Content uploaded by Bowen Tan
Author content
All content in this area was uploaded by Bowen Tan on Sep 07, 2022
Content may be subject to copyright.
REVIEW ARTICLE
Advances and trends of hydrogel therapy platform in localized
tumor treatment: A review
Bowen Tan
1
| Lingxiao Huang
2
| Yongzhi Wu
1
| Jinfeng Liao
1
1
State Key Laboratory of Oral Diseases,
National Clinical Research Centre for Oral
Diseases, West China Hospital of Stomatology,
Sichuan University, Chengdu, China
2
Department of Basic Research, Sichuan
Cancer Hospital & Institute, Sichuan Cancer
Center, School of Medicine, University of
Electronic Science and Technology of China,
Chengdu, Sichuan, China
Correspondence
Jinfeng Liao, State Key Laboratory of Oral
Diseases, National Clinical Research Centre for
Oral Diseases, West China Hospital of
Stomatology, Sichuan University, Chengdu
610041, China.
Email: liaojinfeng.762@163.com
Funding information
Sichuan Science and Technology Progam,
Grant/Award Number: 2020YJ0065; National
Natural Science Foundation of China, Grant/
Award Number: 31972925; Sichuan University
Spark Project, Grant/Award Number:
2018SCUH0029; State Key Laboratory of Oral
Disease, Grant/Award Number:
SKLOD202016
Abstract
Due to limitations of treatment and the stubbornness of infiltrative tumor cells, the
outcome of conventional antitumor treatment is often compromised by a variety of
factors, including severe side effects, unexpected recurrence, and massive tissue loss
during the treatment. Hydrogel-based therapy is becoming a promising option of can-
cer treatment, because of its controllability, biocompatibility, high drug loading, pro-
longed drug release, and specific stimuli-sensitivity. Hydrogel-based therapy has
good malleability and can reach some areas that cannot be easily touched by sur-
geons. Furthermore, hydrogel can be used not only as a carrier for tumor treatment
agents, but also as a scaffold for tissue repair. In this review, we presented the latest
researches in hydrogel applications of localized tumor therapy and highlighted the
recent progress of hydrogel-based therapy in preventing postoperative tumor recur-
rence and improving tissue repair, thus proposing a new trend of hydrogel-based
technology in localized tumor therapy. And this review aims to provide a novel refer-
ence and inspire thoughts for a more accurate and individualized cancer treatment.
KEYWORDS
hydrogel, localized tumor treatment, postoperative tumor therapy, tissue repair
1|INTRODUCTION
Cancer, ranked as one of the most life-threatening diseases world-
wide, was responsible for 9.6 million deaths (lung cancer held the
leading fatality rate, 18.4%) and 18.1 million new occurrences (lung
cancer and breast cancer shared the highest diagnostic rate, 11.6%) in
2018
1
according to GLOBOCAN (Global Cancer Observatory). Also,
based on this statistical analysis, one in eight men and one in
10 women will be attacked by this disease.
1
With the acceleration of
the aging process of the society,
2
insufficient popularization of
cancer-related knowledge, high-risk habits that might lead to cancer
3,4
and so on, the proportion is rising by leaps and bounds year by year.
Research institutions and patients' families spend huge sums of
money each year on tumor-related treatments,
5
but the overall thera-
peutic results of conventional anticancer therapies still need to be
improved. Therefore, the burden of clinical treatment is mounting.
Surgical resection, radiation therapy, and chemotherapy are three
main methods for cancer treatment.
6
However, the outcome often
discourages us. First, the intense severe effects caused by chemother-
apeutic drug and rays, such as radiation-related xerostomia,
7
neuropathy,
8
autoimmune-related side effect,
9
and urogenital system
dysfunction.
10
Second, unmanageable recurrence due to the
Abbreviations: Alg-PDA, alginate-polydopamine; AMA-DA, methacrylated alginate
dialdehyde hydrogel; BT-CTS, bifunctional chitosan-based; CA4P, combretastatin A4
disodium phosphate; Car/gel, carboplatin loaded poloxamer hydrogel; Ce6, chlorin e6; CPT-
SAPD hydrogel, camptothecin -based self-assembling prodrug hydrogel; DMA,
dimethacrylate; F127/F68, pluronic P407/pluronic P188; FEPL, F127-ε-poly-L-lysine
hydrogel; FK, tumor-penetrable peptide sequence of Fmoc-KCRGDK; GA-Cur, glycyrrhetinic
acid modified curcumin; GDDC-4, poly(PG-P[DPAx-co-DMAEMAy]-PCB); GelMA, alginate-
gelatin methacryloyl; HCC, hepatocellular carcinoma; HTS, hypertonic saline; MB, methylene
blue; MMT, magnetic-mediated hyperthermia; mPECT, methoxy poly(ethylene glycol)-b-poly
(ε-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-un-decanone); PCL-PTSUO-PEG,
3-caprolactone/1,4,8-trioxa[4.6]spiro-9-undecanone/poly(ethylene glycol); PDNPs, prodrug
nanoparticles; PECE, poly(ethylene glycol)- poly(ε-capro-lactone) -poly(ethylene glycol).;
PEGDA, polyethylene glycol diacrylate; PNAm-PDAAu, poly[N-acryloyl glycinamide-co-
acrylamide (AAm)]-polydopamine-gold nanoparticles; ROS, reactive oxygen species; ZnPC,
zinc phthalocyanine.
Received: 29 May 2020 Revised: 29 June 2020 Accepted: 7 July 2020
DOI: 10.1002/jbm.a.37062
J Biomed Mater Res. 2020;1–22. wileyonlinelibrary.com/journal/jbma © 2020 Wiley Periodicals LLC 1
infiltrative growth characteristics of malignant tissue, hyperactive pro-
liferation ability, and local immunosuppressive microenvironment.
11,12
Third, additional damages to both physical and psychological health.
For example, impairment of organ functions and mental health, tissue
loss, and defects in corresponding areas due to surgical resection,
13
are increasingly valued in the formulation of clinical tumor treatment
plans. Therefore, improving or developing new treatment methods
remains a difficult challenge and a long-term mission.
With the rapid development of molecular biology, oncology, phar-
macology, materials science, and other disciplines, the combined treat-
ment methods of various fields have received extensive attention. In
the last few years, a better understanding and application of
nanoparticles,
14,15
electrostatic spinning,
16,17
and hydrogel
18,19
has
broadened novel ways for cancer treatment. Notably, the introduction
of hydrogel in cancer therapy is a promising strategy with its superior
properties. Evidence of existing studies has verified the feasibility and
superiority of hydrogel-based therapy strategies. Advantages are
mainly reflected in four aspects: (a) Biocompatibility. Excellent bio-
compatibility is one of the crucial test standards that determines the
fate of hydrogel in biomedicine. Biocompatible and biodegradable
hydrogels effectively avoid intense immune rejection and systemic
organ toxicity,
20
which is the precondition for the normal therapeutic
functions. (b) Controllability. Compared with traditional methods,
hydrogel-based system exhibited drug sustained drug release proper-
ties. As a result, the localized therapeutic drug concentration can be
ensured and the side effects caused by a high blood concentration of
drugs can be constrained.
21
In addition, specific stimuli-sensitivity is
also able to make treatment controllable. By adding predetermined
sensitive agents or employing specific modifications in the system,
reaction to hydrogel can be triggered by pH,
22
visible light,
23,24
near
infrared (NIR),
25,26
alternating magnetic field (AMF),
27
ultrasound,
28,2
and temperature.
30
Therefore, antineoplastic protocols would be tai-
lored in desire for a more individualized treatment. (c) High drug load-
ing ability. Anticancer drugs (doxorubicin (DOX), cisplatin (CDDP),
paclitaxel (PTX), docetaxel (DTX), etc.) and other essential components
such as photosensitizers, magnetic particles, vascular disrupting
agents (VDA), immunomodulatory factors, and catalytic agents can be
co-encapsulated in this system, and then the appropriate concentra-
tion of drugs would be maintained around the tumor through local
implantation. In this regard, the problem of low solubility and quick
metabolism can be solved by embedding drugs into the large capacity
warehouse.
