked
accessible, for instance, the wounds of eye, lung, and ear. More- alginate to effectively encapsulate various cells to different
over, further manipulation of the formed hydrogel is alleviated biomedical applications.
since theses hydrogels conform to complex shapes and sizes
in vivo. In this regard, Smeds et al. fabricated methacrylated algi- 5.1.2. Starch
nate hydrogel through UV or visible photolysis as the corneal Starch is an inexpensive hydrophilic, biocompatible, and
wound sealant. They reported that the mechanical properties biodegradable polysaccharide composed of linear amylose and
(swelling, compression, and creep compliance) depend on the branched amylopectin segments [84,139–141]. It has been exten-
degree of methacrylate modification and the fabricated hydrogel sively used for a variety of biomedical purposes, including con-
is suitable for sutureless ophthalmic surgical procedures [56]. It trolled drug delivery [84,142,143], tissue regeneration [144–146],
was found thet the combination of light-crosslinking chemistry wound dressing [147–149], and cell encapsulation [150,151]. How-
with the bioprinting concept improved the stability of the pro- ever, there are some limitations such as low mechanical properties
duced structures [137,138]. Innovatively, Yu et al. combined the and the difficulty in obtaining homogenous solutions that have sig-
UV-crosslinking chemistry with a 3D printing fabrication tech- nificantly lowered the popularity of starch for various biomedical
nique. They modified alginate with poly(ethylene glycol) diacrylate applications [83]. Due to these undesirable properties, polymeric
(PEGDA) and poly(vinyl alcohol) (PVA) to improve the molding blends involving starch, matrix reinforcements as well as physical
properties and cytocompatibility of the resultant hydrogel. The and chemical modifications have been proposed and implemented
modified hydrogel was processed to a 3D scaffold by a bioprinter to compensate for the pitfalls, while also taking advantage of desir-
equipped with four longwave (365 nm) UV lamps to provide able aspects of this material [83,152].
in situ photo-polymerization during the printing. They reported Starch-based hydrogels have received considerable interest due
that the incorporation of PEGDA and PVA not only improved the to their similar mechanical properties to soft tissue and their
mechanical properties and scaffolding ability but also increased potential for other applications such as injectable polymeric blends
cell attachment and viability [128]. In a similar approach, Joen for tissue regeneration [153–155]. Despite the aforementioned
et al. [131] combined cell-laden oxidized and methacrylated algi- challenges of starch hydrogels and lack of significant works on
nate hydrogel with a 3D printing technique to construct compli- preparing starch-based hydrogels in the literature as compared
cated 3D tissue structures. They suspended human bone to other similar polymers, photo-crosslinking remains one of the
marrow-derived mesenchymal stem cells (hMSCs) into the modi- few strategies which seems to result in hydrogels with an accept-
fied alginate and utilized freeform reversible embedding of sus- able range of properties [85]. Sodium benzoate and methacry-
pended hydrogels (FRESH) 3D bioprinting to fabricate a 3D lamide are two most investigated modifications for preparing
structure. They applied dual crosslinking, ionic and covalent, to photo-crosslinkable starch-based hydrogels [85,156].
provide suitable mechanical strength and stability. Interestingly, Methacrylamide modification has been directly and indirectly
they reported that the fabricated cell-laden hydrogels were cryop- employed to create starch-based photo-crosslinkable hydrogels
reserved evaluated by freeze-thawing the cell-laden hydrogels and [85,157]. Li et al. used UV polymerization of acryloylated starch
confirmed by proliferation and differentiation potential, DNA con- blend with 3-dimethyl(methacryloyloxyethyl)ammonium propane
tent, and alkaline phosphatase (ALP) activity measurement of sulfonate to fabricate photo-crosslinkable hydrogels designed for
hMSC-laden microgels derived from cryopreserved. They demon- potential industrial applications [157]. Nieuwenhove et al. devel-
strated the promising potential of the developed highly innovative oped starch-based IPN hydrogel using methacrylic and pentenoic
bottom-up strategy to construct cell-laden 3D structures with var- anhydride as photo-sensitive materials for stem cell engineering.
ious shapes applicable for TE of different tissues (Fig. 1). They showed that the presence of the starch increased cell detach-
Stimuli-responsive hydrogels are fascinating for biomedical ment, while this phenomenon can be adjusted and engineered by
applications, especially for drug/cell delivery and TE applications. changing the ratio of starch to the other polymer(s) in the blend
Boddupallia et al. [77] synthesized photo-crosslinked stimuli- [85].
responsive methacrylated alginate hydrogel through step-growth, Unlike other polymers, such as cellulose, sodium benzoate is a
and mixed-mode as the TE scaffold for chronic wound healing fairly established choice for fabrication of photo-crosslinkable
treatment. Their findings demonstrate that the fabricated hydro- starch-based hydrogels, which has proved to result in proper
gels exhibited compressive moduli in the range of 8.3 ± 0.3 to 22. crosslinking as compared to other photo-sensitive materials
6 ± 0.3 kPa. Moreover, they reported that the hydrogels were pH- [156,158–160]. For instance, Follain et al. prepared a blend solution
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 ubility, abundancy, and similar properties to soft tissues, there is
material and the optimized ratio of starch/PVA/sodium benzoate still a huge gap which should be thoroughly investigated and
led to desired improved mechanical properties [160]. addressed to obtain long-waited promising results for photo-
Overall, the body of work involving photo-crosslinkable starch crosslinkable starch-based hydrogels.
hydrogels are fairly limited and sporadic work involving methacry-
lamide and sodium benzoate modification are only supplemented 5.1.3. Cellulose
by few works based on gamma radiation and Irgacure 2959 Cellulose is an inexpensive, biocompatible and enzymatically
[85,160]. A list of selected works on this topic has been included biodegradable linear glucose homopolymer polysaccharide with
in Table 1. Considering the potentials of starch due to its water sol- tunable water solubility, and chemical and physical homogeneity
Table 1
The specifications of photo-crosslinked starch-based hydrogels fabricated for various biomedical applications.
Hydrogel type Type of photoinitiator Applied light (nm), duration In vitor/in vivo Potential biomedical Refs.
(min) and intensity (W cm2) model applications
Modified starch hydrogel Irgacure 2959 254, 2 In vitro drug Ophthalmologic drug [84]
release profiles delivery
Gelatin and starch hydrogel Irgacure 2959 250–450, various, 0.01 AdMSC Adipogenesis, osteogenesis [85]
and cell encapsulation
Wheat starch based films SB 365, various, 0.034 – – [156]
Acryloylated starch and 3-Dimethyl(methacryloyloxyethyl) 365, 10, 8 – – [157]
‘‘zwitterionic” monomer ammonium propane sulfonate
hydrogel
Starch-based films SB 365, various, 0.034 & 0.1 – – [158]
Thermoplastic starch sheets SB 254, various, various – – [159]
Starch based blends SB 365, 120, 0.034 – – [160]
Abbreviations: AdMSC: Adipose-derived mesenchymal stem cells, SB: Sodium benzoate.
[161–163]. Generally, cellulose can be obtained from plant and Amongst widely used methods for photo-crosslinkable
bacterial sources with the same chemical structure [164]. How- cellulose-based hydrogel fabrication, modification with functional
ever, bacterial cellulose is purer than the plant cellulose both have groups have been constantly used and optimized throughout the
promising applications in diverse filed of biomedicine [165]. literature. Methacrylate is the most widely used functional group
Although its pure form has been successfully used in a variety of for the functionalization of cellulose backbone to obtain photosen-
biomedical applications, it is predominantly used as a precursor sitive polymer solutions. Early work on methacrylate modification
for ester-based derivatives such as carboxymethyl cellulose, and of cellulose and cellulose-derivative hydrogels involved methacry-
cellulose nitrate derivatives [161,166]. Alternatively, it can also late modification of carboxymethylcellulose [179] cinnamoyl-
be used as composite or blend component, serving as a natural isopentyl cellulose [180], and methylcellulose [181], which mostly
constituent of a structure, which improves the mechanical and bio- relied on photo-crosslinking as the main step of hydrogel rein-
logical properties of said structure through its versatile and easily forcement/fabrication. Building upon previous work on methacry-
manipulatable composition [167,168]. Different physical forms of late modified carboxymethyl cellulose, Hossen et al. reported on
cellulose with various micro- and macro-morphology can used, the fabrication of methacrylate functionalized carboxymethyl cel-
which include but are not limited to cellulose nanofibers, lulose and cellulose nanofibrils hydrogels [181]. The authors
cellulose-based hydrogels, and cellulose-based membranes [161]. adopted an interesting approach that revolved around preparing
Amongst the various formats of cellulose structures, cellulose- mechanically robust composite of cellulose nanofibrils and
based hydrogels were the most-investigated for applications in methacrylate modified carboxymethyl cellulose, followed by
biomaterial-guided tissue regeneration [169], three dimensional lyophilization and rewetting. Shrinkage and swelling were con-
cell culture [170,171], drug delivery [172,173], and wound healing trolled by tuning the ratio of carboxymethyl cellulose and cellulose
