Gelatin-based scaffolds: An intuitive support structure for regenerative therapy

Gelatin-based scaffolds: An intuitive support structure
for regenerative therapy
Adib Bin Rashid1
, Nazmir-Nur Showva2
and
Md Enamul Hoque2
Abstract
Advanced regenerative therapy aims to repair pathologically
damaged tissue by cell transplantation in conjunction with
supporting scaffolds. Gelatin-based scaffolds have attracted
much attention in recent years due to their great bio-affinity that
encourages the regeneration of tissues. Nowadays, by
strengthening gelatin-based systems, cutting-edge methods like
3D bioprinting, freeze-drying, microfluidics and gelatin func-
tionalization have shown excellent mimicry of natural tissue. The
fabrication of porous gelatin-based scaffolds for wider tissue
engineering applications including skin, cartilage, bone, liver,
and cardiovascular is reviewed in this work. Additionally, the
crosslinking procedures and the physicochemical characteris-
tics of the gelatin-based scaffolds are also studied. Now, gelatin
is considered one of the highest potential biomaterials for
impending trends in which the gelatin-based scaffolds are used
as a support structure for regenerative therapy.
Addresses
1
Department of Industrial and Production Engineering, Military Insti-
tute of Science and Technology (MIST), Dhaka, Bangladesh
2
Department of Biomedical Engineering, Military Institute of Science
and Technology (MIST), Dhaka, Bangladesh
Corresponding author: Hoque, Md Enamul (enamul1973@gmail.com)
Current Opinion in Biomedical Engineering 2023, 26:100452
This review comes from a themed issue on Futures of BME: Sustain-
able Medical Materials 2023
Edited by Seeram Ramakrishna, Aldo Roberto Boccaccini, Mina
Zare and Kirsi Mikkonen
Received 6 October 2022, revised 6 December 2022, accepted 5
February 2023
Available online xxx
https://doi.org/10.1016/j.cobme.2023.100452
2468-4511/© 2023 Elsevier Inc. All rights reserved.
Keywords
Biomaterials, Gelatin, Scaffolds, Regenerative therapy, Tissue
engineering.
Introduction
Due to its cutting-edge methods for repairing damaged
tissues, tissue engineering has attracted much interest
in recent years. Traditional therapies often restore the
injured tissue’s final structure to the healthy tissue or
organ but do not completely refurbish the affected tis-
sue’s functional and structural responsibilities [1].
Diseases and injuries that destroy tissue are major
causes of mortality globally, accounting for millions of
deaths annually. Tissue damage profoundly affects the
quality of life and increases healthcare costs. By repair-
ing, recreating, or enhancing the function of damaged
tissue, tissue engineering could manage diseases
including chronic wounds, osteoarthritis, heart disease,
and organ impairment [2].
To encourage the proliferation of new cells and facilitate
healing, tissue engineers often use biomaterials. These
should not only act as a supporting structure for cells but
also supply cells with both structural support and
beha vioral signals. As gelatin has low toxicity, excel-
lent biodegradability, and biocompatibility, it has been
integrated into various scaffolding methods [3]. For
example, Yao and colleagues have shown gelatin-based
scaffolds’ potential to enhance osteogenesis both
in vitro and in vivo by stimulating osteoclasts [4].
The development of self-healing hydrogels is another
tactic that has been gaining traction as of late due to its
growing importance. The latter demonstrates that it is a
potentially useful substitute in highly loaded tissues,
like bone, because of the regeneration qualities that
exist after these tissues collapse. The gelatin amino
groups were joined with the amylopectin aldehyde
groups in the process by which Vahedi et al. developed a
gelatin-based injectable and self-healing scaffold [5].
This resulted in hydrogels that could recover their form
while maintaining their rheological features.
A significant amount of thought has also been put into
producing hydrogels that can adhere to injured tissues
and/or have conductive qualities. Gelatin, which can
improve cell adherence, could be used as a stage to
incorporate adhesive hydrogels into tissue [6]. In a
analogous manner, gelatin’s tertiary structure can
improve the mechanical features of sticky hydrogels [7].