31
(d) Less invasiveness. The injectability makes hydrogel
implantation less traumatic compared with surgical methods, so
hydrogel-based therapies are helpful for a good prognosis.
32
To sum
up, by introduction of photothermal therapy (PTT), magnetic-
mediated method, photodynamic therapy (PDT), immunotherapy, and
chemotherapy, within single platform, a novel integrated, biocompati-
ble, efficient, and individualized hydrogel-based localized cancer ther-
apy has been materialized. Illustration of hydrogel-based localized
cancer therapy is shown in Figure 1.
Furthermore, one non-negligible side effect of cancer treatment
is the encroachment of normal tissue. Undeniably, removement or
clearance of carcinoma tissue leads to tissue loss, which might lower
the quality of patients' life, or even cause catastrophic influence that
threatens survival rate.
33-35
Therefore, a “kill two birds with one
stone”idea was put forward in recent years: eliminating tumor tissue
at the first stage, and providing appropriate scaffold or stimulating
factor to facilitate tissue regeneration at the second stage. Hydrogel is
adequately qualified for this job due to its specific sensibility to differ-
ent signals, controlled drug release capacity, and facilitating histogene-
sis function, so once the abnormal tissue has been eliminated,
surrounding normal host stem cells can directionally move to the
defect area and then form new tissues through proliferation and dif-
ferentiation.
36
Several attempts based on this idea have been success-
fully realized.
37-39
Moreover, with a tendency to accurate and
individualized therapy in the future, hydrogel is expected to be a
promising option in combined treatment of localized tumor therapy
and tissue engineering.
Herein, our review focused on the hydrogel-based localized direct
tumor treatment as well as its role in preventing postoperative tumor
recurrence in recent years. Simultaneously, we discussed the new
trends of hydrogel application in tumor-killing and tissue repair.
Finally, the challenges of hydrogel faced in cancer therapy were ana-
lyzed and the future potential of clinical translation was speculated.
2|THE CLASSIFICATION, PREPARATION
OF HYDROGEL, AND ITS ADVANTAGE IN
TUMOR THERAPY
Hydrogel, a three-dimensional mesh gel constituted by interlaced
hydrophilic polymers, has powerful water absorbing ability, appropri-
ate porosity, and suitable constraining force,
40,41
which provides
homelike media for cells to live and serves as a biomolecule container
for sustained local treatment.
42-44
According to the source, hydrogel derives basically from nature
and synthesized composition. Alginates,
45
collagen,
46
hyaluronic acid
(HA),
47,48
gelatin,
49,50
chitosan,
51
cellulose,
50,52
and silk fibroin
(SF)
53,52
are representative natural hydrogel materials, which are
widely considered biocompatible for histogenesis, drug encapsulation,
and tissue filling. Nevertheless, poor mechanical properties are the
shortcomings hindering the wide application of those natural-derived
hydrogel.
55
With appropriate adjustment, hydrogels would demon-
strate improved performance in strengthening, stiff, and stretchable
behavior.
56,57
Presently, optimizing the performance of hydrogels
seems to be an inevitable tendency and requires the joint efforts of
researchers. In addition, synthesized materials are also diverse, includ-
ing alcohols, acrylics, and their derivatives such as poly vinyl alcohol
(PVA),
58
poly caprolactone (PCL),
59
polyethylene glycol (PEG),
60
poly
lactic acid (PLA),
61
poly glycolic acid (PGA),
62
and poly lactic-co-
glycolic acid (PLGA).
63
Interestingly, these polymers are often com-
bined with one another or with other substances to form a composite
hydrogel for desirable properties. For instance, the boronic ester
dynamic covalent bond between PVA and phenylboronic acid modi-
fied hyaluronic acid (HA-PBA) contributed to the self-healing capacity
as well as the injectability of the composite hydrogel.
47
Based on the
2TAN ET AL.
size and shape, hydrogels can be divided into macro-hydrogel (colum-
nar, globose, fibrous, membranous, porous spongy, etc.) and
microhydrogel (nanoscale and micron scale).
64
Macro-hydrogels refer
to gels that are larger than millimeters in size, which can be implanted
via injection or surgical incision and plays an important role in cancer
treatment. Compared with classic macro-hydrogels, microhydrogel is
becoming increasingly popular due to its micro scale and potential in
targeted drug transportation. Like the κ-carrageenan-based nanogel/
hydrogel nanocomposites and chitin nanogels fabricated by simple
mechanical stirring process, could improve levodopa delivery
65
and
hold antibacterial properties,
66
respectively. Specially, hydrogel micro-
spheres demonstrated excellent cell encapsulating ability, making it an
efficient novel tissue-engineering strategy based on cell therapy (such
as cardiac repair
67
and angiogenesis
68
). Additionally, hydrogels can be
roughly categorized into traditional and smart hydrogels. Traditional
hydrogels are equipped with some basic characteristics: the special
porous structure that supports molecular dispersion and substance
interchange; the rigid construction formed by chains resistant to dis-
solution; flexibility results from extensibility and compressibility of
chains. Compared with traditional hydrogel, smart hydrogel
69
pos-
sesses special properties and stimuli-sensitivities, including
injectability,
70
self-assembly ability,
71
self-healing capacity,
72
and it
can respond to specific signals (pH,
73
temperature,
74
enzyme,
75
light,
76
etc.). Smart hydrogels are favored by researchers owing to
their unique environmental responsiveness, and the successful appli-
cation of hydrogels with these properties in controlling drug release,
in vivo environmental adaptation, and treatment methods has also
proved their application prospect in medicine.
Water-soluble or hydrophilic polymers with hydrophilic groups or
appropriate cross-linked lattice structures can form hydrogels through
cross-linking. Crosslinking provides improved performance for hydro-
gel system by forming interactions between polymerized monomers.
77
Physical crosslinking and chemical crosslinking are two main routes of
hydrogel synthesis. Physical crosslinking includes hydrogen bonding,
78
crystallization,
79
protein interaction,
80
ion interaction mediated
crosslinking,
81
and means from amphiphilic grafting and block
polymers,
82,83
while chemical crosslinking involves the use of
enzymes,
84
free radical polymerization,
85
and chemical reactions with
complementary groups.
86
Crosslinked hydrogels are equipped with
superior properties, including the resilience,
87
enabling the system to
better adapt to the internal environment; the shape memory property
and the unique conductivity brought by the introduction of ion (Ca
2
+
),
88
expanding the applications of hydrogel in load-bearing structures
and electronic field; the mechanical tunability that gave hydrogel
adjustable stiffness,
89
making it adapt to various use requirements.
Interestingly, some photosensitizers also functioned as cross-linking
agents for polymerized monomers of hydrogels.
90,91
The dual roles of
these agents would receive more attention on the design of photo-
therapy for hydrogel-based cancer treatments, and the concept of
reducing the introduction of extra substances is likely to be material-
ized for reaching a high-efficient treatment. In practice, the cross-
linking methods of hydrogels are often mixed, which makes the same
FIGURE 1 Illustration of hydrogel-based localized therapy
TAN ET AL.3
hydrogel system more complex and diverse. The successful applica-
tion of these materials also makes people aware of the unique posi-
tion of multifunctional materials in the biomedical field. In the future,
multi-property hydrogels may become a therapeutic trend with great
potential.
The biomedical applications of hydrogel include cell culture,
92
diagnosis,
94
tissue engineering,
94
and drug delivery system (DDS).
95
Its similarity to extracellular matrix (ECM)
96
opens an access to cell
delivery therapy and regenerative medicine in histogenesis and tissue
repair. Besides, the importance of hydrogels as drug storage vault is of
great interest, and according to different purposes, hydrogels of vari-
ous sizes, structures, and ingredients have been applied in different
aspects: tissue regeneration
97
; anti-inflammatory
98
; antimicrobial
99
and antitumor.
