Nanotechnology Reviews 2022; 11: 2493–2512
Review Article
Feng Wang*, Yu Gao, Hao Li, Lihui Zhou, Huijing Shi, Sining Feng, Jing Chen, and Ziqing Mei*
Effect of natural-based biological hydrogels
combined with growth factors on skin wound
healing
https://doi.org/10.1515/ntrev-2022-0122
received December 21, 2021; accepted May 6, 2022
Abstract: Skin wound healing is a continuous and com-
plex process affected by many factors. Growth factors
play an important role in the process of wound healing.
Local application of growth factors can significantly pro-
mote wound healing. However, the degradation and time
dependence of growth factors require appropriate delivery
systems to help them play a role in wound healing. In
recent years, wound dressing products with hydrogels as
matrix materials or main components have shown obvious
advantages in promoting wound healing. By modifying the
hydrogel or combining it with other factors or materials
that are beneficial to wound healing, the healing effect
can be further enhanced. This review will introduce the
research status of growth factors and hydrogels based on
natural biological materials in skin wound repair and
review the effects and research progress of the combination
of growth factors and hydrogels in skin wound healing.
Keyword: skin wound healing, natural-based biological
hydrogels, growth factors, therapeutic effects, biocompatibility
1 Introduction
Skin is the largest organ of the human body. It is wrapped
on the surface of the body and is in direct contact with the