[87,88] amongst other potential and previously investigated appli- nanofibrils, showing that a higher fraction of carboxymethyl cellu-
cations. Such hydrogels can be categorized into native cellulose lose induces more swelling while more cellulose nanofibrils pro-
hydrogels, cellulose derivatives hydrogels, and composite hydro- tected the hydrogel against excessive swelling [181].
gels containing a cellulose component [161,174]. Each category
presents various advantages and deficiencies and requires unique 5.1.4. Chitosan
and efficient fabrication strategies to engineer physical and chem- Chitosan is an aminated linear and natural polysaccharide
ical properties of the hydrogels in addition to modulating the cell- obtained through the deacetylation of chitin via chemical or enzy-
or tissue-substrate biological interactions [174,175]. For instance, matic hydrolysis under severe alkaline conditions or in the pres-
composite hydrogels containing a cellulose component provide ence of particular enzymes (e.g., chitin deacetylase) [186,187].
the opportunity can be potentially blended with natural polymers Chitin is the second most abundant natural polymer worldwide
to form a composite hydrogel scaffold for an inexpensive and after cellulose and is found in the exoskeleton of insects (e.g., Bee-
relatively-simple strategy for tissue regeneration and controlled tle cocoon, Cuticle, and Ovipositors), the cell walls of fungi (e.g.,
drug delivery due to improved biodegradability and tunability by Aspergillis nidulans and Mucor rouxi), shell of crustaceans (e.g., Crab
change in composition ratios and overcoming the cellulose hydro- and Shrimp), and Centric Diatoms (e.g., Algae and Thalassiosira flu-
gel fabrication challenges, such as dissolving in solvents to obtain a viatilis) [188]. The rigid structure and poor solubility in aqueous
homogenous structure [161,176]. solutions, as well as high levels of acetylated groups are hindered
The fabrication strategy is undoubtedly the most deterministic chitin applicability, while the deacetylation process enhances the
factor for obtaining a hydrogel structure with desired mechanical, amount of amine groups, solubility, biocompatibility, and
swelling, morphological, chemical and biological outcomes [175]. biodegradability. Chitosan is composed of the deacetylated unit
Photo-crosslinking has been proposed and implemented as one (D-glucosamine) and the acetylated unit (N-acetyl-D-
of most reliable, versatile and effective method for obtaining glucosamine) linked by b-(1 ? 4) glycosidic linkages. Chitosan
hydrogels with well-defined geometries as an alternative for tradi- has found a wide range of industrial and biomedical applications
tional functionalized crosslinkers. This technique often involves UV due to its various physicochemical and biological properties. Chi-
radiation in the presence of a photo-sensitive component such as tosan is biocompatible, biodegradable, mucoadhesive, antibacte-
methacrylate groups which creates free radicals and help covalent rial, antifungal, and analgesic [189].
crosslinking of the polymer backbone [177,178]. Such methods Among different structures, chitosan-based hydrogels have
provide a platform for various applications such as in situ crosslink- promising properties suitable for various biomedical applications
ing of injectable polymers, which have gained considerable atten- such as drug delivery, TE, cell therapy, and single-cell analysis
tion in recent years. A summary of light-induced cellulose [190,191]. Abundant hydroxyl (–OH) and amine (–NH2) functional
hydrogels has been provided in Table 2. groups in the structure of chitosan can be utilized to crosslink the
Table 2
The specifications of photo-crosslinked Cellulose-based hydrogels fabricated for various biomedical applications.
Hydrogel type Type of photoinitiator Applied light (nm), duration In vitro/in vivo model Potential biomedical Refs.
(min) and intensity (W cm2) applications
CMC Irgacure 2959 368, 10, 1.2 MSCs Nucleus pulposus [177]
replacement therapies
CMC Irgacure 2959 368, 10, 1.2 hMSCs Nucleus pulposus [178]
replacement therapies
CMC Irgacure 2959 368, 10, 1.2 Nucleus pulposus cells Cartilaginous TE [179]
Multilayered assembly of Benzophenone and 4,40 -bis 254/360, 50/150 – – [180]
cellulose derivatives (diethylamino)-benzophenone)
Methylcellulose hydrogels Irgacure 2959 368, 10, 1.2 hDFs Soft tissue [181]
reconstruction
Cellulose nanofibrils based Irgacure 2959 320–390, 40, 35 – – [182]
CMC – c 60Co, 10 or 1 kGy/h Biodegradability Biomedical devices [183]
Bacterialcellulose/acrylic – c 60Co, , 35 or 50 kGy – Drug delivery [172]
acid
Bacterial cellulose/acrylic Irgacure 2959 c 60Co, 35 and50 kGy Mouse fibroblast Wound healing and TE [86]
acid
Hydroxypropylcellulose Cinnamoyl 245, -, 60 Swiss albino mouse embryo TE applications [184]
fibroblast cells (RCB1642)
CMCand glycol chitosan o-Nitrobenzyl alcohol 405, –, 0,02 L-929 fibroblast SD rats Anti-adhesion barrier [185]
for wound isolation
bacterial cellulose/acrylic – 35 kGy Keratinocytes and fibroblasts Wound dressing and [89]
acid 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 It is known that the biological properties such as biocompatibil-
6.3 ammonium groups can be obtained from the amine groups to ity, degradation, and swelling rates are associated with the
produce pH-responsive hydrogel [192]. Chitosan-based structures crosslinking parameters. In this regard, Hu et al. [95] compared
are biodegradable through the enzyme’s activity such as lysozyme the effects of three different blue light initiators (riboflavin (RF),
which is nonspecific and ubiquitous in all mammalian tissues. The fluorescein (FR), and camphorquinone (CQ)) as well as the irradia-
byproducts of the degradation are oligosaccharides, which are tion time on the properties of methacrylated glycol chitosan
either used for glycoproteins and glycosaminoglycans or easily (MeGC) hydrogel. They observed that MeGC hydrogel initiated
excreted from the body. Moreover, chitosan can open the tight with RF was more biocompatible and exhibited proper mechanical
junctions of epithelial cells and facilitate drug penetration and properties. Although the longer light exposure produced strong
delivery [193]. Either native chitosan or in combination with other hydrogel, the biocompatibility was compromised. Ma et al. [94]
natural/synthetic polymers can be crosslinked to form a hydrogel. used photo-crosslinking approach to fabricate injectable hydrogel
Various approaches have been reported to produce chitosan hydro- based on (methacryloyloxy) ethyl carboxyethyl chitosan
gel such as self-crosslinking in the elevated pH or by dissolving in a (EGAMA-CS), N,N-dimethylacrylamide (DMMA), and polyethylene
non-solvent [194], freeze-thawing [149], electrostatic interactions glycol dimethacrylate (PEGDA) as the bone TE scaffold. They
[195], and chemical crosslinking through the addition reactions, reported that the fabricated hydrogel was biocompatible and effec-
condensation reactions, and free-radical polymerization [193]. tively support bone cell attachment and proliferation. In the same
Photo-crosslinked chitosan hydrogels have been developed in scenario, Yuan et al. [197] fabricated thermo-responsive glycidyl
various fileds. Qiao et al. [90] conjugated photo-sensitive 4- methacrylate-modified hydroxypropyl chitin (GM-HPCH) as the
azidophenylacetic acid (AZ) to C-2-amino of hydroxyethyl chitosan TE matrix based on photo-crosslinking technique. They used amino
(HECTS) to form photo-crosslinked chitosan hydrogels as the car- groups instead of hydroxyl groups in HPCH to react with the epoxy
rier of heparin for treatment of glaucoma surgery. They first pro- group in GM. They observed that the reversible thermo-sensitive
duced AZ from 4-aminophenylacetic acid (AA) and then the sol–gel transition was at lower temperatures compare with HPCH,
obtained AZ was conjugated to HECTS through EDC/NHS coupling which can be attributed to the hydrophobicity of the methacrylate
chemistry. The resulted HECTS-AZ crosslinked via UV radiation groups. Moreover, some properties (e.g., swelling, degradation rate,
for 30 s to form a hydrogel. They reported that the heparin loaded and stability) were tunable with the varying the concentration of
HECTS-AZ hydrogel exhibited prolonged-period drug release and methacrylate groups and UV exposure time.
provide maintained filtration bleb and decreased intraocular pres- In another study, thiol-terminated poly(vinyl alcohol) (T-PVA)
sure (IOP) after glaucoma filtration surgery (GFS). In another sce- was grafted to maleic chitosan (MCS) to enhance mechanical
nario, Zhou et al. [96] fabricated (methacryloyloxy)ethyl strength and reduce the gelation time of photo-crosslinked inject-
carboxyethyl chitosan (MAOECECS) from chitosan and ethylene able hydrogel. The authors utilized thiol-ene photo-polymerization
glycol methacrylate through Michael-addition reaction. They used for the conjugation due to its low or even no oxygen inhibition
Irgacure 2959 as the photoinitiator and the resulted solution effect, fast process, and producing networks with proper mechan-
exposed to UV light for 15 min to form a hydrogel. They reported ical and physical properties. They reported relatively fast gelation
that the fabricated hydrogel was biocompatible with adjustable time (<120 s), enhanced compressive strength (0.285 ± 0.014 MP
swelling and degradation rate. Qi et al. [196] fabricated chitosan a), and stiff (G’= ~5500 Pa), which have a direct correlation with
grafted methyl acryloyl glycine (MAG) photo-crosslinkable hydro- the amount of T-PVA. Moreover, the fabricated hydrogel was able
gel. They demonstrated that the grafting reduced the crystallinity to support L929 cells attachment and proliferation critical for tis-
and thermal stability compared with pure chitosan, while the sue engineering applications [93].