Cao et al. developed an organic hydrogel with good
tackiness, stretchability, and mechanical features [8].
On the other hand, Hu and colleagues came up with a
conductive hydrogel to reconstruct peripheral nerves. In
this case, conductivity was accomplished through
graphene oxide, while the cell adhesion and biocom-
patibility features were enhanced through gelatin.
The most recent developments in the arena of tissue
engineering involving gelatin are the primary focus of
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this review. The utilization of gelatin biomaterials for
tissue replacement, scaffolds, and cell support will be
discussed in this article. The current difficulties, the
most recent developments, and the most significant
outcomes of gelatin-based methods are also discussed in
this review.
Overview of gelatin
Gelatin is a congealing prepared from animal collagen
that is tasteless, translucent, colorless, or light yellow. It
is a biopolymer with a high molecular weight that is
produced when proteins are hydrolyzed. Pig, cow, fish,
and poultry collagen are often used to make gelatin.
Animals’ tendons, ligaments, bones, and skin all contain
gelatins. Due to its unique amino acid composition,
which Gly-Pro-Hyp dominates, gelatin has some unique
functional properties, such as the ability to gel, the ca-
pacity to bind, increased viscosity, and the ability to
produce film-foaming [9].
Gelatin has been incorporated into several systems since
the advent of biomaterials for tissue regeneration,
including scaffolds, injectable hydrogels, and drug de-
livery methods [10,11]. Its promising features, like low
toxicity, biocompatibility, and, biodegradability, promote
greater cell proliferation, differentiation, and adhesion
by body enzymes (metalloproteinase) without causing
any immune reaction. Additionally, due to its afford-
ability, it has been used to create various systems,
including hydrogels for the sustained delivery of
chemotherapeutic agents in cancer treatment and mi-
croparticles for the augmentation of bone regeneration
in a broad variety of tissues (bone, neural and skeletal).
Gelatin is also well recognized for its capability to absorb
water. This quality is extremely appreciated in tissue
regeneration because porosity allows nutrition and
oxygen transport for healthy cell development [12,13].
The manipulation of gelatin comes with several possible
downsides, even though there are many benefits; this
material is acceptable for use in tissue engineering. This
polymer’s lack of thermo stability is a characteristic that
immediately comes to mind; at different temperatures,
it may either take the shape of a solid or a gel. Cross-
linking the gene sequences in question chemically or
physically is one of the most prevalent ways of getting
around this constraint [14,15].
Recent advancement of gelatin-based
scaffold fabrication
Nowadays, fabrication technologies (Figure 1) that can
simplify the inclusion of cells and growth factors are
extremely trendy for optimal scaffold construction.
Advanced production strategies that create highly
configurable scaffold geometric shapes are needed for
specific medical necessities and to fabricate patient-
specific implants. These techniques must be able to
produce the scaffolds in large quantities. Freeze drying,
electrospinning, 3D printing/additive manufacturing
(AM), and microfluidic devices are some current methods
that can produce gelatin-based scaffolds. Other conven-
tional methods include gas foaming, phase separation, and
particle leaching. AM can be broken down further into
digital light processing (DLP), direct ink writing (DIW),
stereolithography (SLA), selective laser sintering (SLS),
and fused deposition modeling (FDM) [16,17].
Bioprinting
Researchers looking at efficient methods for fabricating
3D scaffolds have shown a significant interest in the
technologies behind 3D printing. The fabrication of a
three-dimensional scaffold can serve as the simulated
microenvironment, which allows the 3D printing tech-
niques to play a vital role in stimulating the intrinsic
characteristics of the natural extracellular matrix (ECM)
[18].