* Corresponding author: Feng Wang, Department of Biology, Key
Laboratory of Molecular Medicine and Biotherapy, School of Life
Science, Beijing Institute of Technology, Beijing, 100081, China,
e-mail: wfeng@bit.edu.cn
* Corresponding author: Ziqing Mei, School of Chemistry and
Biological Engineering, University of Science and Technology
Beijing, Beijing 100083, China, e-mail: Marina1977@163.com
Yu Gao, Hao Li, Lihui Zhou, Huijing Shi, Sining Feng, Jing Chen:
Department of Biology, Key Laboratory of Molecular Medicine and
Biotherapy, School of Life Science, Beijing Institute of Technology,
Beijing, 100081, China
Open Access. © 2022 Feng Wang et al., published by De Gruyter.
International License.
external environment. It has the functions of protection,
excretion, regulating body temperature, and feeling external
stimulation [1]. The tight and intact skin structure is the
decisive factor for the proper functioning of the skin [2].
However, under the action of a variety of adverse factors,
the integrity of the skin is easily damaged to form wounds,
which then lose its normal structure and function. The
regenerative ability of skin makes the majority of skin inju-
ries basically recover after a period of time, but the skin
healing process is dynamic and continuous, and this process
is easily affected by a variety of external factors [3]. Infection,
burns, bedsores, diabetes, and other factors can cause the
abnormal healing process of skin wounds, resulting in non-
healing or delayed healing of wounds and the formation of
chronic wounds [4]. Therefore, it is very important to carry
out appropriate intervention and protection measures in the
process of wound recovery and provide a suitable environ-
ment and conditions for wound healing.
Wound dressings can cover the skin wound surface,
protect the damaged skin, and play a certain role in pro-
tecting the wound [5]. Traditional wound dressings such
as gauze, cotton balls, and other natural fibrous materials
can keep the surface of the wound dry while insulating
the wound from the outside environment and acting as a
physical barrier [6]. However, traditional wound dres-
sings have problems, including scabbling with exudate
and wound adhesion. Therefore, it is of great significance
to develop a more suitable dressing for wound healing
[7]. The ideal wound dressing should have the following
abilities [8]:
1) maintain a moist environment for the wound, pre-
venting wound surface moisture from evaporating
and drying,
2) excellent gas exchange ability, allowing oxygen to
contact the wound through the dressing,
3) good water imbibition, and preventing the buildup of
fluid seepage on the wound surface,
4) antimicrobial properties or sterilization ability, redu-
cing the occurrence of wound infection opportunities,
5) hemostatic function,
This work is licensed under the Creative Commons Attribution 4.0
2494  Feng Wang et al.
6) good adhesion, close attachment to the wound,
7) certain mechanical strength, preventing physical sec-
ondary injury to the wound,
8) good biocompatibility, no allergic reactions, and
9) economic raw materials that are easy to obtain and
inexpensive.
Under the background of the ideal wound dressing
mentioned above, an increasing number of materials
have been developed and applied for the preparation of
wound dressings in recent years, such as fiber spinning,
semipermeable membranes, fiber sponges, hydrogels, etc.
Among these materials, hydrogels are the most competi-
tive candidates for wound dressings due to their excellent
hydrophilicity, adhesion, permeability, and biocompat-
ibility [9]. Compared with synthetic hydrogels, natural bio-
material hydrogels from living organisms and the natural
environment are easier to prepare and have better biocom-
patibility and degradability [10]. In addition, the matrix
materials of natural hydrogels are rich in functional groups,
which provide corresponding binding sites for stable binding
of growth factors. The growth factor loaded into the hydrogel
extends the time it is hydrolyzed, thus prolonging the dura-
tion of the growth factor’s action. The sustained-release
ability of the hydrogel can make the growth factor release
steadily and continuously, avoiding the early high concen-
tration and aggregation of growth factor and the rapid
attenuation of concentration in the later period when the
growth factor is directly applied. Therefore, using natural
hydrogels as carriers for carrying growth factors in skin
wound healing has inherent advantages and good applica-
tion prospects.
Although using hydrogels as wound dressings can
protect wounds to a certain extent, hydrogels themselves
lack the ability to regulate and promote the healing pro-
cess of skin [11]. Growth factors are polypeptide sub-
stances secreted by cells that regulate cell growth and
cell function by binding with specific cell membrane recep-
tors [12]. In the process of skin wound repair, a variety of
growth factors are secreted and released successively or
simultaneously in the injured area, participating in the
repair process of neovascularization, collagen synthesis,
inflammatory regulation, epithelial regeneration, and so
on [13]. Adding growth factors to dressings can cause
growth factors to directly act on local wounds to regulate
skin healing while releasing long-term effects, which has
good application prospects and effects [14]. This review
introduces the normal structure of skin and the local patho-
logical changes and healing process of skin after wound
formation. Next we introduced the role and application of
various growth factors in skin wound repair. Finally, we
describe the properties of natural biomaterial hydrogels
and the effect of combining hydrogels and growth factors
in skin wound repair and briefly summarize the advantages
and disadvantages of this treatment combination. This
review will systematically introduce the mechanisms and
effects of the combined application of various natural hydro-
gels and growth factors in wound repair. In this article, we
summarize the common natural hydrogels and growth fac-
tors corresponding to skin injury repair, and introduce the
advanced experimental combinations of natural hydrogels
and growth factors in recent years, so as to provide reference
for the future research on natural hydrogels and growth
factors as therapeutic combinations.
2 Characteristic of wound healing
2.1 The structure and function of normal skin
tissue
Normal skin tissue consists of the epidermis and dermis.
The epidermis layer is located on the outside of the skin.
More than 95% of the cells in the epidermis are keratino-
cytes, with the rest made up of melanocytes, Merkel cells,
and Langerhans cells [15]. As shown in Figure 1, the epi-
dermis is divided into a corneous layer, transparent layer,
granular layer, spinous layer, and basal layer from out-
side to inside [16]. The structural integrity and activity of
the cells in each layer increased from the outside to the
inside, and the cells in the inner layer gradually trans-
formed to the outer layer over time [17]. The cells of the
corneum have been completely keratinized, and the des-
mosomes between the cells are loose and shed to form
dandruff [18]. The lucidum layer consists of 2–3 layers of
flattened cells with fuzzy cell boundaries and the absence
of nuclei and organelles [19]. The cells in the granular
layer are mainly spindle cells, with nuclei and organelles
that begin to degenerate, and there are many lamellar
granules and keratohyalin granules in the cells [20].
There are a large number of spinous cells in the stratum
spinosum, which have a strong protein synthesis func-
tion and can synthesize a large number of keratin fila-
ments and lamellar granules [21]. At the same time, the
desmosomes between the spinous cells are closely con-
nected, which can prevent external substances from pene-
trating the epidermis and has the function of protection
and isolation [22]. The basal layer is the most important
part of the epidermis. The self-renewal and repair of the
epidermis mainly depends on the basal cells attached to
the basal membrane in the basal layer [23]. These basal
cells are the stem cells in the epidermis with the ability to
 Biological hydrogels combined with growth factors on skin wound healing
Figure 1: Normal structure of skin. Normal skin tissue consists of the epidermis and dermis. The epidermis is divided into a corneous layer,
transparent layer, granular layer, spinous layer, and basal layer from outside to inside.
proliferate and differentiate [24]. In the process of prolif-
eration, basal cells can separate from the basal membrane
and differentiate into spinous cells, which can replenish
the number of spinous layer cells and play a role in self-
renewal [21]. After skin injury, the number and activity of
basal cells have an important influence on the healing
effect.
The dermis is a dense connective tissue located below
the epidermis, which is divided into the papillary layer and
the reticulated layer. There are abundant capillaries in the
papillary layer, which protrude to the epidermis to form
papillary structures, increasing the contact and connection
between the epidermis and dermis and facilitating the epi-
dermis to obtain nutrients from the dermis [25]. The reticu-
lated layer contains a large number of collagen fibers, which
interweave to form a network that provides skin with tough-
ness and elasticity [26]. Under normal conditions, the basal
cells in the basal layer of the epidermis obtain nutrients from
the dermis, and while proliferating and renewing them-
selves, some of the basal cells differentiate into spinous cells
to supplement the number of spinous cells and maintain
normal epidermal functions [27]. As time passes, the cells
in the lateral layers gradually shift to the more lateral
layers until they fall off as keratinocytes.
2.2 Physiology of wound healing
The normal skin tissue structure can protect the internal
tissues and organs of the body from damage by external
harmful substances and is the first barrier to maintain
homeostasis of the human body environment. When
the skin is injured by external factors such as surgery,
external forces, chemical reagents, heat, and electric cur-
rent, the normal physiological structure of the skin is
 2495
damaged, and the protective effect of the body weakens
or disappears. The process of skin wound healing can be
divided into four continuous stages, namely, hemostasis,
inflammation, proliferation, and remodeling, as shown
in Figure 2 [28]. When injury occurs, the blood vessels
in the damaged area rupture, the subcutaneous matrix in
the blood vessels is exposed, and the glycoproteins on
the platelet membrane bind with the collagen of the base-
ment membrane, making the platelets adhere to and be
activated [29]. Activated platelets release endogenous
ADP and TXA2, which in turn promote irreversible aggre-
gation of platelets, resulting in platelet thrombosis [30].
In addition to hemostasis, platelets can also release cyto-
kines and growth factors such as interleukin (IL)-1β,
tumor necrosis factor (TNF)-α, fibroblast growth factor
(FGF), and platelet derivation growth factor (PDGF) together
with the cells in the injured area and promote the migration
of neutrophils and macrophages in the wound area [31]. In
the early stage of inflammation, neutrophils first accumu-
late in the wound area and phagocytose and release reactive
oxygen species (ROS), antimicrobial peptides, proteolytic
enzymes, and other substances to remove necrotic tissues
and pathogens [3,32]. Mast cells and macrophages then
arrive at the damaged area to remove remaining cell debris
and neutrophils [33].
At the later stage of inflammation, macrophages develop
an anti-inflammatory, profibrotic phenotype that promotes
the proliferation of fibroblasts, keratinocytes, and endothelial
cells by secreting a variety of growth factors and cytokines
[34,35]. Under the action of FGF, fibroblasts provide the ske-
leton structure for cell migration, proliferation, and growth
to the wound area through the synthesis of type III col-
lagen, proteoglycan, and fibronectin [36]. At the same
time, endothelial cells at the wound site proliferate and
migrate under the stimulation of factors such as VEGF and
2496  Feng Wang et al.

Figure 2: The stages of wound repair and their major cellular components [28]. The process of skin wound healing can be divided into four
continuous stages, namely, hemostasis, inflammation, proliferation, and remodeling.

angiopoietin, forming a new capillary network, which is
necessary for tissue regeneration and granulation tissue
formation and transportation in the injured area [37]. Kerati-
nocytes from near the injured area migrate to the injured area
under the stimulation of growth factors and promote the
epithelialization of the epidermal tissue through proliferation
and differentiation [38]. When wound repair enters the remo-
deling stage, the remaining temporarily transplanted cells in
the damaged area are apoptotic, and fibroblasts synthesize
type I collagen, elastin, and other extracellular matrices [39].
Type III collagen in the extracellular matrix (ECM) of the
injured area was gradually replaced by type I collagen, the
collagen fibers rearranged into a lattice-like structure, and
the skin tissue in the injured area regained strength and
toughness similar to normal tissue [40].
divided into endogenous factors and exogenous factors. Age
is one of the endogenous factors affecting wound healing
and repair. With increasing age, the thickness of the cuticle
decreases, the activity of macrophages decreases, and the
release of growth factors and cytokines decreases [41]. These
factors lead to a prolonged proliferation period and an
increase in the time required for wound healing. In addition,
the body’s hormone level also has a certain effect on wound
healing. For example, estrogen can promote the re-epithe-
lialization of keratinocytes and the angiogenesis of endothe-
lial cells in the process of wound healing, which has a