porosity was favorable and dependent on the concentration of In addition to TE and drug delivery, chitosan-based hydrogels
the photoinitiator. can be utilized for enzymes immobilization applications. Monier
et al. [92] modified chitosan with cinnamoyl chloride to immobi- minus aldehyde), which provide a multitude of functionalization
lize b-galactosidase via the entrapment technique. They reported strategies to create crosslinkable HA hydrogels. Applying these
that the crosslinking was conducted through the cycloaddition strategies is imperative because the use of un-crosslinked soluble
reaction [2p + 2p] between the grafted cinnamate moieties HA has restricted by the poor mechanical properties, rapid
induced by UV irradiation. The results showed that the entrapped in vivo degradation, and clearance [203,204]. Therefore, to obviate
enzyme preserved around 80% of its initial activity and was stable these limitations, HA can be crosslinked through physical, chemi-
against pH and temperate changes. In another innovative study, cal, and enzymatic methods either with a bi-functional reagent
glucose oxidase (GOx) was immobilized onto the methacrylated or with the synthesized highly reactive derivatives of HA. A num-
chitosan photo-crosslinked hydrogel to fabricate a glucose- ber of prevalent crosslinker agents and derivatives of HA are shown
responsive DDS for diabetic’s periodontitis therapy. First off, in Scheme 5.
methacrylic anhydride was grafted on chitosan polymer and cross- Photo-polymerization has been widely exploited to render
linked via UV irradiation to form hydrogel film. The fabricated mechanically strong and stable HA hydrogels either in vitro or
hydrogel was surface-activated by glutaraldehyde (1% v/v) and in vivo [205–207]. In this regard, photo-crosslinkable hydrogels
GOx attached to the hydrogel. They proposed that the hydrogen have developed by modification or grafting of HA with photoactive
ions (H+) generated during oxidation of ambient glucose to glu- moieties and by mixing HA with other natural/synthetic polymers.
curonide by immobilized GOx can alter the structure of pH- HA has been extensively derivatized with photoactive moieties,
responsive hydrogels and trigger the release of the loaded drugs. including methacrylate [208], cinnamic acid [209], tyramine
The authors loaded metronidazole into the enzyme immobilized [210], coumarin and hexamethylenediamine [211] (Scheme 5).
hydrogel and the antibacterial activity was assessed against Por- The HA-methacrylate hydrogels are the most common deriva-
phyromonas gingivalis. They reported that the fabricated hydrogel tive of HA used in photo-polymerization, and can be made by mod-
exhibited good mechanical properties and the bonding capacity ifying HA with glycidyl methacrylate [212,213], methacrylic
and activity of immobilized GOx preserved. Moreover, it was anhydride [104] and N-3-aminopropyl methacrylamide [214].
shown that the fabricated hydrogel was glucose-responsive and The synthesis, characterization and in vitro/in vivo studies of HA-
the presence of glucose increased the release of metronidazole methacrylate hydrogels for a broad range of biomedical applica-
and exhibited significant antibacterial ability in high glucose con- tions have been extensively performed (reviewed in [208,215–
centration solution [91]. Table 3 summarized the studies con- 217]).
ducted on light-induced chitosan hydrogels. Coumarin, as a photocleavable group, has grafted onto HA
chains to forming photo/thermo-responsive nanogels containing
5.1.5. Hyaluronic acid paclitaxel for cancer chemotherapy [218]. The coumarin methacry-
Hyaluronic acid (HA, also known as hyaluronan) is a natural, late modified HA was able to self-assemble into nanogels (hydro-
non-sulfated, linear polyanion glycosaminoglycan that consists of dynamic radius of ~ 110 nm) with high stability and prolonged
repeating disaccharide units of D-glucuronic acid and N- blood circulation time due to strong hydrophobic interactions
acetylglucosamine connected by b-1,4 and b-1,3 glycosidic bonds and p–p stacking that resulted to efficient internalization in cancer
[200]. It is a biopolymer found abundantly throughout the body, cells and tumor tissues [218]. Another study by Beninatto et al.
which synthesized primarily in fibroblasts and then extruded into demonstrated that HA-coumarin solidified upon near-UV irradia-
ECM. HA-based biomaterials have used for multifarious biomedical tion via a clean [2 + 2] photo-induced cycloaddition reaction with-
applications owing to its inherent characteristics comprising high out initiator [101]. Such hydrogels provided the porous structure
hydrophilicity, unique rheological behavior, biodegradability, bio- with good permeability and were also capable of supporting the
compatibility, non-toxicity, non-immunogenicity, and non- survival and proliferation of encapsulated fibroblasts.
inflammatory [201,202]. HA contains many free active sites in its Tyramine (Tyr), a phenolic photoactive moiety, has also shown
native chemical structure (acetamide, carboxyl, hydroxyl, and ter- 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 cm2)
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
MHGC 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), MHGC: Methacrylated hexanoyl glycol chitosan.
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
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 chlorhexidine-loaded nanogels (Fig. 2) [232]. The nanogels-
applied as a vehicle to facilitate intra-articular injection of chitosan loaded hydrogel provided the enhanced mechanical properties
microspheres encapsulating cordycepin [97]. This combination due to higher crosslinking density, stable antibacterial effects, the
resulted in synergistically preventing the progression of degenera- rapid hemostasis capacity and accelerated wound healing.
tive changes in induced osteoarthritis. In a similar study, the Ultimately, the main characteristics of the photo-crosslinked
photo-crosslinked gelatin methacrylate/methacrylated HA (5:2 HA and HA-based hydrogels are shown in Table 4.
w/v) hydrogels combined with crizotinib-loaded chitosan micro-
spheres demonstrated retarding the progression of osteoarthritis
and ameliorated cartilage matrix degradation [98]. 5.1.6. Dextran
The photo-dimerizable hydrogels composed of cinnamoyl- Dextran, a non-ionic hydrophilic homopolysaccharide, is com-
modified HA and alginate containing basic fibroblast growth factor posed mainly of linear a-1,6 linked D-glucopyranose residues with
was made that demonstrated sustained release kinetics [228]. about 5–10% a-1,3 linked side chains [234]. Dextran is broadly
Blends of methacrylated gelatin, alginate and HA biopolymers applicable in biomedical applications owing to its biocompatibility,
reported as the stable, non-toxic and biocompatible hydrogel scaf- biodegradability, low toxicity, high natural abundance, and simple
folds for heart tissue regeneration [229]. Furthermore, the photo- modification [235,236]. It contains plenty of hydroxyl functional
crosslinked alginate hydrogel containing interpenetrating HA groups, which turns it suitable for derivatization and crosslinking
chains was used for encapsulating MSCs, which led to robust chon- process (Scheme 6) [237]. Dextran and its derivatives can easily
drogenic differentiation and high cell viability [78]. transform to organized 3D hydrogel structures, in which network
PEG can be also combined/conjugated with HA-based hydrogels formation is established by either physical crosslinking (e.g.,
to specifically tune physicochemical properties and cellular inter- ionic/hydrophobic interactions, hydrogen bonding, and crystalliza-
action/behavior. In this respect, a PEG-peptide was conjugated tion) [238] or chemical crosslinking (e.g., radical polymerization,
onto glycidyl methacrylate-modified HA. They found that the photo-polymerization, and enzymatically or chemically reaction
stable hydrogels were formed via UV photo-crosslinking with tun- of complementary groups) [237].
able material properties and high peptide conjugation efficiencies Dextran can be modified by photoactive moieties to incorporate
[207]. The same researchers have reported the bovine serum functional groups into the structure. In this way, the photo-
albumin-containing poly(lactic-co-glycolic acid) (PLGA) micro- crosslinked dextran-based hydrogels were first developed by Kim
spheres embedded into glycidyl methacrylate HA–PEG hydrogel et al. via UV crosslinking of vinyl groups that incorporated in dex-
scaffolds for controlled release of proteins in TE applications tran by substitution of maleic anhydride [239], acrylate [240] and
[230]. Besides, integrating a PEG diacrylate into hydroxyapatite methacrylate [240] moieties (Scheme 6). Dextran/poly(D,L-lactic
NPs-reinforced HA hydrogels revealed that mechanical perfor- acid) hydrogels have been made from hydrophilic dextran acrylate
mances enhanced because of the presence of the second PEG and hydrophobic poly(D,L-lactic acid) diacrylate macromere by UV
network and the NPs [231]. In 2018, Zhu et al. developed a crosslinking to generate hydrogels with controlled swelling prop-
photo-crosslinking hydrogel dressing for controlling bleeding and erties [241,242]. The hydrogels formed by photo-crosslinking of
wound repairing composed of aminoethyl methacrylate HA and unsaturated vinyl groups introduced onto the polymers backbones
methylether methacrylate mPEG hydrogel that incorporated with 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 cm2)
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
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) improve rheological properties and be crosslinked in situ [245].
derivatized with glycidyl methacrylate copolymer for the prepara- One other of dextran derivatives having methacrylated PEG moi-