100
The introduction of hydrogel to antitumor field has
received widespread attention due to its excellent biocompatibility,
biodegradability, controllable drug release capacity, and directed ther-
apeutic ability, which observably minimize the toxicity toward normal
cells and enhance tumor cell killing efficiency by promoting local che-
motherapeutic drug concentration.
101
More importantly, hydrogel holds its unique advantages as a car-
rier in local administration for tumor therapy. Recently, injectable
hydrogels have received much more preference. Based on the
thermo-sensitivity, sol–gel transformation can be realized via the tem-
perature difference between inside and outside.
102
The shape change
property of injectable hydrogels has enlarged the contact area
between gel and irregularly distributed carcinoma tissue, so the thera-
peutic index would be elevated. And the injectable property could also
lessen the trauma, thereby reducing the postoperative infection possi-
bility. Photo-triggered methods (e.g., PTT, PDT) are also less invasive,
saving patients from skin tumor occurrences and damages to body
function usually brought by conventional irradiation rays.
103
Besides,theseveresideeffectcausedbyantineoplasticdrugsis
another clinical problem that hinders patients' health recovery. By
encapsulating drugs into hydrogel with special responsive proper-
ties, the drug release might be more controllable, thus pushing the
cancer treatment for a more individualized direction. pH-sensitive
hydrogel is widely chosen for an accurate drug release, because
tumor generally presents an acidic microenvironment.
104
Enzyme-
responsive hydrogel also stands out, for some enzymes (e.g., matrix
metalloproteinase [MMPs]
105
)highlyexpressedbycancercells.
Self-healing capacity of hydrogel is paid another attraction. With
appropriate mechanical strength, hydrogels are ideal substitutive
filler in the tissue loss area such as muscle and bone, which can bear
stress from both inner side and outer side of body momently.
106
This property improves the stability of hydrogel in situ, as well as
the long-term function. In conclusion, the powerful potential of
hydrogels in cancer treatment demonstrated above makes the
hydrogel-based platform a novel therapeutic tool. Notably, this plat-
form is not only applied to the direct treatment of local tumors, but
also holds an amazing effect on preventing tumor recurrence after
surgery, which has been experimentally confirmed that with the par-
ticipation of hydrogels, the local treatment effect of postoperative
chemotherapy drugs is significantly enhanced,
107
and the risk of
residual tumor cell metastasis is also greatly reduced, indicating a
better prognosis of patients.
3|THE APPLICATION OF HYDROGELS IN
LOCALIZED TUMOR TREATMENT
Tumors are clinically classified as nonsolid tumors and solid tumors.
Solid tumors are characterized by local mass formation and can be
clinically examined by X-ray, CT scan, ultrasound or palpation of mass
reactions.
108,109
Hydrogel-based therapy restricts therapeutic effect
to a local area, namely, localized solid tumors as its mainly selective
targets. Gathering these solid tumors that happen in different cells,
tissues or organs all over the body together, we concluded a general
picture of hydrogel-based cancer therapy (Figure 2). However, esta-
blishing tumor models and selecting appropriate treatment strategies
are unavoidable problems that scientists and clinical doctors have to
face with. So, they need to pay more attention to the evaluation of
in vivo tumorigenicity, physical and chemical properties of anticancer
drugs, drug therapeutic characteristics, and prognostic analysis.
3.1 |Hydrogel-based direct localized cancer
treatment
According to recent researches, chemotherapy is the main force in
local tumor treatment, and the introduction of hydrogel platform
makes the chemotherapy effect more centralized and efficient. Simul-
taneously, with the emerging of photothermal conversion, magnetic
FIGURE 2 Common localized cancers treated by hydrogels
4TAN ET AL.
induction and other technologies, photosensitizer- and magnetic
particle-mediated treatment have received extensive attention.
Besides, cancer immunotherapy and VDA-mediated therapy also
exhibit powerful therapeutic effect on eliminating tumor and
preventing metastasis. Notably, combination therapy in hydrogel plat-
form seems to be preferred by researchers, and a large number of
experimental results also confirm the efficiency and feasibility of this
method. Here in Table 1, some representative studies on hydrogel-
based tumor therapy are summarized. Furthermore, scientists are
working on exploring novel materials that are extraordinarily compe-
tent with outstanding biocompatibility and controllability for reaching
a less invasive and more personalized cancer treatment regimen.
Chemotherapy is one of the traditional tumor-killing techniques,
and with the introduction of hydrogel, large doses of drugs can be
retained in situ for a long period sustained release, thus saving the
patients from receiving extra surgical invasion. Besides, multidrug
treatment is also a promising option that demonstrates powerful syn-
ergistic effect by aiming at different targets in tumor-related path-
ways. Therefore, hydrogel-based drug delivery will be a desirable
technique in chemotherapy plan design.
DOX is the most commonly utilized clinical anticancer drug as
well as an experimental model drug which exhibits extensive anti-
tumor property.
110
By inserting into the base pair of DNAs, DOX
effectively inhibits DNA replication as well as the nucleic acid synthe-
sis, and finally induces apoptosis. However, the toxicity of DOX to
nephridium, myocardial tissue, and bone marrow as well as the drug
resistance effect is still a hard nut to crack.
111
Therefore, exploring
novel DDS with superior performance for enhancing the targeted
therapeutic effect would be a desirable solution. Leixia Mei et al.
112
designed an RGD (Arg-Gly-Asp)-derived peptide conjugate (1-RGDH)-
based hydrogel loaded with DOX through electrostatic interactions
for the improvement of drug delivery. And they found that the intro-
duction of DOX effectively facilitated the viscoelastic and shear-
thinning properties of this hydrogel system, which set an example for
overcoming negative effects that often bought by drug loading to the
system. The evidence that DOX-loaded hydrogel performed better
than the DOX solution group in anticancer experiment against
nonsmall-cell lung cancer cells A549, and the pH-responsive capacity
exhibited by hydrogel composite also proved the utilization potential-
ity of this strategy. Other DOX delivery techniques based on different
interactions were also fascinating, such as the Schiff-based reac-
tion
113
between DOX and L-lysine, which contributed to the pH sensi-
tivity (accelerated DOX release in pH 5.5), and the liposomal
doxorubicin (DOX-Lip) embedded PLGA-PEG-PLGA hydrogel with an
improved stability and prolonged therapeutic effect,
114
which also
emphasized the suitable role of liposome serving as a delivery
dosage form.
Apart from DOX, hydrogel-based delivery of other anticancer
drugs shows great potential. Such as PTX, a natural anticarcinogen,
acting by targeting microtubules in cell caryomitosis.
115
Hoon et al.
116
designed a glycol chitosan (GC)/ beta-cyclodextrin (β-CD)/PTX com-
posite hydrogel for ovarian cancer drug delivery. The water solubility
of PTX was improved by combining with β-CD for a prolonged drug
stability. Besides, the visible light-cured property made the system
more regulative, simultaneously, visible light was much safer than
ultraviolet (UV), avoiding sunburn or other skin diseases.
117
As the
most widespread polysaccharide in nature, cellulose
118
is an easily-
acquired and well-stocked material, which is also a desirable drug car-
rier for cancer treatment. Ning et al.
119
prolonged the release period
of loaded PTX by mixing hexadecyl amine and nanocellulose together
to form the hydrogel network for the anticancer activity. The pH-
responsive release (below 5.5) as well as the followed in vitro cytotox-
icity studies of HepG2 and A549 cells also bore out the anticancer
potential of cellulose-based hydrogel composite.