2.3 Factors affecting wound healing

Wound healing involves many factors, and it takes a long

time from the occurrence of injury to the completion of
remodeling. Figure 3 illustrates common factors that affect
skin healing. The factors affecting wound healing are mainly Figure 3: Factors affecting wound healing.
 Biological hydrogels combined with growth factors on skin wound healing
certain promoting effect on wound healing [42]. Glucocorti-
coids and cortisol can inhibit the body’s own immune
inflammatory response, which restricts the migration and
aggregation of white blood cells to the injured area during
inflammation [43]. The healing process can also be influ-
enced by genetic factors. Studies have shown that keloids
are a wound repair abnormality with a strong genetic ten-
dency. In such people, excessive collagen deposition leads
to the formation of a large number of fibrous scars on the
wound surface, resulting in scar healing [44].
In addition to the influence of the body’s own factors
on wound healing, exogenous factors are also the main
factors affecting wound healing. Local infection after skin
injury is an important factor affecting wound healing. When
the wound is infected by S. aureus or other Streptococcus,
a large number of white blood cells migrate and gather to
the injured area, and the bacteria are removed by phagocy-
tosis of white blood cells. The process of removing bacteria
will cause the release of bacterial endotoxin, resulting in
necrosis and inflammation of the local tissues [2]. In addi-
tion, due to the increase in proinflammatory cytokines, the
number of released growth factors decreased, which inhib-
ited the growth of cells in the proliferation stage, resulting
in delayed wound healing or unhealing [45]. The nutritional
status of the body is another important factor affecting
wound healing. In the process of wound healing, a variety
of trace elements, vitamins, fatty acids, and proteins are
necessary, and the loss of any nutrients will cause the delay
of wound healing [46–48]. In addition, many chronic dis-
eases affect wound healing by interfering with platelet acti-
vation, the inflammatory response, epithelial formation,
and matrix remodeling. Diabetes, for example, affects the
migration and activation of white blood cells to the damaged
area and increases the release of proinflammatory cytokines,
leading to chronic inflammation [49]. Diabetes also causes
abnormalities in microvascular formation that inhibit kerati-
nocyte- and fibroblast-mediated epithelial reformation and
ECM remodeling [50]. Drugs and unhealthy lifestyle habits
such as smoking and drinking can also affect wound healing.
Smoking can increase the aggregation and adhesion of plate-
lets, raising the risk of blood clots [51]. Alcohol inhibits the
body’s immune response and reduces collagen formation
and matrix metalloproteinases (MMP) concentrations [52].
3 The role of growth factors in
wound repair
Growth factors are polypeptide substances secreted by cells
that regulate cell growth and cell function by binding with
specific cell membrane receptors. According to growth factor
 2497
source or the cell type that combines to play an effect,
growth factors can be divided into platelet derivation growth
factor (PDGF), vascular endothelial cell growth factor (VEGF),
epidermal growth factor (EGF), fibroblast growth factor (FGF),
nerve growth factor (NGF), transformation growth factor
(TGF), etc. Growth factors are secreted by cells in an autocrine
or paracrine manner in the synthesis and release to the envir-
onment through binding with specific receptor proteins on the
surface of the cell membrane, regulating cell proliferation dif-
ferentiation and the function of cells, including immune reg-
ulation, hematopoietic regulation, apoptosis, angiogenesis,
and tumorigenesis. In the process of skin wound repair, a
variety of growth factors are secreted and released successively
or simultaneously in the injured area, participating in the
repair process of neovascularization, collagen synthesis,
inflammatory regulation, epithelial regeneration, and so on.
Table 1 lists the growth factors involved in the process of skin
wound healing. The specific roles of various growth factors in
skin wound repair are as follows.
3.1 Role of PDGF
PDGF is a basic protein stored in the platelet α particles. It
is a dimer glycoprotein formed by two peptide chains
linked by disulfide bonds [53]. According to the difference
of two peptide chains, PDGF can be divided into 5 types:
PDGF–AA, PDGF–BB, PDGF–CC, PDGF–DD, and PDGF–AB
[54]. A variety of cells, such as macrophages, fibroblasts,
and endothelial cells, can secrete and synthesize PDGF
[55,56]. PDGF is involved in the whole process of wound
healing and plays an important role in promoting wound
healing. In the inflammatory stage, PDGF can promote the
migration of neutrophils and macrophages to the injured
site [57]. In addition, PDGF can stimulate macrophages to
secrete synthetic TGF-β, further enhancing the chemotactic
effect on inflammatory cells [55]. PDGF can also promote
the proliferation and differentiation of fibroblasts and pro-
mote the synthesis of ECM of fibroblasts [53,58]. PDGF can
promote the migration and proliferation of vascular endothe-
lial cells at the injury site and promote the formation of new
blood vessels [59]. During remodeling, PDGF can stimulate
the differentiation of fibroblasts into myofibroblasts, upregu-
late the expression, synthesize MMP, and regulate the degra-
dation and remodeling of ECM [60].
3.2 Role of FGF
There are 23 types of FGF families, among which FGF–2,
FGF–7, and FGF–10 are related to wound repair. FGF is
produced by keratinocytes, fibroblasts, endothelial cells,
2498  Feng Wang et al.

myofibroblasts, and upregulates MMP synthesis

Inhibits inflammation and reduce scar formation

smooth muscle cells, chondrocytes, and mast cells. When

myofibroblasts, and reduce collagen synthesis

Stimulates fibroblasts and differentiates into
injury occurs, the concentration of FGF increases sharply
in the injury area and stimulates the migration of macro-
phages, white blood cells, and neutrophils to the injury

Inhibits terminal differentiation of

area [61]. FGF can directly promote the proliferation and
differentiation of fibroblasts, vascular endothelial cells,
and smooth muscle cells, and promote the formation of

Promotes scar formation

Promotes scar formation

granulation tissues [62,63]. In addition, FGF can also
and scar formation
promote epithelial mesenchymal transformation by binding
with TGF–β1 [64]. FGF can also promote the secretion of
Remodeling

EGF, promote the proliferation of epidermal cells, regulate

the differentiation of fibroblasts to myofibroblasts, and
accelerate wound contraction activity, which is conducive
to early wound coverage [62]. FGF can inhibit terminal dif-
Promotes keratinocyte proliferation and angiogenesis
Promotes the synthesis of collagen, elastic fibers, and

ferentiation of myofibroblasts and reduce glial scar hyper-

synthesis, and promotes vascular endothelial cells

Stimulates epithelial cell proliferation and division

Promotes vascular endothelial cell migration and

plasia during wound remodeling [65]. bFGF can also reduce

Promotes fibroblast proliferation, improves ECM

proliferation of fibroblasts and endothelial cells

fibronectin and promote granulation formation

Promotes EMT of keratinocytes and promotes

collagen synthesis and scar formation by increasing procol-

lagen mRNA degradation and inhibiting mRNA transcrip-
proliferation and granulation formation

tion [66].
and promotes wound shrinkage
migration and proliferation

3.3 Role of VEGF

VEGF is a family that includes VEGF–A, VEGF–B, VEGF–C,

Promotes EMT
Proliferation

VEGF–D, VEGF–E, and placental growth factor (PGF).