tion of dextran hydrogels containing methacrylate groups by UV eties (Scheme 6) has been applied to produce hydrogels with
irradiation [107]. They showed that the hydrogels were formed higher elasticity and degradability, aiming to improve the extreme
by intramolecular and/or intermolecular crosslinking of the fragility and lack of typical hardness of gels made of dextran
methacrylate residues as well as a co-crosslinking reaction methacrylate [246].
between the two polymers. The similar hydrogels loaded with In another strategy, a copolymeric dextran-based hydrogel was
beclomethasone dipropionate have been used for treating inflam- fabricated by photo-crosslinking of precursor blend solutions of
matory bowel diseases, resulted in the biocompatible hydrogels urethane methacrylated dextran and 2-hydroxyethyl methacrylate
with a prolonged drug release and negligible hydrolysis in simu- (HEMA) intended for in situ curing tissue adhesives. The copoly-
lated gastric/intestinal fluids [243]. Moreover, it has been reported merization of HEMA and the modified dextran remarkably
the synthesis and photo-patterning in microfluidic channels of increased the adhesion strength to 86 times that of Tisseel (a com-
dextran-glycidyl methacrylate hydrogel (Scheme 6) along with a mercial fibrin adhesive) and resulted in less cytotoxicity to L929
crosslinker, N,Ń-methylene-bisacrylamide [244]. This photo- cells [247].
patternable hydrogel could reduce the duration of photo- Dextran-based hydrogels have also used as delivery vehicles for
crosslinking process and degrade via enzymatic breakdown. In loading and controlled release of bioactive molecules such as
another study, an injectable and pH-sensitive hydrogel made up drugs, proteins/peptides, and nucleic acids. Doxorubicin has been
of binary mixtures of dextran methacrylate and a carboxylated incorporated into photo-crosslinked dextran-methacrylate hydro-
derivative of scleroglucan was submitted to UV irradiation to gels that revealed a delayed and controlled release profile [248].
Besides, 2-phenylpropionic acid functionalized with methacrylic phorquinone photoinitiator in combination with tertiary amines,
groups bound to dextran methacrylate has been used for the as co-initiators to enhance the efficiency of the photo-curing
preparation of photo-crosslinked hydrogels without initiator [260]. The free radicals, excited camphorquinone and co-
[249]. The hydrogels were able to retain the drug in acid solution initiators, are generated by electron transfer and hydrogen
simulating the conditions of the gastric tract and provided a sus- abstraction that can initiate a radical polymerization to form the
tained release system. Also, vancomycin has been incorporated biocompatible hydrogels. Synthesis of the methacrylate-modified
into photo-crosslinking hydrogels composed of methacrylated dextran hydrogels can also be achieved by electron-beam irradia-
dextran/poly(L-glutamic acid)-g-hydroxyethyl methacrylate tion without any additives, that resulted in the formation of
intended for enhanced drug loading and long-term antibacterial crosslinked structures through unsaturated carbon double bonds
effects [108]. of methacrylate substituents, which showed non-cytotoxic effects
Dextran-based IPN and semi-IPN hydrogel systems are other on mouse fibroblasts L929 cells [261].
feasible approaches to fabricate the photo-crosslinked dextran- As a promising strategy, small interfering RNA (siRNA) have
based hydrogels for biomedical applications. Pescosolido et al. incorporated in dextran-based hydrogels to inhibiting/promoting
developed photo-crosslinked IPN/semi-IPN hydrogels based on cal- the aberrant expression of disease-causing genes. In this way,
cium alginate and dextran methacrylate derivative, in which drugs dextran-HEMA microgel has been loaded with atto647-siRNA aim-
or proteins can be dispersed/delivered [108,250]. Upon UV irradia- ing for better control over the intensity of gene silencing effect and
tion the methacrylate moieties crosslinked and alginate chains are release of encapsulated siRNA [113]. The same group developed
interspersed within the chemical hydrogel network, leading to the anti-luciferase siRNA loaded cationic dextran-HEMA nanogels
injectable hydrogels with improved mechanical strength. The same to enhance endosomal escape that found it able to silence the luci-
authors also developed another IPN hydrogels made from dextran- ferase gene in hepatoma cells without relevant cytotoxicity [114].
HEMA and calcium alginate with tailorable degradation and In another work, the photo-crosslinked hydrogels composed of
mechanical characteristics suitable as protein delivery systems methacrylated dextran and methacrylated linear poly(ethylene
[251,252]. Besides, they developed 3D printed semi-IPNs hydrogels imine) were developed [112]. Such hydrogels were capable of
made from HA/dextran-HEMA encapsulated with the chondrocyte forming electrostatic interactions with siRNA and provided con-
cells for bioprinting applications in TE [253]. trolled/sustained delivery of siRNA with extended deGFP silencing.
The biocompatible thermo-sensitive hybrid hydrogel comprised Dextran-mono(2-acryloyloxyethyl) succinate hydrogels incorpo-
of dextran-allyl isocyanate (Dex-AI) and N-isopropylacrylamide rated with RGD peptide and siNoggin siRNA have also been
(NIPAAm) was created by Zhang and colleagues through UV reported to induce human mesenchymal stem cells (hMSCs) osteo-
photo-crosslinking [254,255]. Hydrogel formation was accom- genesis. The hydrogels allowed prolonged siNoggin release over
plished by the molecular crosslinking NIPAAm to Dex-AI and 7 weeks with tunable cell adhesion that increased osteogenic dif-
Dex-AI to Dex-AI through the unsaturated functional groups ferentiation in encapsulated hMSCs [111].
(>C = C < ) as well as urethane linkage in the ally isocyanate groups In the other strategy, dextran-based hydrogels have combined
located in Dex-AI. In a similar study, dextran was substituted with with cells and growth factors/cytokines to provide sufficient cell
maleic anhydride and photo-polymerized with NIPAAm that growth and enhance TE performance. In this respect, photo-
formed hydrogels responsive to the temperature and pH, by crosslinkable epoxy benzophenone-modified carboxymethyl dex-
crosslinking carboxylic acid groups and doubles bonds in the tran hydrogels incorporated with silica NPs were either com-
maleic acid segments [256]. Dextran hydrogels based on dextran- pounded with cytokines (stromal-derived-growth factor and
allyl isocyanate-ethylamine and PEG-diacrylate have been also bone morphogenic protein) [262,263] or with osteoblasts and
prepared through UV photo-crosslinking to form hybrid biodegrad- endothelial cells [264]. The findings indicated the cytokines further
able hydrogels having pH sensitivity with improved protein release enhanced cell proliferation, migration, and angiogenesis as well as
[257]. the cells significantly induced the bone formation in mice calvarial
Tanna et al. developed glucose-responsive UV-polymerized defects.
dextran-based hydrogels using acrylic derivatives of dextran and Some of the main characteristics of the photo-crosslinked
concanavalin A (Con A), a sugar-binding lectin with a reversible dextran-based hydrogels in above-mentioned studies are shown
strong affinity to glucose for the design of a self-regulating/ in Table 5. Overall, the results of these studies have shown unique
closed-loop insulin delivery system [109,110]. They revealed that features of dextran-based hydrogels fabricated with photo-
covalently crosslinking of the acrylated monomers occurred, in polymerization techniques for biomedical purposes such as drug
addition to physical entanglements, therefore the crosslinked delivery and TE. Physico-mechanical properties of the hydrogels
hydrogels have been able to keep the activity of reversible binding can be modulated by inserting proper photoactive molecules to
to glucose as well as controlled insulin diffusion as a function of dextran chains. These structures demonstrated significant out-
glucose content. In a similar study, a glucose-sensitive hydrogel comes, especially when combined with growth factors, siRNA
composed of methacrylate modified dextran–Con A and PEG and cells. However, definitely further studies required to perform
dimethacrylate have been synthesized by UV polymerization. The in vivo investigations.
findings showed the hydrogels could prevent component loss
and maintained glucose sensitivity to a certain extent [258]. 5.2. Polypeptide-based photo-polymerizable hydrogels
Visible light and electron-beam irradiation have also applied for
the fabrication of dextran-based hydrogels. In this regard, visible 5.2.1. Collagen
light irradiation was used to fabricating the dextran- Collagen is a protein-based polymer, which naturally synthe-
methacrylate hydrogel by riboflavin and l-arginine (as sized in most mammals (25% of protein) and is the main protein
photoinitiator/co-initiator) to avoid UV crosslinking limitations of the ECM. Collagen has mainly a structural role in the tissues
[259]. During the visible light irradiation, generation of radical- and its orientation, packing, and density determine the mechanical
anionic riboflavin and radical-cationic L-arginine occurred, which properties in various tissues [266,267]. Collagen family has at least
initiates the polymerization reaction by covalent bonding of the 16 members, but types I, II, and III comprise 80–90% of the collagen
amine species to the dextran methacrylate hydrogel backbone. in the body. These types pack together to form long thin fibrils
Additionally, HEMA-coupled dextran precursor was applied to syn- structure, while there are other forms such as two-dimensional
thesize hydrogels by visible light in the presence of cam- 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 (Wcm2)
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