Other anticancer drugs loaded hydrogel system were also
reported. Such as 5-fluorouracil (5-FU) loaded methylcellulose hydro-
gel, which was equipped with excellent injectability and thermo-sensi-
tivity. With a favorable in vitro antitumor effect against KB oral
TABLE 1 Recent studies of hydrogels directedly applied in localized tumor treatment
Hydrogel Therapy type Drug/agent Cell line Cancer model Ref.
GA-cur Chemotherapy Curcumin HepG2 HCC [215]
Chitosan Chemotherapy- PTT DTX MCF-7 Human breast adenocarcinoma [216]
FER-8 Chemotherapy PTX HepG2 HCC [217]
Agarose PDT-PTT MnO
2
/Ce6 4T1 Human breast cancer [218]
PB/gellan Chemotherapy-PTT PB/CA4 4T1 Human breast cancer [219]
mPEG-b-PELG Chemotherapy CA4P/CDDP C26 Mouse colon cancer [132]
F127/F68 Chemotherapy-PTT TPGS/PTX SW620 AD300 Human colon tumor [142]
GelMA Chemotherapy ATRA U-87 MG Glioblastoma [125]
MC Chemotherapy 5-FU KB Oral cancer [220]
PCL-PTSUO-PEG Chemotherapy-PDT DOX/ZnPC 5,637 cells Bladder tumor [221]
GelMA Chemotherapy Gemcitabine MG63 Osteosarcoma [222]
mPECT/GDDC -4/α-CD Chemotherapy DOX/siBcl-2 SKOV3/HeLa Human ovarian cancer/human cervical cancer [223]
PEGDA PDT TiO
2
/MB HeLa Human cervical cancer [148]
TAN ET AL.5
cancer cell line, this system was expected to be a desirable approach
for the improvement of chemotherapy in head and neck cancer. Self-
drug delivery (SDD) is a novel technique that transports drug by itself
without any extra carriers, thus decreasing the introduction of unnec-
essary materials. As an easily obtainable prodrug of 5-FU,
5-fluorouracil acetic acid (5-FuA) exhibited self-gelation property.
120
The type of FuA-15 showed desirable anticancer efficiency in
melanoma cell line (B16F10), making it a promising technique for skin
cancer drug delivery.
120
Moreover, an alginate/modified β-CD hydro-
gel
121
was designed to be the carrier of 5-FU loaded nanoparticles, the
delayed and long-term release of 5-FU guaranteed the localized thera-
peutic function. Interestingly, the pressure-controlled drug release sen-
sitivity that this system demonstrated made it a potential candidate for
cancer therapy in pressure-bearing tissue such as brain, bone, or adre-
nal tumor. Glioblastoma (GBM) is considered to be the most common
and aggressive malignant brain tumor around the world, for a morbidity
of 3–5 individuals per 100,000 residents.
122
Based on the fact that
blood–brain barrier (BBB)
123
is one important limiting factor that
restrains intravenous drugs from arriving tumor sites, hydrogel based-
localized therapy becomes more attractive and acceptable. Such as
Pluronic F127 and N,N,N-trimethyl chitosan (TMC) hydrogel-based
sustained release of DTX
124
; Alginate-GelMA hydrogel containing
ATRA-loaded particles
125
; PEG-DMA polymer hydrogel prolonged PTX
release from PLGA-NPs.
126
In these three systems, the local release of
drugs was well controlled, and the finally in vitro and in vivo studies
have shown good antitumor effect, especially the PLGA-NPs/PEG-
DMA hydrogel double-release system, which not only extended the
drug release speed and period, but also effectively reduced the toxicity
to the surrounding tissue, making it a potential antitumor DDSs for
future cancer therapy. With the participation of hydrogel, the patients'
prognosis and survival rate has witnessed a great improvement, com-
pared with conventional chemotherapy.
Combined treatment of at least two biomolecules in chemother-
apy has also obtained much attention from researchers, which is con-
firmed to be beneficial to kill tumor with reduced chemotherapeutic
dosage, less side effects, and good prognosis.
127
A DOX/ p-Cur (phos-
phorylated curcumin) co-delivered hierarchical responsive nanocarrier
was designed by encapsulating DOX into mesoporous silica
nanoparticles (MSNs) and adding p-Cur in the outside hydrogel coat-
ing layer.
128
Researchers found that drugs (DOX and p-Cur) were
released in sequence due to the pH-responsive collapse of MSNs and
the GSH-triggered hydrogel coating (PEG) dissociation, outside in can-
cer tissue and inside of tumor cells, respectively. The enhanced Hela
cell apoptosis also proved the effectiveness of DOX and p-Cur com-
bined delivery. Besides, a novel synthetic DTX and DOX co-delivered
PPDL/PEG/PPG (PDEP) hydrogel
129
was applied for treating liver
cancer. This copolymer hydrogel showed excellent self-healing prop-
erty and thermostability, which could be injected accurately toward
carcinoma tissue and quickly transformed into gel in situ, maintaining
the localized drug concentration for a long time.
To deal with colorectal cancer (CRC), one of the most malignant
tumors that originates from colon and rectum, which severely affects
public health,
130
the collaborative DDS containing more than two
drugs is well worth studying. Oxaliplatin (OXA)/tannic acid
(TA) nanoparticles-hydrogel
131
was demonstrated favorable anti-
angiogenesis and anticancer function based on the synergistic effect
of OXA and TA. In animal experiment, OXA/TA NPs-hydrogel effec-
tively controlled the CT26 peritoneal colon tumor nodular size, and
the result of a prolonged life span of mice was also strong proof
supporting future hydrogel intraperitoneal anticancer application.
Another example is the CA4P/CDDP co-delivered mPEG-b-PELG
(methoxy poly(ethylene glycol)-poly(γ-ethyl-L-glutamate) diblock
copolymers) polymer hydrogel system,
132
which exerted the anti-
tumor effect by switching off the blood supply as well as eliminating
carcinoma tissue in situ. As shown in Figure 3, CA4P demonstrated
well cooperation with CDDP for controlling cancer progression when
tumor size reached 370 mm,
3
revealing an obvious inhibitory effect
exerted by joint effect on tumor at later stage. For lung cancer treat-
ment, CA4 could also cooperate with other elements. Sanjay Pal
et al.
133
synthesized a self-assembled lithocholic acid-dipeptide hydro-
gel (TRI-Gel) for co-delivery of DOX, CA4, and dexamethasone (DEX).
Beyond the anticancer effect of DOX and the antiangiogenesis of
CA4, the anti-inflammatory function of DEX contributed to the abro-
gation of carcinoma tissue. More importantly, researchers found
DOX/CA4/DEX showed well cooperation in regulating tumor micro-
environment via altering sphingolipid metabolism, thus shutting down
the high-speed multiplication of cancer cells, which provided novel
direction for cancer therapy. Particularly, for the treatment of GBM, a
quercetin/temozolomide (TZM) co-delivered HA hydrogel
134
was
designed, which showed precise targeting and enhanced anticancer
capacity, owing to the recognition of CD44 (marker of GBM cell) and
inhibition of inflammatory factors by using quercetin. Besides, the
localized concentration of TZM was heightened, along with the anti-
cancer effect, which made the cancer therapy more efficient and
accurate.
PTT
135,136
is another thriving tumor-killing method that has
attracted widespread interests from biomedical scientists due to its
nearly nontoxic property and precise targeting ability. By human-
controlled light-triggered localized heat, tumor tissue would be
ablated while the damage to normal tissue is constrained to the mini-
mum level. Hemoglobin (Hb) is a natural component of human blood,
which can be decomposed without systemic toxicity. Based on the
finding of near infrared light-responsive capacity of Hb, a PEG/Hb
hydrogel
137
was first reported to deal with lung cancer, in which the
majority of tumor cells and vessels were cleared after the generation
of localized heat. The light-triggered heating property of Hb hydrogel
made it a novel and promising PTT mediator, which could be utilized
in more biomedical fields. Besides, a Prussian blue (PB) nanospheres-
loaded thermo-sensitive Pluronic F127 hydrogel was designed for
PTT against breast cancer that was ranked as the leading life-
threatening cause in female tumor.