When injury occurs, activated platelets release VEGF to
improve the lumen permeability of residual vessels, which
is conducive to the migration and aggregation of inflam-
matory cells to the injured area [67–69]. VEGF promotes
and stimulates macrophage and TGF-β
Promotes inflammatory cell migration

Promotes inflammatory cell migration

Table 1: Effects of major growth factors on wound repair in different periods

the proliferation, migration, and differentiation of vascular

Promotes inflammatory response

endothelial cells and the formation and functionalization

Chemotactic inflammatory cells

of new capillaries during the proliferation phase [70,71]. In

addition, VEGF can also promote lymphatic vessel forma-
tion by activating VEGFR–2 [72]. VEGF is also associated
with scar tissue formation during remodeling. Wilgus T. A.
found that injection of recombinant VEGF into wounds can
Inflammation

increase scar formation [73].

secretion

3.4 Role of EGF

Increases vascular

In the EGF family, EGF, heparin-binding EGF (HB–EGF),

permeability
Hemostasis

and TGF–α are mainly related to wound repair [74,75].

Platelet granules can release EGF during hemostasis, and
epithelial cells migrate from the wound to the wound
surface [76]. In the inflammatory stage, EGF can chemo-
taxis macrophages and fibroblasts to the wound surface
TGF–β1/2
Growth

and promote the inflammatory response [77]. EGF can

factor

PDGF

VEGF

NGF
EGF
FGF

stimulate the proliferation and division of endothelial

 Biological hydrogels combined with growth factors on skin wound healing
cells and epithelial cells so that the epithelial cells migrate
to the surface and promote wound shrinkage [78]. During
remodeling, EGF inhibits the inflammatory response, reduces
TGF–β1 expression, mediates collagen formation, and reduces
scar tissue formation [79].
3.5 Role of TGF–β
TGF–β mainly includes three types: TGF–β1, TGF–β2, and
TGF–β3, among which TGF–β1 plays a dominant role in
wound healing [80]. TGF–β1 can promote the aggrega-
tion of inflammatory cells such as neutrophils and macro-
phages during inflammation [81,82]. TGF–β1 promotes
the synthesis of collagen, elastic fibers, and fibronectin
in fibroblasts and the formation of granulation tissue
[83]. TGF–β1 regulates epithelial mesenchymal transfor-
mation and promotes cell migration, angiogenesis, and
fibrous tissue proliferation [84]. TGF–β1 is involved in the
synthesis of type I and III collagen during wound remo-
deling, inhibits the synthesis of MMP, reduces the degrada-
tion of collagen, and promotes the formation of scar tissue
[85,86]. TGF–β1 and TGF–β2 had similar effects on wound
healing, while TGF–β3 had opposite effects. TGF–β3 inhibits
inflammation and protein synthesis, reducing scar forma-
tion by inhibiting collagen formation [87,88].
3.6 Role of NGF
In addition to playing a role in the nervous system, NGF
also plays an important role in wound healing. NGF can
promote the proliferation and migration of fibroblasts
and keratinocytes and improve the synthesis level of
ECM [89]. NGF also promotes angiogenesis and myofibro-
blast differentiation and promotes wound contraction by
promoting collagen synthesis [90].
4 Characteristics of hydrogels
based on natural biological
materials and growth factors
In the process of wound healing, an appropriate local
environment of the wound will be beneficial to wound
healing and repair. The ideal wound dressing should
have the following characteristics: good biocompatibility;
 2499
suitable hydrophilicity and water absorption; mainte-
nance of the moist wound environment; air permeability
and heat insulation ability; antibacterial properties; sui-
table adhesion to the wound surface; and non-adhesive
properties [91–93]. Traditional wound accessories, such
as gauze, can isolate the wound from the outside world,
but they cannot keep the moist environment of the wound
and easily stick to the wound to form secondary damage
during replacement, which has certain deficiencies in pro-
moting wound repair [94]. Hydrogels are hydrophilic 3D
gels that generally have good hydrophilicity, adhesion,
permeability, and biocompatibility [95]. These character-
istics make hydrogels very suitable for wound dressings.
In addition, by modifying the hydrogel, the hydrogel can
have more biological functions conducive to wound repair.
Hydrogels can be divided into natural biological materials
and synthetic materials according to the source of raw
materials. Natural biological materials have been widely
used in the preparation of wound excipients due to their
good biocompatibility and degradability [10]. Common
natural materials include chitosan, alginate, collagen, fibrin,
gelatin, etc. The following part of this review will introduce
the properties of various natural materials and their applica-
tion with growth factors in wound healing.
4.1 Chitosan
Chitosan is the product of the natural polysaccharide
chitin removing part of the acetyl group, which has good
biocompatibility and degradability. Meanwhile, chitosan
also has antibacterial and antitumor properties, which
make it very suitable for the preparation of wound dres-
sings [94]. Chitosan can also participate in wound healing.
Chitosan can enhance the expression of GPIIB–IIIA on
the platelet membrane and promote platelet adhesion to
the vascular wall [96]. In addition, positively charged chit-
osan can also interact with a large number of negatively
charged substances on the surface of activated platelets to
promote platelet aggregation [97]. Through the above
mechanisms, chitosan can promote wound hemostasis,
induce RBC aggregation, and inhibit fibrinolysis. In addi-
tion, chitosan can increase the secretion of IL-8 in fibro-
blasts, accelerate the inflammatory process, and promote
angiogenesis [98,99]. Chitosan with a low molecular weight
can also promote the proliferation of fibroblasts, enhance
the synthesis and secretion of collagen, and promote the
growth of granulation tissue [98]. Chitosan also has an inhi-
bitory effect on bacterial growth, which may be achieved by
destroying the bacterial cell wall and membrane, chelating
2500  Feng Wang et al.

Table 2: Summary of chitosan hydrogel loaded with growth factors in wound healing

Other polymers used Factors loaded Outcomes Ref.