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 cm2 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 cm2 Fibroblast L929 cells Osteoblasts As biomaterials for bone regeneration [263]
cells Endothelial cells
Epoxy benzophenone-modified carboxymethyl dextran NA 254, 60, 10.4 J cm2 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.
immunogenicity, as well as biological properties such as cell singlet oxygen (1O2), superoxide anion (O2), and hydroxyl radicals
attachment, migration, and differentiation regulation, collagen (OH) under interaction with APS. The SO2 4 as well as the excited
has been widely used in various fields of biomedical [267,268]. state sensitizer can oxidize aromatic amino acids such as trypto-
Despite these properties, collagen suffers from low structural sta- phan, tyrosine, and cytosine residues in the side chain backbone
bility and mechanical strength upon hydration, which hinders its of collagen. In the crosslinking process, Tyr-Tyr bridge forms
clinical applications. In this regard, intermolecular crosslinking through the reaction between two tyrosyl radicals in the side chain
through different physical and chemical approaches can enhance of collagen. The authors reported that, although the radiation oxi-
mechanical strength and stability. Among the various forms of col- dized some amino acids in the structure of collagen, the triple-
lagen, hydrogel structure has gained tremendous attention in helical conformation was preserved confirmed by SEM, Raman
biomedical applications due to mimicking ECM structure, high spectroscopy, circular dichroism (CD) FTIR spectral studies.
water retention capacity, and high swelling ratio, as well as the Nguyen et al. [271] evaluated the effects of photoinitiator type
above-mentioned properties [269]. Collagen can be chemically (i.e., I2959 and VA086) and concentration (i.e., 0.02% and 0.1%) as
crosslinked by EDC/NHS, glutaraldehyde, and Genipin to form well as crosslinking time (1 min and 10 min) on compressive
hydrogel structure. Despite their high efficacy, using these strength, gel morphology, and stability of methacrylated collagen.
crosslinking agents induce cytotoxicity and cells are restricted They reported that the photo-chemical crosslinking reduced the
being seeded on the surface of the hydrogels rather than encapsu- porosity and subsequently water retention ability of collagen
lated into the hydrogel. On the other hand, photo-chemically hydrogel compared with un-crosslinked hydrogels. They also
crosslinking using biocompatible photoinitiator, a minimal amount observed that increasing the concentration of the photoinitiators
of UV exposure and visible light circumvent the previous and crosslinking time enhanced the compressive modulus and
approaches issues and provide encapsulation of cells within the the stability of hydrogel. Moreover, they pointed out that VA086
3D structure of hydrogel. Various scientists have developed was more biocompatible than I2959 and cell-mediated mineraliza-
photo-chemically crosslinked collagen hydrogels using different tion was significantly higher on VA086 crosslinked hydrogels com-
photoinitiators and crosslinking lights for drug/cell/gene delivery, pared with I2959.
TE, enzyme immobilization, and so on. Yang et al. [272] fabricated photo-crosslinked methacrylamide-
Nagaraj et al. [270] fabricated crosslinked collagen through vis- modified collagen hydrogel to control actin traction and subse-
ible light irradiation using erythrosine B (EB) and methylene blue quent contraction of the collagen matrix and differentiation of
(MB) as the photosensitizer in the presence of ammonium persul- BMSCs toward chondrogenic lineage. The authors proposed that
phate (APS). This crosslinking method was based on free radical the collagen hydrogel can induce chondrogenic differentiation,
mechanism and APS was used as the electron acceptor to facilitate while its low mechanical properties cannot withstand agents the
oxygen-free radicals formation upon irradiation. In this scenario, traction of cells which results in collagen matrix contraction. This
the photosensitizers, EB and MB, excited by visible radiation and collagen matrix contraction is a non-physiological mechanical
convert to short-lived singlet excited state following intersystem stimulus, which disrupts the actin cytoskeleton and subsequently
crossing to form a longer-lived triplet state then reach to the compromises cell viability and also dedifferentiates the differenti-
ground state via energy transfer and free radical formation. The ated chondrocytes. They used collagen type I extracted from calf-
absorbed energy can be transferred to molecular oxygen which skin modified with methacrylamide and crosslinked via UV
subsequently generates ROS such as sulfate radical anion SO42, 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].
shown in Fig. 3, BMSCs possessed round shapes in the first attach- enteral component, collagen, and has grabbed considerable atten-
ment with the collagen matrix. The cells exhibited spread shape, tion in the biomedical and food processing applications. Despite
actin microfilaments expressed, and the collagen fibers bunched its brilliant properties, gelatin suffers from low mechanical
up around the cells in collagen one day after cell seeding in the col- strength and should be crosslinked to retain desired structures
lagen group. Interestingly, in this group on day 2, BMSCs lost the during the handling and also in the site of action. However, gelatin
cytoskeleton filaments and changed back to the round shapes. Con- can be physically crosslinked, it’s physical network is also unstable
versely, in CMA group, the cells demonstrated high actin expres- at higher temperatures and breaks down. Therefore, it’s mechani-
sion and spreading forms with robust cytoskeleton structure. cal and thermal stability should be improved for long-term
Moreover, dispersive fibers distribution without aggregation was biomedical applications at 37 °C [127,277,278].
observed around the cells in this group. It is apparent in CD and Photo-crosslinking is a rapid, effective, convenient, and safe
MD groups that the addition of cytochalasin D inhibited the actin crosslinking approach that avoids the applications of some toxic
polymerization and subsequently, the arrangement and distribu- chemical crosslinking agents. In this regard, gelatin should be func-
tion of collagen fibers remained constant over time. They con- tionalized by photo-reactive side groups, such as acrylates and
cluded that the observed aggregation of collagen fibers is related methacrylates, or blended/grafted with other polymers containing
to the traction of the actin cytoskeleton in the low strength hydro- the photo-reactive side groups [279]. Various studies have been
gel. On the other hand, photo-crosslinked hydrogel withstands conducted in this concept and magnificent breakthrough achieved.
against the actin pulling induced contraction and induced powerful Gelatin-methacrylate (GelMA) is an attractive photo-crosslinkable
expression of the cytoskeleton as illustrated in CMA group. In CD derivative of gelatin, which obtains by conjugating the primary
and MD groups, cytochalasin D inhibited the interplay of cell and amino groups of gelatin with methacrylate pendant groups. GelMA
matrix. This study critically demonstrated that proper mechanical retains the unique properties of gelatin but exhibits desirable
strength is vital for cell viability, proliferation, and differentiation. activities of photo-crosslinkable hydrogels such as mild gelation
Some studies combined collagen-based hydrogels with a 3D conditions and biocompatibility [279]. Moreover, it is possible to
printing technique to construct well-designed cell-laden architec- simply adjust the mechanical strength, thermal stability, degrada-
ture. In a study, Stratesteffen et al. [130] blended collagen with tion rat, and biological activities of GelMA by varying the polymer
methacrylated gelatin (GelMA) and tailored the mechanical and crosslinking density through changing the methacryloyl modifica-
rheological properties to obtain desired 3D drop-on-demand print- tion degree. GelMA has extensively used in various fields of biome-
ing characteristics. Firstly, gelatin was methacrylated, cells (HUVEC dicine such as drug delivery and TE [280,281].
and hMSC), collagen type I, and photoinitiator added to the solu- Parthiban et al. [282] covalently conjugated VEGF-mimicking
tion. The resulted solution was printed using a custom-built 3D peptide (AcQK) to GelMA to induce microvascular network forma-
drop-on-demand bioprinter. The authors reported that the combi- tion within GelMA by encapsulated cells. They used the acrylated
nation of collagen with GelMA provided a bioink with improved peptide to conduct the conjugation process. They observed that
printing properties suitable for microvalve-based bioprinting the conjugation significantly compromised the mechanical
device, sufficiently low viscosities. The fabricated bioink exhibited strength of the hydrogel which was attributed to the interference
acceptable elastic shear modulus and gelation time suitable for of the peptide with the crosslinking process. They proposed that,
cell-laden bioprinting approaches. Moreover, they showed that with the presence of acrylated peptide, the generated free radicals
the fabricated construct was biocompatible and the interconnected attack both the methacrylate groups of GelMA and acrylate groups
architecture, as well as cell attachment sites of GelMA-collagen, in the peptide. Hence, the free radical propagation reaction is ham-
enabled HUVEC and hMSC to rearrange into tubular formations pered in comparison with pure GelMA polymer. Moreover, they
and subsequently provide angiogenesis. Using collagen as the observed that there is a direct correlation between the concentra-
bioink for nozzle-based 3D printing techniques may encounter tion of acrylated peptide and the compliance of the hydrogel
clotting the nozzle. Hence, some researchers conducted studies matrix (Young’s modulus) since generated free radicals are con-
to develop a nozzle-free fabrication method with acceptable reso- sumed by peptides to form a covalent linkage. Interestingly, the
lution. In this regard, Drzewiecki et al. [129] modified collagen type incorporation of the peptide increased the pore size as the function
I with methacrylamide (CMA) and utilized as the bioink for free- of loosening the network. The authors also utilized human umbil-
form fabrication of TE scaffold. They fabricated fibril hydrogel ical vein endothelial cells (HUVECs) as the model to assess the bio-
through the self-assembly of CMA, utilized a patterned photomask logical effects of conjugated AcQK. They observed that, apart from
to photo-crosslinking into the intended pattern, and finally cooled the biological activities of AcQK, their effect on the hydrogel matrix
the hydrogel to remove unphoto-crosslinked regions through the compliance (reduction) and pore size (increasing) improved the
cold-melting process. The beneficial feature of collagen for this vascular network formation. They conducted that the cell migra-
nozzle-less hydrogel patterning is based on its ability to form a fib- tion possibilities (determines by mechanical properties of hydro-
rillar hydrogel at temperatures above ~ 20 °C. The authors reported gel) are as critical as the presence of vasculature, inducing
the resolution on the order of ~ 350 lm for this method, which can biological cues. In conclusion, they proposed that the incorporation
be conducted with or without cells. They in vitro and in vivo studies of acrylated peptide provides additional possibilities to tailor the
demonstrated that the fabricated photo-crosslinked CMA hydrogel mechanical properties, as well as induce desired biological
was biocompatible. activities.
In an innovative approach, Smith et al. [116] applied GelMA
5.2.2. Gelatin hydrogel to construct biologically based replacement teeth as the
Gelatin is a biopolymer with fascinating physicochemical and alternative over the currently used dental implants. They encapsu-
biological properties such as adjustable biodegradability, excellent lated HUVECs, porcine dental mesenchymal (pDM) progenitor
biocompatibility, non-carcinogenicity, low antigenicity, and cells, and post-natal porcine dental epithelial (pDE) within GelMA
immunogenicity [273–275]. Generally, gelatin is obtained from and implanted subcutaneously onto the backs of female Rowett