138
The excellent photo–heat con-
version capacity, stability and the anticancer effect through peri-
tumoral injection also indicated the great prospect of PB-based
hydrogel system.
6TAN ET AL.
When PTT causes heat-induced cancer cell ablation, localized
temperature changes can also lead to structural alteration of the
hydrogel network, thus influencing the drug release kinetics. Herein,
chemo-PTT is preferred due to its minimal invasion. Meanwhile, the
combination of chemotherapeutics and photothermal materials largely
reduce the toxicity to surrounding tissues and lengthen the therapeu-
tic time, and the pain experience of patients during the whole thera-
peutic process would be lessened compared with the single
chemotherapy or radiotherapy. A novel DOX@Pd gel
139
was reported
to be efficient in treating solid tumor, NIR laser triggered the heat pro-
duction of Pd nanosheets (NSs) to ablate carcinoma tissue, simulta-
neously, the local release of DOX from hydrogel was accelerated. This
joint chemo-photothermal therapeutic effect has been tested by his-
tological analysis and blood examination and been verified more
powerful than monotherapy. Moreover, Y. Zheng et al.
140
designed a
CS/MBP/DOX (CMD) hydrogel where MoS
2
/Bi
2
S
3
-PEG responded to
the NIR to build hyperthermia while DOX acted as cancer cell killer. In
addition, the antibacterial capability
141
of CS-based hydrogel added
more features and potential in this multifunctional material. Another
example is Gold nanorods/D-alpha-tocopheryl PEG 1000 succinate/
Paclitaxel (GNRs-TPGS-PTX) gel,
142
by which the PTT effect last for
approximately 5 min, shrinking the carcinoma tissue without damag-
ing surrounding normal cells. Then, this long-term drug delivery was
proved to prevent the reoccurrence of cancer. The short-term hyper-
thermia created by this system alleviated the discomfort to the body.
Besides, the proportion of drugs and materials could be adjusted
according to individual differences before implantation, which made
the curative process more acceptable and humanized. Localized
FIGURE 3 (a,b) Illustration of the local co-delivery of CA4P and CDDP based on a thermo-sensitive polypeptide hydrogel. (c,e) Average
tumor volumes and (d,f) average body weights with the single treatment of various therapeutics when the tumor volumes reached 110 mm
3
(c,e) and 370 mm
3
(d,f) (g) ex vivo H&E staining and TUNEL assay of C26 tumor tissues with the single treatment of various therapeutics (G1,
saline; G2, blank gel; G3, CA4P@Gel; G4, CDDP@Gel; G5, free CA4P and CDDP; G6, CA4P&CDDP@Gel) when the tumor volumes reached
370 mm
3133
TAN ET AL.7
temperature needs to be high enough to kill cancer cells (over
45C),
143
which is well above the body temperature (could bring dam-
age to normal cells) and is uncomfortable or even unbearable. There-
fore, a low-temperature (below 45C) PTT
144
opened up novel routes
in cancer therapy (Figure 4). 2, 20-azobis[2-(2-imidazolin-2-yl) pro-
pane]-dihydrochloride/sodium alginate (AIPH/ALG/Ink) hydrogel was
triggered by NIR-II laser light to form low thermal condition, then
AIPH generated alkyl radicals to kill tumor cells. This method has been
proved biologically safe. Furthermore, low hyperemia could protect
normal cells from injuring. Meanwhile, the effective HCT116 cells
apoptosis induction caused by cooperation of PTT and ROS toxicity,
as well as the observable shrinkage of tumor volume in antitumor
experiment in vivo also revealed the fascinating therapeutic effect of
AIPH/ Ink/ALG hydrogel.
PDT
145
is a light-sensitive, high-efficient, and less invasive anti-
cancer therapy. ROS generated by photosensitizers effectively
induces tumor cell apoptosis and cuts off the blood supply of carci-
noma tissue, moreover, local hypoxia can therefore be alleviated, thus
FIGURE 4 (a) Schematic illustration of 44C low-temperature produced by traditional Hu-Ink triggered AIPH to generate alkyl free radicals.
(b) Syringeable AIPH + Ink + ALG hydrogel was intratumorally injected into tumor-bearing mice. The main principles of the transformation from
ALG solution to hydrogel was performed. (c) Photosensitive AIPH + Ink + ALG hydrogel for localized tumor ablation. (d) Infrared thermal images
of different treatments with NIR laser irradiation (1,064 nm, 0.5 W/cm
2
) or not. (e) curve of tumor temperature rose with irradiation time. (f)
Photographs of representative mice and tumors dissected from each group at 15th day once their treatment has finished. H&E and TUNEL
staining of tumor slicing at the end of treatment. (g) Confocal photos of Calcein-AM/PI stained HCT116 cells after treatments
145
8TAN ET AL.
activating the antitumor immunity from the suppressed state.
146
The
introduction of hydrogel has realized the sustained production of ROS
in situ, leading to the enhancement of localized therapeutic effi-
ciency.
147
Such as the PEGDA hydrogel containing methylene blue
sensitized mesoporous TiO
2
nanocrystals designed for cervical cancer
treatment.
148
With the promotive effect of MB, TiO
2
generated more
ROS for alleviation of hypoxia in tumor microenvironment, which
resulted in more Hela cells apoptosis in anticancer experiment.
Combined therapy is relatively more popular than monotherapy
because it can yield the greatest returns on investment. Wang
et al.
149
synthesized a novel nano DOX-ICG (Indocyanine green)
MMP-responsive hydrogel (NDIMH) for anticancer study. The MMPs-
responsive property and ICG-based FL imaging enhanced the accu-
racy of hydrogel implantation. ICG was not only a PTT responder, but
also a mediator of NIR fluorescence and photoacoustic imaging, which
made it the mainstay of the chemo-phototherapy. Moreover, this
study found an elevated cellular uptake of DOX in ICG-involving con-
dition, which might support the synergistic effect of DOX and ICG in
anticancer treatment.
The combination of PDT and immunotherapy has also received
great attention. Zhou et al.
146
has successfully applied a prolonged
oxygen-generating phototherapy hydrogel (POP-Gel) on a long-term
tumor treatment (one injection, 5 days' curative effect). The improve-
ment of hypoxia by generating ROS via calcium superoxide (CaO
2
)
and catalase (CAT) in tumor microenvironment could lead to stimulat-
ing of intensive immune reaction as well as downregulation of hypoxia
inducible factor (HIF)-1αand vascular endothelial growth factor
(VEGF), thus decreasing the possibility of metastasis (mechanism was
showed in Figure 5.). Also, comparison of tumor volume and lung
metastasis condition revealed the powerful anticancer effect of POP-
gel, indicating that the combination of PDT with hydrogel was a prom-
ising option. Besides, Z. Meng et al.
150
designed a light-triggered in
situ gelation system (Ce6-CAT/PEGDA), Ce6 served as a photosensi-
tizer for the production of ROS, while CAT catalyzed H
2
O
2
to relieve
the hypoxia condition, thus saving the localized immune system from
suppression. The minimal invasiveness and localized therapeutic accu-
racy of PDT have made it an attractive and promising technique for
the future treatments. Beyond ROS-related immune therapy, immu-
nomodulatory agents-based hydrogel system is also fascinating.
CDN,
151
Anti-CD47,
152
and IL-2
153
are representative agents that
have been reported by boosting the host's immune system for anti-
cancer effect. With the participation of hydrogel, the immune therapy
efficacy was significantly improved and immune related side effects
were alleviated. And a better understanding of immune related anti-
cancer mechanism as well as the designing of biomaterials is becoming
indispensable for future cancer therapy.
Magnetic heat treatment is another promising method in cancer
therapy. Interestingly, the introduction of hydrogel has made the in
situ magnetic medium-based heat generation more concentrated.