PAA and pHEMA EGF Better wound healing rate [103]

CNC EGF Accelerates granulation formation, promotes collagen deposition, and accelerates [105]
the healing process
Alginate EGF Promotes fibroblast proliferation and promotes wound healing [106]
PDA and Cip EGF Enhances antibacterial effect and shortens the wound healing cycle. [107]
HA EGF and CNP Promotes ECM remodeling and epithelial reformation and accelerates granulation [108]
formation
OHA EGF and insulin Promotes fibroblast proliferation and promote collagen deposition. [109]
Pluronic EGF Promotes epidermal differentiation. [104]
PEG VEGF and PDGF Promotes angiogenesis, accelerates wound reepithelialization and wound healing. [110]
HA VEGF Vancomycin Reduces inflammation and promotes angiogenesis. [111]
PLGA PDGF Promotes granulation formation and collagen synthesis and reduces autophagy [112]
Azide and lactose FGF Promotes granulation formation, angiogenesis, and epithelial formation. [113]
PEG EGF and FGF Promotes fibroblast proliferation and enhances wound healing. [114]
Collagen FGF Promotes dermal cell proliferation and accelerates collagen production. [115]

with metal cations, interacting with intracellular targets, and
deposition on the bacterial surface [100–102]. Table 2 listed
some combination of chitosan and growth factors in skin
wound healing.
The hydrogel form of chitosan applied in wound repair
can retain the properties of chitosan itself and has better
flexibility, moisture retention, adsorption capacity, and
air permeability. On this basis, hydrogel-like chitosan
can be further modified and combined with growth factors
to construct a more suitable composite dressing for wound
healing. Yao et al. prepared a chitosan-PAA-pHEMA hydrogel
(CSPAH) by UV polymerization grafting poly(acrylic acid)
(PAA) and poly(hydroxyethyl methacrylate) (pHEMA) and
loaded EGF into the hydrogel to promote wound healing.
The results showed that the hydrogel had good thrombosis
ability and antibacterial activity. At the same time, CSPAH
can effectively delay the release of EGF, which can be as long
as 7 days or even longer, enhancing the activity of EGF in the
wound site. Animal experimental results shown in Figure 4
illustrated that CSPAH loaded with EGF could significantly
improve the wound healing rate. HE staining results showed
that epithelial migration, inflammatory cell migration and

Figure 4: Representative images and HE staining results of wound surface healing over time in CSPAH, CSPAH-incorporating EGF, com-
mercial dressings, and the control at days 10 and 20. HEMA: hydroxyethyl methacrylate; CSPAH: chitosan-PAA-pHEMA; EGF: epidermal
growth factor; PAA: poly(acrylic acid) [103].
 Biological hydrogels combined with growth factors on skin wound healing
neovascularization were more obvious in the EGF group [103].
Choi and Yoo prepared a Pluronic/chitosan hydrogel con-
taining EGF and showed that chitooligosaccharide and
rhEGF in the hydrogel significantly enhanced epidermal
differentiation during wound healing [104]. Mariia et al.
prepared a cellulose nanocrystal (CNC)-enhanced chitosan
hydrogel (CS-U-CNC-EGF) loaded with EGF by the freeze-
drying method. The results showed that granulation tissue
formation in the wound area was significantly accelerated,
collagen deposition was increased, and the wound healing
rate was significantly improved in the treatment group
[105].
In addition to EGF, chitosan can also be combined
with VEGF and PDGF to improve wound angiogenesis.
Yang et al. prepared visible light curable GC hydrogels
capable of continuously releasing VEGF and PDGF to
promote angiogenesis in the injured area, accelerate
wound reepithelialization, and promote wound healing
by continuously releasing VEGF and PDGF [110]. Huang
et al. prepared a tunable sequential drug delivery system
based on chitosan/hyaluronic acid (HA) and PLGA micro-
spheres, which promoted angiogenesis by carrying VEGF
and vancomycin, reduced the inflammatory response
caused by the bacterial growth, and promoted wound
healing [111]. Xu et al. prepared a thermosensitive chit-
osan hydrogel containing PLGA microspheres and loaded
it with PDGF for the treatment of skin injury. The results
showed that hydrogels containing PDGF could promote
the formation of granulation tissue and collagen, reduce
the level of autophagy and promote wound healing.
Fibroblasts play an important role in wound healing
and proliferation [112]. Obara and others used ultraviolet
radiation crosslinking chitosan (Az-CH-LA) in aqueous
solution containing FGF, prepared flexible water inso-
luble gel, and applied water gel to diabetic mouse skin
defects. The results showed that hydrogels containing
FGF raised wound granulation tissue, blood capillaries,
and epithelization levels, significantly induced wound
contraction, and accelerated wound closure [113].
4.2 Alginate
Alginate is a kind of natural anionic polysaccharide com-
pound extracted from the cell wall of brown algae and
some bacterial strains, such as nitrogen-fixing bacteria
and Pseudomonas. They are long chain polymers com-
posed of 1,4-β-crosslinked d-mannuronic acid and 1,4-α-
crosslinked guluronic acid [116]. Alginate from algae is
insoluble in water, but its sodium salts are solvable.
Adding Ca2+ to alginate solution can precipitate alginate
 2501
in a gel state [117]. Alginate can be divided into the M
region (mannuronic acid-rich region), G region (guluronic
acid-rich region), and MG region (rich in both uronic
acids) [118]. The proportion of MG in alginate from dif-
ferent sources is quite different, and the different propor-
tion of MG determines the different properties of alginate
[119]. For example, alginate gels with high G content have
greater hardness, while alginate saltwater gels with high M
content are softer and more elastic [120]. Alginate is non-
degradable in mammals due to the absence of alginase
[121]. Some studies believe that alginate has certain immu-
nogenicity, which can cause toxicity or immune response
in the body, but this is not caused by alginate itself. Heavy
metals and impurities in the extraction and preparation of
alginate are the causes of this problem [122,123]. Alginate
has certain antibacterial and antiviral properties [124,125].
In addition, alginate can promote hemostasis by activating
platelets and promoting thrombin clot formation [126]. Dry
alginate is not suitable for wound surfaces because dry
alginate is highly absorbent and can cause wound adhe-
sion [127]. However, the alginate hydrogel showed good
water retention, which is conducive to keeping the wound
environment moist and promoting wound healing [128]. At
the same time, alginate hydrogel can ensure good adhe-
sion to the wound and will not adhere to the wound tissue,
so the removal will not cause secondary injury to the
wound [129]. These properties make alginate hydrogels
have the potential to be used in wound dressings. Table 3
lists some combination of alginate and growth factors in
skin wound healing.
Since alginate brine gel itself cannot promote cell
migration and cell adhesion, it has good application pro-
spects to load growth factors into alginate hydrogels or
modify hydrogels with other substances to obtain a better
effect. As shown in Figure 5, Zhu et al. constructed a zinc-
doped bioactive glass (ZBG)/succinyl chitosan (SCS)/oxi-
dized alginate (OAL) composite hydrogel (GEL–ZBG) and
embedded EGF into the hydrogel to improve cell prolif-
eration and tissue remodeling in the wound bed. The
results showed that the hydrogel had good antibacterial
properties and that the addition of EGF improved the early
healing speed of wounds. Histological results showed that
GEL–ZBG loaded with EGF could promote the migration
and enrichment of fibroblasts to the wound area, promote
the growth of granulation tissue and neovascularization,
and increase the deposition level of collagen and collagen
fibers [130]. Liu et al. prepared a HAAL hydrogel composed
of HA and sodium alginate by ion and covalent cross-
linking, loaded it with EGF in the hydrogel, and found
that the EGF-loaded HAAL hydrogel showed enhanced
cell proliferation and adhesion [131]. Rezaei et al. con-
structed a dual drug delivery system in which EGF and
2502  Feng Wang et al.