Using 3D scanner to produce a specified CAD model of
the damaged organ, AM makes it possible to manufac-
ture customized three-dimensional scaffolds for indi-
vidual patients. Tytgat et al. used extrusion-based 3D
printing to construct photo-cross-linkable methacry-
lated gelatin (Gel-MA) scaffolds with pore sizes 200e
600 mm [19].
The most recent developments in 3D bioprinting have
prepared the way for a new trend known as 4D bio-
printing, which has shown encouraging outcomes. These
developments have been made possible by the im-
provements in 3D bioprinting. Using 4D bioprinting,
3D-printed items can modify their behavior in response
to environmental conditions, like pH or temperatures.
This novel approach offers several benefits, the most
significant of which is the facilitation of the creation of
structures that are more adept at imitating real tissue
and adjusting to interfaced tissues [20].
Electrospinning
Electrospinning is a procedure that includes drawing a
stream of an electrically charged polymer that is in a
viscous condition or solution into fiber using electro-
static forces. The three essential elements that make up
this process are the high-voltage power supply, the
spinneret with the syringe pump, and the metal col-
lector. Typically, a scaffold is made by connecting the
spinneret and the fiber collector to opposite-ended
electrical terminals. This results in the creation of an
open structure. The difference in potential between the
terminals allows the material to be pulled out and
deposited onto an accumulator, which makes the pro-
duction of nanoscale fibers easier [21,22].
Electrospinning was used by Heidari et al. to produce
nanofibrous mats utilizing gelatin, PCL, and graphene to
apply them in neural tissue engineering. Antibacterial
2 Futures of BME: Sustainable Medical Materials 2023
Current Opinion in Biomedical Engineering 2023, 26:100452 www.sciencedirect.com

capabilities have been shown by these electrospun mats,
as well as controlled medication release. Because of their
high biodegradability and hydrophobicity, these mats are
ideally suited for use as electrically conductive scaffolds
for the proliferation of neural cells [23].
Using emulsion electrospinning, Akbarzadeh et al.
created gelatin-PCL/PVA nanofibers. By adjusting the
electrospinning process parameters, polymers, organic-
to-aqueous phase ratio, solvents, and surfactants, they
could modify the scaffold’s fiber shape, pore size, bio-
logical, and mechanical properties. They proved that the
structure had promise for carrying both hydrophobic and
hydrophilic drugs [24].
Freeze-drying
Gelatin’s porous three-dimensional construction per-
mits for the flow of oxygen and nutrients, which pro-
motes cell endurance and increases rates of cell
adhesion. But for approaches to regenerative therapy,
porosity is always preferred [25]. The pore diameter can
be changed using the freeze-drying process, creating a
restructured permeable structure that can enhance cell
adhesion and the ability of gelatin to regenerate as a
biomaterial [26]. Freeze drying creates mechanically
durable gelatin-based scaffolds with pore diameters
ranging from 20 to 200 m and a porosity of about 90%.
Echave et al. recently used the Freeze-Drying method
to create a gelatin-based scaffold that is enzymatically
cross-linked [27].
Microfluidic device
Because of the potential for high gas pressure and organic
solvents to damage cells, microfluidic devices have
become more critical in creating scaffolds [28]. To define
micro and nano scales, microfluidics has been proposed as
a reliable high-tech solution. The size of the devices may
provide the perfect environment for developing cells and
tissues. More specifically, their crucial benefit over other
methods is the study of the cell’s activities while it is in a
microenvironment under controlled conditions. Micro-
fluidic devices and microfabrication procedures both
have the potential to be used in the generation of
numerous artificial tissue topologies. For instance,
microfabrication methods enable scientists to manufac-
ture hydrogel-based blocks, microparticles, and fibers
that may directly or indirectly be used as a scaffold in
tissue engineering [29]. Cell-loaded polyvinyl alcohol
Figure 1
Gelatin-based scaffold fabrication systems for tissue engineering [17].