hydrolysis and denaturation of collagen and possesses collagenˈs Nude rats. Mechanical measurement using force volume–atomic
natural properties, including matrix metallopeptidase (MMP) sen- force microscopy (FV-AFM) illustrated that increasing concentra-
sitive sites and Arg-Gly-Asp (RGD) adhesive motifs, which modu- tion of GelMA and the photoinitiator enhanced the elastic moduli.
late cell-mediated matrix degradation and cell attachment, Moreover, cells-laden hydrogel indicated as Gel 3 with the compo-
respectively [276]. Moreover, it is more processible than its par- sition of GelMA (5% w/v) and photoinitiator (0.1% w/V) exhibited
the elastic moduli similar to the natural dental pulp tissue. In vivo materials is a critical parameter in the most of the biofabrication
studies revealed that GelMA constructs consisting of pDM-HUVECs systems, for instance, the viscosity in the range of 3.5 and
in 5% GelMA and pDE–HUVECS within 3% GelMA supported differ- 12 MPa is applicable in inkjet bioprinting and higher viscosity
entiation dental cell and formation of vascular mineralized dental results in non-uniform structures and or clogging the nozzle.
tissue. The authors concluded that, the fabricated 3D biomimetic Therefore, precise temperature control during the biofabrication
tooth bud model can be eventually considered as a bioengineered process of thermally unstable substances is needed which on the
tooth replacement. other hand increase the cost and complexity of biofabrication sys-
Photo-crosslinkable gelatin-based biomaterials have been con- tems. An alternative approach is to develop thermally stable mate-
sidered as the akin and wound care constructs in the form of skin rials. Wang et al. [285] produced cold soluble gelatin as the source
substitute or wound dressing materials [115,280]. Sun et al. [117] material for GelMA hydrogel with low viscosity and thermal stabil-
combined electrospinning with photo-crosslinking of GelMA to ity at room temperature. They reported that GelMA prepared from
fabricate 3D fibrous scaffolds for improved vascularization process. a cold soluble gelatin exhibited similar biological properties to por-
Nanofibrous GelMA was fabricated by the electrospinning method cine skin gelatin-based GelMA while it had improved thermal sta-
and then, crosslinked under UV radiation. The physicochemical bility and partially low viscosity at room temperature. They
properties, as well as biological activities of the prepared GelMA concluded that the fabricated cold soluble gelatin-based GelMA
nanofibers were compared with electrospun gelatin nanofibers can be considered as the promising alternative bioink for biofabri-
chemically crosslinked by glutaraldehyde. They observed that cation applications applicable in regenerative medicine and TE.
GelMA fibers had a better water swelling property than pure gela- In an innovative approach, Wang et al. [286] combined a flow-
tin and formed highly porous matrix architecture. Mechanical per- focusing droplet microfluidic system with GelMA photo-
formance comparison illustrated that GelMA fibers were more crosslinking concept to produce cell-laden, solid-like, and core–
flexible/compliant than gelatin fibers. The in vitro studies showed shell microgels for micro-TE applications (Fig. 4a). They used min-
that the fabricated nanofibrous GelMA support proliferation, and eral oil, GelMA, and methyl cellulose (MC) for the continuous flow,
migration of human dermal fibroblasts (HDFs) and HUVECs into core and shell, respectively. They showed that the flow rates and
the scaffolds, which facilitates vascularization. Moreover, the the concentration of the polymers determined the overall size
in vivo study confirmed the results of the in vitro results by a higher and the stability of the microgels, as well as the shell thickness
flap survival rate and more microvascular formation than control and the core diameter. They observed a direct correlation between
groups. The authors suggested that the combination of electrospin- core and shell flow rates with the core and shell diameter, respec-
ning with photo-crosslinking of GelMA can provide sophisticated tively. The authors indicated that the overall size, core diameter,
3D scaffolds desired for the complex engineered tissues. and shell thickness are easily adjustable using the flow rates while
In a similar study, Kim et al. [115] fabricated a bi-layer hybrid the core-shell structure is preserved (Fig. 4b). They also assessed
scaffold based on chitosan/human hair keratin nanofibrous mat the biocompatibility of the microgels using HepG2 and HUVECs
and GelMA hydrogel as the skin graft. They fabricated chitosan/ cells in a co-culture method. They encapsulated the cells within
keratin nanofibers via the electrospinning method and set as the the core and observed the proliferation of both cells. Moreover,
top layer and GelMA hydrogel considered as the bottom layer. To they reported that the production of albumin and urea increased
mimic the native skin tissue, they encapsulated fibroblasts in the as the function of the biological activities of the cells in the co-
hydrogel matrix and HaCaT cells on the nanofibrous layer. They culture method due to the cell–cell interactions. Interestingly, they
reported that the incorporation of chitosan improved the mechan- observed increasing the core size with the proliferation of the cells,
ical properties and preserved the porous structures in the wet which revealed the flexibility of the microgels against cells-
form. Moreover, the combination of the nanofibrous mat with induced remolding of the microgels. The authors concluded that
GelMA hydrogel circumvents fastidious handling and suturablity the fabricated core-shell microgel can be considered as the promis-
of the hydrogel and improves its handling during the implementa- ing microcarriers for the culture of heterogenous cells with poten-
tion. They concluded that the fabricated bi-layer scaffold mimics tial applications in the fabrication of organoids, microtissues, and
the dermis and epidermis of skin tissue and supports the prolifer- stimuli-responsive materials. Table 6 summarized the studies con-
ation and functions of HaCaT and NHDFs cells. ducted on photo-crosslinked gelatin-based hydrogels.
Oktay et al. [283] fabricated a smart electro-responsive trans- In conclusion, the studies revealed and documented the gelatin-
dermal drug delivery system for skin disease treatment, which based photo-crosslinkable materials not only exhibit fascinating
can release a specific amount of the drug at pre-determined time biological properties but also offer tunable mechanical and mor-
points. They encapsulated poly(styrene sulfonate)/poly(3,4-ethyle phological performances, as well as effective integrability with a
nedioxy thiophene) (PSS/PEDOT) into GelMA hydrogel and used wide range of biofabrication methods. In this concept, the integra-
5-fluorouracil (5-FU) as the model drug. They simply dispersed a tion of gelatin-based photo-crosslinkable materials with the elec-
proper amount of PSS/PEDOT into GelMA sole and irradiated with trospinning, rapid prototyping, and microfluidic methods resulted
UV light to induce photo-crosslinking. They applied electric field in fascinating and sophisticated structures applicable in a wide
(1.5 V) perpendicularly to the hydrogel to assess the effect of the range of biomedical applications.
electrical stimulation on drug release from the hydrogel. The
authors reported that the electrical stimulation increased the 5.2.3. Silk
amount of drug released from 18.2 to 23.3%, which is related to Silk is defined as highly oriented spun protein fibers, which are
de-swelling effect of the electrical stimulation. Upon the electrical produced by some creatures mainly silkworms, comprised of two
stimulation the network size is changed, hydrogel shrinks, and the fibroin strands wrapped with the glue-like sericin protein [299].
encapsulated drugs squeeze out from the hydrogel. The authors Sericin constitutes 25–30 wt% of total silkworm cocoon and should
suggested that the fabricated electro-responsive hydrogel-based be removed by proper de-gumming processes [300]. The silk
DDS enables non-invasive, reliable, remote, and repeatable drug fibroin (SF) is built of a heavy chain (Mw ~ 325 kDa, 85%, w/w)
delivery with accurate dosage, timing, and duration. and a light chain (Mw ~ 26, kDa, 15%) linked together by a
Despite the wide applications of GelMA, it’s thermal instability disulfide bond as well as a glycoprotein, P25, with a 6:6:1 M ratio
is a concerning issue in the biofabrication applications. Kolesky [301–303]. SF is a large hydrophobic protein made up of (Gly-Ala-
et al. [284] have shown that the shear moduli and viscosity of Gly-Ala-Gly-Ser) six amino acid repeat units, which can form anti-
GelMA significantly changed at around 25 °C. The viscosity of the parallel b-sheet structures that intra/inter-connected by hydrogen
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 min1) 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 includes the photo-polymerization of SF in the presence of reduc-
unique structure, ease of processing, high mechanical strength, ing agents accompanied by covalent bond formation between
excellent biocompatibility, absent or minimal immunogenicity, active photo-reaction groups of SF mainly tyrosine residues. Whit-
tunable degradation, and facile modification possessing, make SF taker et al. suggested the facile ruthenium-catalyzed photo-
as a suitable biomaterial for multifarious biomedical applications, crosslinking method for the fabrication of photo-crosslinkable SF
such as TE, drug delivery and regenerative medicine [305–307]. hydrogel with impressive modulus values (~71 MPa). Under visible
By tailoring the preparation conditions, the various morphologies light and tris(2,2-bipyridyl) dichloro ruthenium (II) hexahydrate
can be generated from SF [304]. 2þ
(RuðIIÞðbpyÞ3 ) as a catalyst in SF solution, tyrosine radicals can
Amongst different SF forms, SF hydrogels are 3D crosslinked be formed, thereby allowing tautomerization of the tyrosine resi-
hydrated matrices that their structural conformation and physico- dues and the formation of SF hydrogel through di-tyrosine links
chemical properties can be modulated. The hydrogel formation can (Scheme 7) [125]. A similar method has been also used to photo-
be achieved by shearing forces (overtaxing or sonication), changing chemically crosslink of the recombinant spider silk protein,
temperature, pH or ionic concentration, as well as exposure to sol- eADF4(C16) hydrogels [312] and regenerated silk fibroin (RSF)/
vents, gases and surfactants [308]. The sol-gel transition (from ran- poly(N-vinylcaprolactam) hydrogels [313]. Such the photo-
dom coil to antiparallel b-sheet structures) of SF occurs during the crosslinking method was utilized for a co-crosslinked hybrid
process of gelation, which may be affected by many factors such as hydrogel combining Rec1-resilin and RSF hydrogels to improve
SF concentration, temperature, pH, and crosslinking agent [309]. water uptake ability and elasticity [314]. This study also confirmed
Further, SF hydrogels can be blended with other natural/synthetic the formation of inter/intra-molecular dityrosine crosslinks as well
polymers [308] and/or chemically/physically crosslinked [310] to as b-turn conformations much more than the random coil and b-
form hydrogels with improved strength properties. However, SF sheet structures. Subsequently, the structural evolution of photo-
hydrogels suffer from poor mechanical properties with low repro- crosslinked RSF and RSF hybrid hydrogels exhibited crosslinked
ducibility and difficulty in the maintenance of homogeneous reac- network structure with hydrophobic domains (dominated by b-
tion conditions in the SF solution [310,311]. sheets in 2–3 nm length scale), hydrophilic domains (dominated
In the same way, photo-crosslinking methods have been by turns and random coil in 4–20 nm length scale) and intercon-
applied for the fabrication of SF-based hydrogels. The first strategy 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.cm2 HUVECs Vasculatured 3D cell-laden scaffold for TE applications [282]
GelMA Irgacure 2959 UV, 30 s, 9.16 W.cm2 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.cm2 (6 W)
GelMA/SF Irgacure 2959 UV (320–500 nm),30 s, 7.0 mW.cm2 MC3T3-E1 Robust and tunable load-bearing cell-laden soft tissue engineering scaffold [127]