Table 3: Summary of alginate hydrogel loaded with growth factors in wound healing

Other polymers used Factors loaded Outcomes Ref.

Zn and SCS EGF Is antibacterial, and accelerates early wound healing, promotes fibroblast [130]
migration, promotes angiogenesis, and increase collagen deposition
HA EGF Promotes cell proliferation and adhesion [131]
PNIPAM and silk fibroin EGF and VANCO Is antibacterial and promotes fibroblast proliferation [132]
Nap–GFFKH FGF and penicillin Inhibits inflammation and accelerates wound healing [133]
Collagen BFGF and VEGF Promotes angiogenesis [134]
PF127 VEGF Accelerates granulation formation and has better wound healing rate [135]
Methacrylate PDGF–BB Promotes angiogenesis and fibroblast proliferation [136]
Dex PDGF and BMSC Promotes angiogenesis and enhances wound healing [137]

pH-sensitive silk fibroin/alginate nanoparticles were embedded
in PNIPAM hydrogel for the treatment of severe infectious burn
wounds. The results showed that the system could significantly
reduce the incidence of wound infection and promote the pro-
liferation and growth of fibroblasts [132].
To rapidly control inflammation and accelerate wound
healing, Cui et al. developed a two-drug delivery system in
which micron alginate fibers, FGF, and penicillin were
encapsulated in instant self-assembling peptide hydro-
gels. The results showed that this two-drug delivery system

Figure 5: (a and b) TEM image for BG and ZBG. SEM images of (c) Gel and (d) Gel–ZBG composite hydrogels. (e) Schematic representation of
the composite hydrogels as wound dressing for wound closure of SD rats [128].
 Biological hydrogels combined with growth factors on skin wound healing  2503

could continuously release FGF and suddenly release anti-
biotics. Animal studies have shown that hydrogels can
quickly reduce wound inflammation and speed up wound
healing [133]. Azarpira et al. mixed alginate oxide containing
VEGF and bFGF into acellular collagen-alginate complex
hydrogels and found that it could significantly improve
blood vessel generation and promote endothelial cell migra-
tion and growth [134]. Chou et al. constructed a thermosen-
sitive and reversible IPN hydrogel by treating alginate with
Pluronic F127 (PF127), which was equipped with VEGF to
further promote tissue regeneration and wound healing
rate [135]. In recent years, PDGF and alginate hydrogels
have been combined to promote wound healing. Babavalian
et al. prepared alginate sulfate hydrogels by photocros-
slinking and applied them in the treatment of rat skin injury
by loading PDGF. The results showed that hydrogels con-
taining PDGF could significantly promote angiogenesis and
fibroblast proliferation and promote wound recovery [136].
Zhang et al. synthesized an injectable hydrogel using
sodium alginate and glucan as a delivery system to deliver
PDGF and BMSCs simultaneously in the wound to promote
wound healing. The results showed that the PDGF/SA/Dex
hydrogel could promote angiogenesis by activating the
PDGF-BB/PDGFR-β-mediated PI3K/Akt/eNOS pathway, thus
accelerating BMSC-mediated skin wound healing [137].
4.3 Collagen
Collagen is the most abundant protein in mammals, accounting
for 25–30% of the total protein. Collagen is widely found in
various connective tissues. Approximately 29 kinds of
collagen have been discovered thus far, among which
type I collagen is the most important type used [120]. Col-
lagen is a major component of the ECM and plays a domi-
nant role in maintaining the biological and structural
integrity of the ECM. Collagen is resistant to protease
hydrolysis and has good biocompatibility as a protein pro-
duced from the organism itself [138]. Although the use of
collagen between species may cause an immune response,
this problem can be avoided to some extent by heterolo-
gous expression in animals or in E. coli [139,140]. Collagen
stimulates cell migration and contributes to the devel-
opment of new tissue. Collagen stimulates and recruits
corresponding cell types, such as macrophages and fibro-
blasts, according to the healing cascade order, promoting
cell aggregation in the wound area [141]. Due to the che-
motactic effect of collagen on fibroblasts, exogenous col-
lagen can stimulate the aggregation of fibroblasts in the
wound and the deposition of endogenous collagen, forming
a local healing environment. Collagen also has a good
moisturizing effect and adhesion to the wound and is
easy to replace without damaging the wound surface. Col-
lagen can also form 3D structures with high tensile strength
and stability through crosslinking and self-aggregation
[142]. Such excellent mechanical properties make collagen
suitable as a matrix material for wound dressings. Table 4
gives the summary of collagen loaded with growth factors
in wound healing.
Collagen is widely used in tissue regeneration and
tissue repair due to its excellent biological properties.
At present, commercial collagen products such as gelatin
sponges have been used in tissue repair and other fields.
Using other materials to modify collagen and load factors
to make it more suitable for wound repair is a research

Table 4: Summary of collagen loaded with growth factors in wound healing

Other polymers used Factors loaded Outcomes Ref.