Gelatin-Based scaffolds Rashid et al. 3

(PVA)/gelatin-based hydrogel microfibers with enhanced
viability and growth potential were created by Gohari
et al. using a flow-focusing microfluidic technique and
enzymatic crosslinking [30]. For cartilage tissue engi-
neering, Liu et al. used microfluidic 3D foaming to create
a gelatin-based hydrogel scaffold having excellent
biocompatibility and homogeneous pore size [31].
Crosslinking methods for gelatin-based
scaffolds
As was already noted, one of the most important aspects
of producing gelatin-based biomaterials is the process by
which the gelatin is cross-linked (Figure 2).There are
three basic groups of cross-linking methods: enzymatic,
chemical, and physical. The basic physical cross-linking
techniques include irradiation (high intensity electron
beam or -irradiation), plasma, and dehydrothermal
treatment. In contrast to physical approaches, chemical
cross-linking includes the creation of covalent bonds
between the gelatin polymeric chains, producing more
stable gelatin hydrogels with tunable physico-mechanical
features. Crosslinkers includes epoxides, acrylamides,
isocyanates, and aldehydes (e.g., formaldehyde and
glutaraldehyde) has been extensively utilized as gelatin
cross-linkers [32].
Alternatively, the enzyme transglutaminase, which is
present in a wide variety of animal and plant species, can
be utilized to facilitate the production of covalent cross-
linking bonds between the gelatin chains. This enzyme
catalyzes the gelatin’s acyletransferase reaction be-
tween glutamine residues and primary amino groups.
Alternately, oxidoreductases like tyrosinase have been
used to effectively crosslink gelatin hydrogels [33].
Applications of gelatin-based scaffolds
Gelatin is a biomaterial still quite prevalent today, and it
has been demonstrated that it can be a component of
potentially useful hydrogels, such as mending them-
selves, adhering to surfaces, or conducting electricity. In
recent scientific literature reports, gelatin-based
hydrogels have been shown to be a versatile and highly
adaptable platform for numerous tissue engineering
uses (Figure 3), including those in the fields of bone,
cartilage, muscle, cardiovascular, neural, liver, and
kidney tissue engineering [34].
Figure 2
Schematic demonstration of typical cross-linking techniques for manufacturing gelatin-based systems [32].

Bone and cartilage tissue regeneration
Replacement of injured cartilage and bone has long used
cells encased in gelatin scaffold. However, materials
used to substitute tissues must have biochemical and
physical qualities similar to those of physiological tissue.
Bone graft substitutes, for example, should mimic the
cortical layer and the cancellous/trabecular layer of bone
[21,35].
Bozorgi et al. developed Cu-substituted nano-
hydroxyapatite/chitosan/gelatin (nHA/Cs/Gel) scaffolds
that mimic the mechanical strength and porous structure
of cancellous bone [36]. Scaffolds of nHA.Cu5%/Cs/Gel
shows prolonged degradation and Cu release, calcium
deposition, proliferation, viability, and osteoblast attach-
ment, making it promising imminent utilization in bone
tissue engineering. Again, Tabatabaee et al. has investi-
gated that poly (2-hydroxyethyl methacrylate)
(PHEMA) and gelatin could provide a biocompatible
structure for bone tissue engineering [37]. Their in-
quiries also exhibit that graphene oxide (GO) undeniably
impacts repairing damaged bone tissue.
Asadi et al. have developed a novel nanocomposite
hydrogel based on gelatin/polycaprolactone poly-
ethylene glycol (Gel/PCEC TGFb1) for cartilage
tissue engineering, which has the potential for the
growth and differentiation of human mesenchymal stem
cells derived from adipose tissue (h-AD-MSCs) [38].
On the other hand, Han et al. used highly concentrated
gelatin and poly (lactic-co-glycolic acid) solution to
formulate a structural and functional biomimetic scaf-
fold by melt electro-writing (MEW) technology for
cartilage repair [39].
Cardiovascular tissue regeneration
Heart patches, which could provide stem cells or
differentiated cardiac cells as a scaffold to build viable
and functional cardiac tissue, are one tissue engineering
technique used to reconstruct the injured cardiac tissue.