GelMA/Collagen LAP UV (365 nm), 5 min, 3.4 mW.cm2 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.cm2 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.cm2 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.cm2 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.cm2 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]
cm2 preosteoblasts
GelMA/Ch Irgacure 2959 UV (365 nm), 30 s, 1.5 W.cm2 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]
cm2 blindness
Cold soluble gelatin-based VA-086 UV (375 nm), 1.5 mW.cm2 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.cm2
GelMA VA-086 Vis (440 nm), 2 min, 10 mW.cm2 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.cm2 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.cm2 ASCs Bioactive cell-laden hydrogel-based scaffold for intervertebral disc repair [294]
AMSA/AG Irgacure 2959 UV (365 nm), 15 min, 1 mW.cm2 L929 cells Hydrogel-based scaffold with tunable mechanical properties for TE [136]
applications
GELMA Irgacure 2959 UV, 30 s, 100 mWcm2 —— 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.cm2 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.cm2 Embryonic Medullary Reticular Cells HA-modified GelMA hydrogel as the scaffold for embryonic neurons for [118]
nerve cell growth induction and maintenance
2

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]
cm2
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.
HO Ru(III) Nearby
O O HO HO HO HO
HO H
-H+ . H
Tyr . H
Tautomerization .
-Ru(II)
SF 1 SF 1 SF 1 SF 1 SF 2 SF 1 SF 2
Tyr radical Intermeduate SF 2
Light
Ru(II)(bpy)32+ Ru(III)(bpy)33+ + SO42- + SO41-
452 nm
2þ
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- the formed crystalline beta-sheets of fibroin chains entangled
geneity of pore size distribution in the microscale decreased by within the PVA 3D network [320]. According to Zhou et al. report,
adding Rec1-resilin or poly(N-vinylcaprolactam) [315]. maleilated chitosan (MCS)/methacrylated silk fibroin (MSF)
The other study was suggested flavin-mononucleotide pho- micro/nanocomposite hydrogels were prepared for cartilage repair
toinitiator, a nontoxic water-soluble variant of riboflavin, could as TE scaffolds. The photo-crosslinking resulted in hydrogel forma-
be used for SF hydrogel fabrication, which can make possible to tion through vinyl groups linkages on the side chains of MCS and
use for abnormal corneal diseases [316]. The mechanism of SF- MSF, as well as the hydrogels loaded with transforming growth
riboflavin photo-crosslinking described as forming inter-covalent factor-1 improved cytocompatibility and cell proliferation toward
bond formation between tyrosine groups under visible light. Incor- to mouse articular chondrocytes [126].
poration of graphene oxide into RSF matrix has been reported to Recently, using a combination of sonication and photo-
improve the mechanical and adhesive properties of RSF-based crosslinking methods, a cell-encapsulated IPN hydrogel based on
hydrogels by a ruthenium mediated photo-crosslinking method GelMA and SF has been made, which was able to apply as a 3D cell
[317]. The photo-crosslinked hydrogel formed tacky hydrogels scaffold for load-bearing soft TE [127]. The sonication process
with high toughness (~2.4 MJm3), which could be attributed to induced the formation of SF b-sheet structures, followed by the
increasing b-sheet content and formation of tyrosine oxidation photo-initiated radical polymerization of GelMA to form the hybrid
products of a proportion of tyrosine amino acids in RSF during hydrogels incorporating MC3T3-E1 pre-osteoblasts.
photo-crosslinking in the presence of graphene oxide. A summary table of the above-mentioned photo-crosslinking
The second strategy comprises techniques involving chemical methods applied for making SF-based hydrogels is provided herein
modification of SF chains which transform reactive amino acid (Table 7). This table represents an overview of types of SF hydro-
residues into reactive olefinic functional groups such as methacry- gels formed by different photo-initiated crosslinking methods,
late and further subjected to photo-polymerization. Kim et al. biomedical studies, and proposed applications.
reported the synthesis of SF-methacrylate hydrogel using a con- Collectively, the photo-crosslinked SF-based hydrogels have
trolled UV photo-crosslinking method, which resulted in hydrogel been constructed by three strategies that they are elucidated along
formation by chain-growth radical polymerization of methacrylate with the principles of their formations. These photo-crosslinking
and also provides good water-solubility, higher elasticity and thix- processes can provide the hydrogels with high applicability and
otropic property [310]. Likewise, the fabrication of dually- tunability that endowed unique structural characteristic properties
crosslinked SF hydrogel scaffolds has been accomplished by the and high performance (e.g., transparency, resiliency, and injectabil-
methacrylated derivative of SF in the presence of diphenyl(2,4,6-tri ity). Additionally, cells and/or bioactive factors can be encapsu-
methylbenzoyl) phosphine oxide photoinitiator for bone TE [318]. lated/delivered in a minimally invasive manner with highly
An SF hydrogel as a bioink for digital light processing 3D printing, in vitro/in vivo compatibility, highlighting their potential suitability
which consists of SF covalently immobilized with glycidyl for designing advanced silk-based hydrogel material in biomedical
methacrylate, has been shown to printability and support NIH/3T3 applications.
cell processes within the hydrogel [319]. The hydrogel formation is
driven by vinyl double bonds formation with each other intra- 6. Conclusions and future remarks
chain or between chains depending on LAP and modified SF con-
centration, and also with physical entanglement of SF chains. Despite the significant progress in the field of biomaterials, the
The third strategy for the fabrication of photo-crosslinked SF- design and development of more efficient biomaterials for biomed-
based hydrogels is combination/blending with other photo- ical applications are still on demand. In general, biomaterials are
crosslinkable materials. An in situ assemblies of SF-based hydrogel categorized into metallic, ceramic, and glasses, polymeric, and
composed of calcium phosphate-coated SF microfibers (CaP@mSF) composite. Among these, polymer-based biomaterials have
and HA dually linked with acrylamide and bisphosphonate groups received a great deal of interest mainly due to their inherent
(Am-HA-BP) as binder developed and implanted into rat cranial physicochemical as well as biological features. The most important
defects with 8 mm of diameter. The dually crosslinked hydrogels advantages of polymeric biomaterials are biocompatibility, steriliz-
containing both Ca2+BP coordination bonds and photo- ability, adequate mechanical and physical properties, excellent
crosslinkages between acrylate groups provided excellent stability, processability in most cases, and manufacturability.
enhanced stem cell proliferation, and osteogenesis in vivo [124]. In Despite the unprecedented physicochemical and biological
a study by Kundu et al. an SF/PVA methacrylate semi-IPN hydrogel properties of natural polymer-based hydrogels, they suffer from
was photo-crosslinked in the presence of Irgacure (I-2959) to tai- some critical drawbacks, as mentioned in the hydrogel section.
loring structural and releasing properties. Upon photo- Therefore, new synthetic, semi-synthetic, and bioengineering
polymerization, the vinyl groups of PVA chains crosslinked and strategies should be developed to address the above-mentioned
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 cm2)
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