Magnetic nanomaterials are widely chosen as the intermediary agents,
such as Fe
3
O
4
nanoparticles, an accessible and abundant material with
multiple functions. Wu et al.
154
designed a magnetic hydrogel
nanozyme (MHZ) containing Fe
3
O
4
@PEI nanoparticles for the
induction of localized hyperemia. The result of animal experiment
in vivo proved the efficiency of hyperemia-induced tumor cell killing.
Simultaneously, the fact that normal cells remained nearly unharmed
during the process also supported the biosafety of this technology.
Additionally, Fe
3
O
4
held enzyme-like property, which triggered the
generation of toxic reactive oxygen radicals (˙OH), thus bringing
destruction to heat shock protein (HSP) 70 and facilitating the forma-
tion of hyperemia.
Beyond the direct anticancer application, hydrogels are widely
used in clinical drug screening, radiation sensitivity screening,
155
accu-
rate labeling and targeting,
156
and so on. Hydrogels mimic the micro-
environment of tumor, so the bioactivities of cell can be reserved in
maximum in vitro cellular experiment, which facilitates more precise
quantitative studies. For example, a GelMA hydrogel-based microen-
vironment
157
has been applied to evaluate the antiangiogenesis func-
tion of TNP-470, which has a profound impact on the development of
antiangiogenic drugs in accurate antitumor research.
3.2 |Hydrogel in preventing the postoperative
recurrence of tumor
Surgery is the most commonly utilized method of cancer therapy,
while the mechanical removement of carcinoma tissue cannot reach
100% clearance, the patients still face a high risk of tumor recur-
rence.
158
Residual cancerous cells are deeply and irregularly embed-
ded into normal cells,
159
which forms barriers to clinical treatment.
Notably, researchers have found that survival tumor cells have stron-
ger invasiveness and proliferation potential, so it is necessary to elimi-
nate cancerous cells in the initial treatment,
160
otherwise the
recurrence would worsen the situation. Besides, there are other fac-
tors affecting tumor recurrence, one important factor is the damage
caused by drugs or radiation to surrounding normal cells, especially
immune cells: the decline in localized immunity hinders self-
scavenging progression, giving cancer cells the comeback opportuni-
ties, and potential goals.
111,161
To sum up, a controllable and localized
therapy can minimize the side effects and maximize the curative
impact. As a promising candidate, hydrogel has already exhibited
attractive power in both in vitro and in vivo experiments. Table 2 has
listed some examples of hydrogels applied in postoperative treatment.
GBM is a highly recrudescent tumor. Due to its infiltrating growth
property, ~90% patients undergoing resection are faced with a high-
risk local recurrence,
162
within about 2 cm around the surgical margin.
The prognosis of patients is poor with a median survival (less than
15 months), and long-term survivors are hardly seen.
163
Standard
treatment schedule includes resection, followed by radiotherapy or
chemotherapy. However, due to the restriction of BBB, low solubility
and rapid metabolism of drug, the final outcome always fails us. To
overcome the transient drug action problem, C. Bastiancich et al.
164
designed a Lauroyl-gemcitabine lipid nano-capsules (GemC
12
-LNC)
based hydrogel as the drug release system for preventing postopera-
tive recurrence of GBM. PTX loaded GemC
12
-LNC hydrogel was
proved to hold an enhanced cytotoxic activity toward cancer cells,
TAN ET AL.9
and PTX showed outstanding cooperative ability with GemC
12
.
Besides, antitumor animal experiments revealed that lifespan of nude
mice in surgical resection and GemC
12
-LNC hydrogel implantation
group was relatively prolonged compared with other groups, indicat-
ing the high-efficiency and necessity of combined therapy in clinical
GBM after treatment regimen. Another hydrogel system focusing on
FIGURE 5 (a) Mechanism by
which the POP-Gel destroys the
primary tumor and inhibits tumor
metastasis. (b) Tumor growth
curves. The arrows represent
administration (black) and
irradiation (red). (c) Images of
tumors resected from the
different treatment groups.
(d) Representative images
showing the gross appearance of
tumor nodules in the lungs (top)
and representative images of
lung sections stained with H&E
(bottom; scale bar = 1 mm).
(Group I: untreated, II: PO-Gel, III:
Vaccine (P-Gel), IV: Vaccine
(POP-Gel), V: (P-Gel) with
irradiation and VI: (POP-Gel) with
irradiation)
147
TABLE 2 Summaries of hydrogels applied in postoperative treatment
Hydrogel system Therapy type Cancer Prognosis Ref
FVIOs/DOX /chitosan dynamic
hydrogel
Chemotherapy-
MMT
Breast cancer DOX-F-MH almost prevented the tumor from reoccurring
in situ. (over 90% tumor shrinkage).
[168]
DOX/HTS/ PEG gel Chemotherapy-
MMT
Breast cancer DOX-HTS-PEG hydrogel + AMF group nearly inhibited
the tumor from growing.
[224]
PDNPs-gel Chemotherapy Breast cancer Hydrogel group showed the best curative effect and the
longest life span (over 70%; 40 days).
[225]
PTX-NPs/ TZM/PEG -DMA gel Chemotherapy GBM Resection + PTX-NPs/TZM/PEG-DMA gel group
demonstrated prolonged median life span (over
100 days).
[165]
CPT-SAPD hydrogel Chemotherapy GBM CPT hydrogels dramatically delayed the reoccurrence of
tumor (slight degree, about 3 weeks after surgery).
[226]
FK hydrogel Immunotherapy Breast cancer Hydrogel group inhibited metastasis (tumor free
percentage 83.3%) and delayed tumor recurrence
(48.1%).
[227]
Car/gel Chemotherapy Cervical
cancer
Car/gel group (57.1%, compared with 100% in other
groups).
[228]
PNAm-PDAAu-DOX hydrogel Chemotherapy-
PTT
Breast cancer Hydrogel with irradiation group showed the lowest
recurrence rate (16.7%).
[229]
10 TAN ET AL.
PTX/TZM co-delivered therapy
165
also demonstrated powerful cancer
recurrence prevention capacity. Compared with single drug delivery,
PTX and TZM functioned synergistically toward killing U87MG cells,
and the long survival days (over 100) of U87MG orthotopic mice that
received resection and PTX/TZM hydrogel treatment also supported
the promising application of this co-delivered system in postsurgical
treatment of GBM.
Combing therapy (resection together with postoperative chemo-
therapy, PTT, PDT, or other strategies) has become the hot spot and
direction of the recent researches. Based on the fact that breast-
conserving therapy (BCT)
166
is mostly chosen for unmarried or preg-
nant female bearing breast cancer, while the high rate of localized
recurrence and distant metastasis often make the ultimate impact dis-
couraging, our team previously designed a DOX-loaded chondroitin
sulfate multialdehyde/branched polyethylenimine/graphene oxide
(CSMA/BPEI/BPEI-GO) hydrogel
167
in preventing the tumor recur-
rence after mastectomy. Owing to the GO-triggered hyperemia and
followed accelerated DOX release, residual breast cancer cells were
maximally eliminated, and the survival rate of mice, in vitro cellular
experiment and in vivo histological analysis verified the biosafety and
anticancer efficiency of this biomaterial. This research also highlighted
the necessity of combining chemotherapy and phototherapy together
to reduce the systemic toxicity, promote anticancer efficiency and
lower the rate of reoccurrence (from 66.7% in single method to 33.3%
in combined therapy). Besides, Fei Gao et al.