HA and Sulfated HA HB–EGF Promotes keratinocyte migration, EGFR signal transduction, and promotes HGF [143]
expression
HA EGF Increases VEGF and HGF release, accelerates wound healing, and promotes [144]
granulation formation
HA EGF and vitamin C Promotes granulation formation, angiogenesis, and accelerates epithelial formation [145]
— EGF Promotes migration of fibroblasts and collagen deposition, and accelerates wound [146]
reepithelialization
Chitosan FGF Accelerates collagen production and promotes TGF expression [115]
— FGF Promotes angiogenesis and promotes epithelial formation [147]
— FGF and Ag Promotes fibroblast proliferation [148]
Chitosan PDGF Increases collagen synthesis and promotes granulation formation [57]
— PDGF Promotes fibroblast proliferation [58]
— TGF–β1 Promote chronic wound healings [149]

Note: “–” means no other polymers were used in the hydrogel synthesis.
2504  Feng Wang et al.
Figure 6: Schematic diagram of HE-EGF-combined hyaluronan/col-
lagen hydrogels as wound dressings for wound healing [143].
hotspot.Thones et al. constructed a HA/collagen hydrogel
containing HA sulfate to promote wound healing through
continuous release of heparin binding EGF-like growth
factor, as shown in Figure 6. In vitro experiments showed
that hydrogels containing HB–EGF induced keratinocyte
migration, EGFR signaling, and HGF expression in dermal
fibroblasts. In a porcine skin organ culture model, it was
found that the growth of the epithelial tip could be signif-
icantly improved [143]. Kondo et al. constructed a HA
collagen sponge dressing made of HA and collagen of
different molecular weights and added EGF to it. They
found that EGF-loaded dressings significantly increased
the release of VEGF and HGF in fibroblasts, promoting
wound healing and granulation tissue formation [144].
Niiyama and Kuroyanagi constructed a new wound dres-
sing composed of HA and collagen loaded with vitamin C
and EGF and found that the new wound dressing pro-
moted granulation tissue and angiogenesis and acceler-
ated epithelial formation in SD rats and diabetic mice
[145]. Cheng et al. prepared a hybrid lyophilized dressing
composed of EGF and recombinant human collagen and
found that this dressing significantly enhanced fibroblast
proliferation adhesion and migration to the wound. Immu-
nohistochemical results showed that the wound healing
rate, epithelial regeneration, and orderly arrangement and
deposition of collagen were significantly accelerated in
rats [146].
Wang et al. constructed a chitosan crosslinked col-
lagen sponge containing FGF and applied it in diabetic
rat wound healing. The results showed that the wound
healing time was shortened, collagen generation was the
fastest, and TGF expression was the earliest, which sig-
nificantly promoted the wound healing of diabetes [115].
Pandit et al. treated full-thickness skin defects in rabbits
by delivering FGF via collagen scaffolds, and the results
showed that FGF collagen scaffolds increased angiogenesis
and epithelial formation and promoted wound healing
[147]. Chakrabarti et al. found that FGF-loaded collagen-
AgSD hydrogels accelerated burn healing in animal models,
alleviated burn inflammation by activating ERK and TRK
pathways, and promoted fibroblast proliferation [148].
Juzith et al. developed a novel complex hydrogel that com-
bines collagen, chitosan, and PDGF, which increased the
levels of antioxidants and lipid peroxides, increased col-
lagen synthesis and granulation tissue production, and
significantly shortened the wound healing time in the
treated group than in the control group [57]. Lin et al.
constructed a collagen scaffold with PDGF targeted binding
for wound repair and found that such collagen targeted
binding PDGF had a longer release cycle, significantly
increased fibroblast proliferation and accelerated wound
granulation tissue formation [58]. Tateshita et al. applied
a collagen matrix containing TGF-β1 to the surface of
wounds, and the results showed that the application of
TGF-β1-treated collagen matrix is effective for preventing
contraction producing the so-called “neodermis” in treating
a delayed healing type model and may be highly beneficial
for treating chronic wounds [149].
4.4 Fibrin
Fibrin is a natural polymer formed during wound healing
and is formed by cleavage of fibrinogen by serine pro-
tease thrombin during wound healing and hemostasis.
Fibrin, along with platelets, is involved in wound hemos-
tasis and provides the basis for subsequent repair. During
the proliferative stage, fibrin and fibronectin can promote
the proliferation and migration of fibroblasts to the wound
site and promote the formation and deposition of collagen
[150]. As the wound repair process progresses, fibrin clots
eventually become deabsorbed by plasmin and participate
in the formation of ECM. Fibrin can also serve as a reser-
voir of growth factors and cytokines during wound repair,
and a variety of cytokines, such as EGF, FGF, and PDGF,
can be found in fibrin clots [151]. Growth factors coated
with fibrin can avoid rapid release and degradation in the
body and prolong the action time of growth factors in
wound repair. This property makes fibrin particularly sui-
table for the delivery of growth factors and cells during
wound healing and has the potential to become a wound
dressing [152]. However, the rapid degradation of fibrin
has always been the main problem restricting its clinical
transformation. Because fibrin can be easily degraded by
plasmin in the body, its ability to maintain growth factors
and cells is significantly reduced [153]. To solve this pro-
blem, there are a variety of modification methods for
 Biological hydrogels combined with growth factors on skin wound healing  2505