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Coordination Chemistry Reviews 420 (2020) 213432

Contents lists available at ScienceDirect

Coordination Chemistry Reviews

Natural polymers-based light-induced hydrogels: Promising

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

Scheme 1. The overall mechanism of photo-polymerization.

the above-mentioned approaches. The overall mechanism of

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

a) Unimolecular homolytic cleavage (Type I)

4.4. What is the best choice?

It is well documented that applying light sources emitting in

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

Abbreviations: AdMSC: Adipose-derived mesenchymal stem cells, SB: Sodium benzoate.

Hyaluronic acid (C14H21O11)n Blue: glucuronic acid

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

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

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

(continued on next page)

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

approaches of natural polymers-based hydrogels. Various strate-

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

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

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

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

in this approach crosslinking density and matrix stiffness can be

As load-bearing soft TE scaffold

As a candidate for bone TE

with a wide range of biofabrication techniques such as microflu-

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

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

h-MSCs Wistar rat

polymerization approach, the low penetration depth and loss of

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

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

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

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

mers or double bonds are the most important drawbacks of this

Applied light (nm), duration (min)

365, variable based on layer type,

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

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

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

365, 15, 0.01

photo-polymerization is a suitable strategy for forming hydrogels

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

toinitiator system (improving the solubility of photosensitizer and

for the fabrication of hydrogels in the biomedical purposes both

Stimuli-responsive natural polymers based-hydrogels can be

fabricated using photo-polymerization approach for the develop-

ment of on demand DDSs or other biomedical devices with remote

trol the frequency and dosage of cargo. Fabrication of hydrogel

comparison with bulk hydrogels, the nanosized hydrogels have

SF-GelMA IPN hydrogels

numerous advantages, including good internalized into cells to

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

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

cine). The most interesting achievement with photo-

polymerization technique in recent years is controlled radical

the synthesis of macromolecules with narrow dispersity, and