168
designed a magnetic
mediated hyperemia/DOX combined therapy for prevention the
recurrence of breast cancer (Figure 6). Based on the magnetic induc-
tion of encapsulated ferromagnetic vortex-domain iron oxide (FVIOs),
the localized temperature could stay around 44C for tumor ablation,
followed by the heat-triggered DOX release for an enhanced cancer
elimination. With the help of hydrogel, tumor volume was constrained
and cancer progression was nearly terminated. Noteworthily, the dos-
age of FVIOs was much lower than the conventional magnetic agents,
indicating the great potential of FVIOs in the design of future thera-
peutic scheme. Moreover, the injectability and pH-sensitivity also
made drug delivery more accurate. Interestingly, this hydrogel showed
excellent self-healing and self-conformal behaviors, which well
supported the in vivo implantation and stabilization. Herein, with the
therapeutic effect of hydrogel platform, tumor progression was
observably constrained according to the tumor volume analysis.
Moreover, starving therapy also shows promising therapeutic
property in prevention of cancer metastasis and recurrence. A novel
extravascular chitosan/ mPEG-Mal/pNIPAAm-co-AAc containing
PEG-SH-modified gold nanorods composite hydrogel was reported,
which acted by shrinking under NIR, thus decreasing the blood supply
and vessel density in tumor area.
169
This particular therapeutic mech-
anism was confirmed in vivo PANC-1 pancreatic cancer and 4T1
breast cancer animal experiment, with a low lung metastasis and
recurrence rate. These results indicated the efficiency of anticancer
treatment via blocking cancerous blood supply and shutting down the
outlet for tumor transferring.
In conclusion, resection and hydrogel-based postsurgical treat-
ment is a promising and effective therapeutic schedule. Hydrogel
filled in the defect area maintains the local drug concentration for a
long time, drastically reducing the possibility of recurrence of residual
cancer cells that normally infiltrate into surrounding normal tissue.
Meanwhile, the local drug delivery restricts blood drug concentration
level, thus greatly alleviating the systemic toxicity. Nevertheless,
residual cancer cells could not be quantitatively calculated, as well as
their aggregation and distributing condition, so the treatment still
faces the problem of imperfect precision. Therefore, an evaluation
system of hydrogel in postsurgical anticancer treatment as well as tis-
sue repair needs to be created in future medical practice.
3.3 |Hydrogel as a new trend for localized tumor
therapy and tissue engineering
In clinical practice, eliminating cancerous tissue undoubtedly leads to
tissue loss, which impairs normal function, appearance and mental
well-being.
35
Besides, postsurgical infection
170
often hinders the
healing process. Therefore, wound-closing and cavity filling are neces-
sary. As a powerful biomaterial, hydrogel is reported to be extensively
utilized in tissue engineering, including skin,
171
bone,
172,173
cartilage,
174,175
muscle,
176,177
adipose tissue,
178
and so on. For tissue
repair after cancer treatment, we summarized some representative
examples here in (Table 3). Herein, a “kill two birds with one stone”
strategy hydrogel is proposed (Figure 7): eliminating tumor followed
by tissue repair. This hydrogel should be equipped with properties
that cover both the two aspects. Hydrogels for cancer treatment have
already been mentioned above. For tissue engineering part, the sup-
port for histogenesis process needs to be emphasized. Functional
groups of hydrogels can provide combination site for cells, such as
natural adhesive proteins laminin and fibronectin,
179,180
which are
essential for cell attachment. And OH and NH
2
surfaces have been
proved to facilitate cell bioactivity such as ALP expression,
181
sign of
osteogenic differentiation. Besides, bioactive scaffolds also demon-
strate huge necessity. The introduction of nano-hydroxyapatite
182
largely improved the cell adhesion ability compared with the original
scaffolds like PVA. Cell adhesion molecules (RGDSP, etc.) integrated
with hydrogel network
183
allowed cells to attach and spread, giving
time for biomolecules such as bone morphogenetic protein (BMP) to
release, and this scaffold was utilized in a rat critical sized defect
model with a good outcome. Moreover, suitable porosity and strength
of hydrogel are also incredible for cells to move in and new vessels to
expand. For example, a novel human-like collagen/carboxymethylated
chitosan (HLC/CCS) hydrogel was reported for wound healing.
184
The
fine repairing outcome was owing to the good mechanical properties
that HLC and CCS helped to attain via stable hydrogen and chemical
bonding, and the 3D porous network structure that mimicking ECM
was also an incredible factor for better tissue construction. For cancer
treatment and tissue engineering, biocompatibility is the precondition.
Host reaction and material reaction are two important steps to evalu-
ate biocompatibility.
185
The smaller the host's reaction to the material,
the less adverse effects it will bring to the body. Similarly, the smaller
the reaction of the material in the body, the better drug release and
TAN ET AL.11
therapeutic function may achieve. Excellent biocompatibility of hydro-
gels can minimize the adverse effect of the introduction of materials
on the therapeutic effect, which has a significant impact on the clear-
ance rate of cancer cells, the survival rate of patients, and the progno-
sis of repair.
In clinical practice, surgery is an important therapy method
treating skin cancers such as melanoma, while many surrounding nor-
mal skin tissues are also removed for preventing recurrence.
186,187
Therefore, skin tissue repair remains a challenge, because massive tis-
sue loss will lead to declined barrier protection, which may result in
postoperative infection as well as electrolyte disturbance
188
caused
by excessive body water loss. Besides, risk factors like diabetes
189
and multidrug resistance
190
can also prolong the healing process.
Herein, there are substantial requirements to design and leverage
integrated therapeutic programs dealing with cancer as well as accel-
erating skin healing. Hongshi Ma et al.
38
designed an oligomeric
proanthocyanidins (OPC)-based hydrogel for PTT in melanoma ther-
apy and postsurgical wound healing. The H&E staining results in ani-
mal experiment part indicated a high cancer killing efficiency in
calcium silicate nanowires (CS)/sodium alginate (SA)/OPC/laser group,
FIGURE 6 (a) Schematic diagram illustrates FVIO-functionalized magnetic hydrogel with optimal adaptive functions for breast cancer
postoperative recurrence prevention. (b) The photograph and schematic illustration of the transformation of GC-ferrofluids to form magnetic
hydrogel. (c) The injectable, self-healing, and self-conformal behaviors of the F-MH. (d) The acid-responsive property of F-MH. (e) Relative tumor
volumes, and (f) relative body weights over time.
169
12 TAN ET AL.
compared with other CS or SA only groups. The utilization of OPC as
a biomimetic photothermal agent as well as hydrogel scaffold was the
attractive point. Unlike polydopamine or melanin-like nanoparticles,
OPC has rarely been reported in PTT, which showed us great future
potential. Furthermore, the supportive function of OPC hydrogel to
the migration and proliferation of human umbilical vein endothelial
cells (HUVECs) and human dermal fibroblasts (HDFs) was also fasci-
nating. The results of in vivo animal experiment verified the promotive
function of OPC hydrogel in angiogenesis and wound healing process.
Antibacterial capacity is also a crucial part for a desirable prognosis.
For example, the F127-ε-poly-L-lysine (FEPL)/F127-Phe-CHO/
BGN@PDA hydrogel, designed by Li Zhou et al.,
191
exhibited multiple
functions including anticancer, anti-infection and wound repair. As
illustrated in Figure 8, the introduction of FEPL as antibacterial com-
ponents effectively restrained the bioactivities of Escherichia coli,
Staphylococcus aureus, and MRSA, which significantly reduced the risk
of postoperative infection. Besides, FCB hydrogel + NIR treatment
basically limited the growth rate of tumor, while other groups failed to
control cancer progression, which emphasized the essential role
photothermal conversion had to play in hydrogel treatment platform.
Furthermore, the skin tissue repair was speeded up without the dis-
turbance of bacteria, which also highlighted the antibacterial function
of materials in tissue repair process.
Bone repair is also a challenging project. Although bone demon-
strates an excellent self-repair capacity, irregular bone fracture, or
massive volume of bone loss still remains as a problem.
192
Besides,
TABLE 3 Summaries of hydrogels applied in tissue repair after cancer treatment
Hydrogel
Cancer
cell TE cell
Repaired
tissue TE in vitro TE in vivo Ref
Alg-PDA 4T1 MCF-10A
cells
Breast tissue MCF-10A seeded on Alg-PDA hydrogel
showed a high proliferation rate.