fibrin, such as adding heparin to fibrin and combining it

with other biological matrix materials [154]. These methods
prolong the degradation cycle of fibrin to a certain extent
and increase the effect and feasibility of fibrin in clinical
applications.
The schematic diagram made by Rahman et al. in
Figure 7 constructed a platelet-rich and fibrin-rich hydrogel
from expired platelet components that contained physio-
logical concentrations of TGF–β1, PDGF, IGF–1, FGF, and
EGF. Application of the hydrogel to skin wounds in SKH–1
mice significantly enhanced angiogenesis in the wound
area. High levels of IL–6 and KC also lasted longer in treated
wounds than in untreated wounds. The epithelialization
and healing of the wound area were significantly acceler-
ated [156]. Certelli et al. constructed a system capable of
instantaneous delivery of engineered VEGF and PDGF–BB
in fibrin hydrogels. On applying this system to a diabetic Figure 7: Schematic diagram of biofunctionalized fibrin gel co-
mouse model of skin injury, it was found that this combina- embedded with BMSCs and VEGF for accelerating skin injury
repair [155].
tion of treatments could establish stable angiogenesis in the
injured area and promote wound growth and healing [157].
Tan et al. constructed a 3D fibrin gel embedded with BMSCs grow on its surface, so in the application, it should be
and VEGF, and BMSCs in the gel differentiated into CD31 + combined with antibacterial substances to enhance its
and vWF + ECs induced by VEGF. Animal studies have antibacterial properties [160].
shown that fibrin gel can stop bleeding quickly without Augustine et al. constructed a poly(3-hydroxybutyrate-co-
secondary bleeding. Fibrin gels containing BMSCs have 3-hydroxyvalerate)/gelatin methacryloyl hybrid patch using
shown the potential to promote neovascularization and GelMA and PHBV, in which EGF was loaded for the treatment
wound healing [155]. of diabetic wound healing. GelMA shows good moisture reten-
tion and water absorption, while the PHBV film provides the
hydrogel with the right mechanical strength. EGF-loaded
4.5 Gelatin patches can promote cell migration, cell proliferation, and
angiogenesis and thereby, the rapid healing of diabetic
Gelatin has homology with collagen and is the product of wounds [161] (Figure 8). Huang et al. constructed a functional
partial hydrolysis of collagen. The structure of gelatin is bilayer skin substitute for wound repair using tissue-engi-
similar to that of the ECM, and it can simulate the struc- neered ECM and gelatin hydrogel doped with microspheres.
ture and morphology of normal tissues well, which is It was found that the bionic skin improved healing in the
conducive to cell migration and growth [158]. Gelatin wound area, showing early epithelial regeneration in the
has temperature reversibility. By adjusting the tempera- wound area [162]. Jin et al. prepared a foam dressing for
ture, hydrogel materials with high tensile strength, dermal skin regeneration using gelatin, HA, and carboxymethyl chit-
structure, and good permeability and water can be pre- osan containing FGF and found that wound healing was sig-
pared [159]. Gelatin molecules also contain a large number nificantly accelerated in animal experiments [163]. Wan et al.
of functional groups, which can be chemically modified or constructed a 3D double-layer hydrogel scaffold loaded with
modified to carry different drugs or growth factors into the PDGF and Ag, which can significantly reduce wound surface
molecules to improve their performance or therapeutic infection, results showed great potential for promoting diabetic
effect. In addition, as a hydrolysate of collagen, gelatin wound healing and fighting bacterial infection [164].
has significantly lower immunogenicity and better histo-
compatibility than collagen [159]. However, gelatin itself is
a hydrophilic protein that usually needs to be modified to
increase its mechanical properties and stability when it is 5 Advantages and disadvantages
used in the preparation of wound dressings or hydrogels
[6]. In addition, gelatin itself lacks certain antibacterial Growth factors can be chemically grafted or directly
properties, and simple gelatin easily causes bacteria to mixed into hydrogels for skin wound healing. As shown
2506  Feng Wang et al.
Figure 8: Schematic diagram of growth factor-loaded in situ photocrosslinkable poly(3-hydroxybutyrate-co-3-hydroxyvalerate)/gelatin
methacryloyl hybrid patch for diabetic wound healing [159].
in Figure 9, compared with traditional dressings, hydro-
gels have better properties, such as moisture retention,
adhesion, air permeability, and biocompatibility [89]. At
the same time, some natural biological materials, such as
chitosan, also have hemostatic ability and certain antibac-
terial ability, which can participate in the pathological
Figure 9: The advantages and disadvantages of the combination of
natural-based biological hydrogels and growth factors for wound
healing.
process of wound healing and play a role in promoting
healing [98]. Growth factors play an important role in
the process of wound healing, and the local wound itself
can secrete growth factors to regulate the progress of the
healing process. Growth factor loaded in hydrogel can
maintain growth factor in the wound area for a longer
time through the slow-release effect of hydrogel to have a
more lasting effect of promoting proliferation and differen-
tiation and accelerating wound healing [16]. However, there
are still some shortcomings in this application (Figure 9).
First, the mechanical properties of hydrogels based on
natural biological materials are mostly deficient, and the
application of hydrogels directly prepared by the materials
themselves into wound dressings cannot provide sufficient
mechanical strength and stability [165]. It is often necessary
to combine with other nondegradable materials or polymer
compounds to improve their mechanical strength. Second,
the degradation rate of hydrogels based on biological mate-
rials needs to be regulated to reach the appropriate length of
time. Some matrix materials, such as collagen, cannot sus-
tain a sufficiently long degradation cycle and need to be
modified to match the degradation time with the wound
healing cycle [166]. In addition, some biological materials
lack antibacterial properties, and their main components
are proteins or polysaccharides, which can easily cause
bacterial breeding, infection, or inflammation [167]. Finally,
the high cost of preparation and preservation of some nat-
ural biomaterials also limits the large-scale clinical applica-
tion of natural biomaterial-based hydrogels [9].
 Biological hydrogels combined with growth factors on skin wound healing  2507

6 Conclusion and future healing dressings, enabling experimenters to more appro-

priately select the corresponding combination to achieve
perspectives better therapeutic effects. Although hydrogels based on nat-
ural biological materials have some shortcomings, it can be
Skin wound healing is a continuous and complex process
predicted that these problems and shortcomings can be
that is affected by many factors. Growth factors play an
partially or completely remedied by modifying the matrix
important role in skin wound healing and are an indis-
materials so that their performance is closer to that of ideal
pensable part of wound healing. Using hydrogels to pro-
skin materials.
vide an environment for local delivery and continuous
release of growth factors can not only promote wound
Funding information: This work was supported by the
healing and growth but also provide a suitable environ-
National Natural Science Foundation of China Grants:
ment for wound surfaces with excellent performance and
21736002, 31961133015 to. F.W. and 31870791 to Z.M.
play a protective role. Existing experimental studies have
proven that hydrogels combined with growth factors
Author contributions: F.W. and Z.M. conceptualized the
based on natural biological materials have very precise
study. F.W. and Z.M. oversaw the literature review involved
therapeutic effects and advantages in the treatment of
in all aspects of designing and writing the manuscript. F.W.,
skin wound healing. This combination provides excellent
Y.G., and Z.M. wrote the manuscript and designed the fig-
moisture, adhesion, air permeability and biocompatibility
ures. H.L., L.Z., H.S., S.F., and J.C. provided input on the
as well as promotes proliferation and growth regulation of
discussion of various sections. All authors contributed to
wound growth that traditional dressings cannot match.
the article and approved the submitted version. All authors
This review focuses on hydrogels constructed from
have accepted responsibility for the entire content of this
natural materials and summarizes the effect of the com-
manuscript and approved its submission.
bination of natural hydrogels and growth factors on skin
wound healing and the potential mechanism of the com-
Conflict of interest: The authors state no conflict of
bination in the healing process. A large number of experi-
interest.
mental results have proved to us that the wound dressing
constructed with natural medical hydrogel as the matrix
Data availability statement: The datasets generated dur-
material has good biocompatibility and is very beneficial
ing and/or analysed during the current study are available
to wound protection and cell growth. Growth factor, as
from the corresponding author on reasonable request.
a kind of peptide substance with multiple functions
secreted by body cells, plays an important role in the
healing process of skin. However, the growth factor pro-
duced by the body itself is very limited in both quantity
and duration, and cannot maintain the required concen-
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