Selecting the appropriate biomaterials for scaffold con-
struction and producing the aligned patterns of ECM-
like formations, which are necessary for the contrac-
tion, retention, and directional growth of cardiomyo-
cytes, are two problems in cardiac tissue engineering
[40].
Bejleri et al. bio-printed a customizable cardiac ECM
hydrogel (cECM)-laden 3D patch using GelMA, human
cardiac progenitor cell (hCPCs), and cECM as the
bioink [41]. This cardiac patch had extensive vascular-
ization, suggesting it might promote better
Figure 3
Applications of gelatin-based scaffolds for tissue regeneration [34].

differentiation and angiogenesis during heart repair.
Recently Nagiah et al. developed furfuryl-gelatin elec-
trospun scaffolds for cardiac tissue engineering [42].
Gil-Castell et al. also created functional scaffolds out of
conductive polycaprolactone/gelatin/polyaniline nano-
fibers for cardiac tissue regeneration [43].
Liver regeneration
Around two million people worldwide decease each year
due to liver cirrhosis, hepatocellular cancer, and viral
hepatitis problems. In addition to immunosuppressive
medications and orthotopic liver transplants (OLT),
tissue engineering may be an effective method for
lowering the mortality rate of liver illnesses [44,45]. Chu
et al. hypothesized that a combination of chitosan/
gelatin (CG) and decellularized liver extracellular
matrix powder (dLECM) prepared from the porcine
liver, would augment wound healing and reduce post-
operative complications after liver surgery [46].
Harwate et al. developed gelatin/chitosan macroporous
scaffolds integrated with customizable hollow channels
for liver tissue engineering [47].
Nerve tissue engineering
Patients with nervous system injuries or traumas often
lose sensory or motor function and have neuropathic
symptoms due to the nerve’s reduced regenerative
ability. Direct end-to-end surgical reconnection is a
typical treatment for minor nerve transection injuries in
the peripheral nervous system (PNS). Autograft, allo-
graft, and xenografts have significant disadvantages,
including donor insufficiency, intricate procedures, and
donor site morbidity. Allograft patients must take
immune-suppressants forever after surgery to avoid
rejection. Biocompatible and biodegradable artificial
nerve grafts can restore nerve function [48].
In this regard, gelatin-based scaffolds could be used to
evaluate morphological and biological signals on in vitro
brain cell behavior. By combining GelMA hydrogel with
poly (2-hydroxyethylmethacrylate) in varying pro-
portions, Dursun et al. created a nerve guide that con-
nects the ends of a damaged nerve (pHEMA) [49]. On
another study, Chen et al. have shown that Poly-
caprolactone/Gelatin (PG) fibrous electrospun scaffolds
with different percentages of Melatonin (MLT) could
be a promising alternative for nerve repair [50].
Ocular tissue engineering
In vitro, gelatin/polycaprolactone (PCL) scaffolds may
be the best substrate for retinal pigment epithelium
(RPE) cells since they are more hydrophilic and degrade
more quickly thanks to the addition of peptide bio-
polymers. Additionally, PCL enhances the scaffold’s
physical characteristics, lowering its cytotoxicity. Hyal-
uronic acid, gelatin-based scaffolds, and carboxymethyl
chitosan (CMCTS) as transplanting carriers to induce
corneal restoration. The produced blend membrane
proved suitable for efficient corneal wound healing and
was transparent and biodegradable [51].
Utilizing electrospinning gelatin and polycaprolactone
(PCL) scaffolds crosslinked with glutaraldehyde (GA),
research has been done on creating synthetic implants
for reconstructing corneal stromal tissue. The results
showed that the material is a good candidate for corneal
repair because it has strong mechanical strength, flexi-
bility, and can enable adhesion and the growth of human
corneal stromal cells (hCSC). Lu et al. created a porous
hydrogel construct based on methacrylated gelatin/
polyethylene oxide for corneal stromal regeneration
[52].
An injectable, photocurable gelatin structure composed
of thiolated gelatin and acrylated gelatin, with tunable
biological, mechanical, and biodegradable features, has
been created as a potential cell-supportive scaffold for
corneal wound restoration. As a potential corneal sub-
strate, the produced hydrogel showed high cell survival
levels and was promised as a scaffold [53].
Periodontal tissue engineering
Many oral disorders, particularly inflammatory condi-
tions like gingivitis and periodontitis, can severely
damage the periodontium, and because of lack of in-
formation, it is challenging to appropriately address such
tissue abnormalities from a therapeutic viewpoint [54].
Polymer-based, biodegradable materials have demon-
strated suitability as scaffolds for in vitro modeling of
intricate biological processes, including the regeneration
of soft and hard tissues, which are crucial in periodontal
tissue engineering. Electrospinning was used by Diet-
erle et al. to create nonwoven-based scaffolds for peri-
odontal tissue engineering with 16% gelatin/5%
hydroxyapatite which was cross-linked by glyoxal [55].
Human periodontal ligament fibroblasts (PDLFs) and
mesenchymal stem cells (hMSCs) may effectively
adhere to and survive on these new in situ cross-linked
electrospun nonwoven scaffolds.
Skin tissue engineering/wound healing
The skin is the body’s largest organ and the first line of
protection against environmental hazards; as such, it is
also the most vulnerable to damage from the outside
world. Acute inflammation, persistent inflammation,
granulation tissue formation, foreign body reaction, and
remodeling are all stages in the wound-healing cascade,
a complex physiological process [56]. Skin grafts and
other therapeutic aids may be necessary depending on
the amount and severity of the injury, making therapy a

complex clinical issue. Techniques involving the appli-
cation of artificial scaffolds to stimulate skin regenera-
tion are currently being explored. The production of
skin tissue designed scaffolds may benefit from using
nanofibers that thrive under optimal conditions.
Recently, Akhtar et al. developed polyvinyl alcohol/
sodium alginate-di-aldehyde-gelatin-based antibacterial
nanofibers by centrifugal spinning intended for skin
tissue engineering [57]. Yu et al. developed a
paeoniflorin-sodium alginate-gelatin skin scaffold to
treat diabetic wounds [58].
Conclusions and future directions
Although our knowledge of gelatin and its applications
for tissue engineering has greatly increased over the past
few decades, much more study is still required to realize
gelatin’s full therapeutic potential. Gelatin is the best
natural source for biomaterials because of its inherent
biocompatibility, assured biodegradability, and avail-
ability. Gelatin is also significantly less expensive and
does not trigger an immunological reaction in the body.
Last but not least, its molecular simplicity makes it
more amenable to alterations for improved functionality.
Gelatin-based biomaterials can be a fantastic addition to
today’s material-based treatments with the right modi-
fications, such as the creation of gelatin/ECM compos-
ites or the combination with other chemicals or growth
factors. The field of biomaterials has advanced quickly
since the introduction of 3D/4D printing, Electro-
spining and microfluidic technologies. Today, gelatin is
used as a basic material in bioink formulation for
manufacturing numerous functional scaffolds that pro-
vide a remedy for repairing injured organs and tissues.
These innovations are expanding the therapeutic pos-
sibilities for gelatin. Drug-delivery systems, self-healing
hydrogels, conductive hydrogels, and sticky hydrogels
have benefited from gelatin’s qualities to enhance their
performance. Gelatin has also been promoted as a ma-
terial for the in vitro testing novel medications or ther-
apeutic routes. It could be helpful when patterns change
and a new era that will equally emphasize disease
diagnosis and therapy. In conclusion, gelatin is a auspi-
cious biomaterial for forthcoming theranostic and ther-
apeutic techniques due to its adaptability to various
conditions.
Declaration of competing interest
The authors declare no conflict of interest.
Data availability
No data were used for the research described in the
article.
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