—[38]
nHA/
rGO
MG-63 rBMSCs Bone tissue Adhesion, proliferation and osteogenesis
mineralization of rBMSCs were
supported by nHA/rGO hydrogel.
Scaffold observably enhanced rat
cranial defects repair.
[194]
BT-CTS B16F10 HUVECs/
HDFs
Skin tissue BT-CTS thermo-gels promoted HUVECs
and HDFs proliferation; HUVECs
showed angiogenic abilities in gels.
Mg
2+
ions released from gel
facilitated chronic wound closure.
[231]
FEPL A375 —Skin tissue —Hydrogel speeded up the collagen
deposition and angiogenesis.
[192]
AMA-DA A549 MeT-5A
cells
Lung tissue Cell viability of MeT-5A was maintained
when cultured in AMA-DA hydrogel.
- [232]
PECE 4T1 —Skin tissue —Hydrogel accelerated fibrosis and the
healing of hair follicles.
[167]
Gelatin 4T1 hMSCs Adipose
tissue
Elevated adhesion and adipogenic
differentiation of hMSCs was observed.
- [233]
FIGURE 7 The properties of
hydrogel in localized tumor treatment
and tissue engineering
TAN ET AL.13
the inaccurate treatment also prolongs the healing process, and even
causes recurrence or secondary damage. Dejian Li et al.
193
designed a
nano-hydroxyapatite and reduced graphene oxide (nHA-rGO) com-
posite hydrogel with excellent photothermal effect, which reached a
localized temperature of 60C after 4 min' irradiation in vivo, thus effi-
caciously limiting the expansion of tumor. Moreover, the promoted
rBMSCs proliferation, adhesion, and differentiation in vitro as well as
elevated mineral deposition in rat cranial defect in vivo also verified
the bone regeneration effect of this scaffold. Another example was
OSA-CS-PHA-DDP hydrogel synthesized by Shiyu Luo's group.
39
PHA was composed of polydopamine (PDA) and n-HA, in which PDA
offered abundant functional groups
194,195
for cell adhesion and migra-
tion. Besides, PDA exhibited intense absorption in the NIR region,
serving as a photothermal agent. Simultaneously, functional groups on
PDA could also provide binding sites for anticancer drug like CDDP.
Therefore, PDA would be a potential candidate for combined therapy
of cancer treatment and tissue engineering.
Since surgical resection is the primary option for breast cancer
patients, the reconstruction of breast tissue is the priority for better
recovery. A 3D printing alginate-polydopamine hydrogel
37
was
designed as a potential candidate for breast adipose tissue engineer-
ing, based on the evidence of elevated proliferation of MCF-10A
human breast epithelial cells seeded on the scaffold. The similar mod-
ulus to breast tissue demonstrated by this 3D hydrogel also revealed
the reconstruction potential. Moreover, the photothermal effect
targeting on the tumor in vivo has made this type of material a prom-
ising alternative in the prevention of tumor recurrence as well as
followed breast rebuilding. To sum up, biocompatible materials that
mimic the human structure would be perfect carriers for tissue repair
after cancer elimination, which might be an attractive and desirable
project in the future.
Although recent studies on hydrogel-based therapy of cancer
treatment and tissue engineering remained limited, several researches
aiming at repairing lost tissue would pave the way for future develop-
ment of integrated hydrogel therapy platform in this field. Postopera-
tive hemorrhage, spasm, and perforation are intractable barriers for
gastrointestinal cancer patients after endoscopic submucosal dis-
section (ESD) treatment, therefore seeking for a valid postoperative
repair method is needed. Akihiro Nishiguchi et al.
196
designed
hydrophobically-modified Alaska pollock-derived gelatin (Hm-ApGltn)
microparticles that could form a stable hydrogel structure in situ when
implanted into submucosal tissue. The material of strong adhesion
and stability offered a solution to prevent wounds from cracking and
facilitated healing after surgery. Besides, postoperative infection cau-
sed by bacteria is another factor that prolongs healing process. There-
fore, surge of interests has been given to antibacterial material in
tissue repair design. For example, the selenium nanoparticles (SeNps)
and mupirocin co-encapsulated chitosan-based hydrogel system
197
FIGURE 8 (a) Scheme showing the preparation and application of FCB hydrogel in tumor therapy and wound healing. (b) Corresponding
statistical data of colonies densities of Escherichia coli,Staphylococcus aureus, and MRSA treated with different samples. (c) Photographs of the
tumors after various treatments on Day 18. (d) Tumor volume. (e) Wound closure rates of the FCB, FCE, and controls. (FCE, F127-Phe-CHO/
FEPL; BGN, BG nanoparticles)
192
14 TAN ET AL.
applied in in vivo mupirocin-methicillin-resistant S. aureus (MMRSA)
inhibition test as well as the wound healing experiment, in which
SeNps, mupirocin and chitosan showed efficient cooperation. Simulta-
neously, accelerated collagen deposition, angiogenesis, and
fibroblastosis were observed with the intervention of hydrogel com-
posite, which suggested this multifunctional material would gain more
attraction in future postoperative treatment. Moreover, biomolecules
also play an essential role in tissue repair process. Such as 5-HMF
(hydroxymethylfurfural), a bioreactor for proliferation and migration
of human skin fibroblasts (HSF), which favored the wound healing
198
process, and quercitrin also demonstrated wide application including
antibacterial and promoting bone cell proliferation.
199
Noteworthily,
biomimetic elements-based hydrogel will be more attractive.
Collagen,
200
alginates,
201
and gelatin-based
202
hydrogel were
reported with outstanding compatibility as well as the tissue repairing
effect. The introduction of different components makes the hydrogel
composite more complicated and multifunctional, which has a great
application prospect in the formation of tumor therapy and subse-
quent tissue repair for the prognosis integration scheme. With the
understanding of the deeper molecular biological mechanisms in the
future and the development of more novel hydrogel composites, we
believe that the hydrogel-based treatment can be developed in a more
precise and personalized direction, and the survival of the patient and
the quality of life will be significantly improved.
4|DISCUSSION
Great efforts have been witnessed in the field of hydrogel-based
localized cancer treatment. However, researchers working on applica-
tions of hydrogel in cancer-related area still have some challenges to
face with.
First, although sustained drug release kinetics of hydrogel can be
assessed in vitro, it remains unclear for the complex situation in vivo,
since the state of hydrogel composite would be affected by the
dynamic, physiological, and biochemical environment. Therefore, the
result of in vitro experiment merely has a limited reference value.
Also, some hydrogel-based DDS could not maintain the sustained
localized drug concentration, one reason lies in the burst release
effect at the primary implantation stage.
203
Simultaneously, the
unpredicted enzyme degradation effect, cell penetration, blood or
interstitial fluid exchange, and body movement can also complicate
the assessment. Herein, exploring a platform that can accurately
assess drug release in the body and how hydrogels interact with the
body will be crucial for a more precise and personalized cancer ther-
apy in the future.
Second, in tissue engineering part, although hydrogels are com-
prehensively utilized, tissue-engineered structure still reveals defec-
tive mechanical properties compared with the original tissue, such as
the tensile properties.
204
In order to maximize the effect of tissue
repair, we need to seek for hydrogels with excellent mechanical prop-
erty as well as tissue framework supporting capacity. Besides, the
interplay of cancer therapy and tissue engineering in the same system
remains unclear. It is difficult to accurately predict the influence of
drugs, hyperthermia, ROS, and other factors on the structure of scaf-
folds in the process of tumor treatment, so there is still a lot of uncer-
tainty in the application of hydrogel in the long-term tissue repair
process. Herein, we recommend that the order of treatment should
be “first cancer, second repair.”Healing is a long process, while killing
process is best shortened to prevent newborn normal cells from abla-
tion together with cancer cells and to minimize the damage to the
body. Besides, by encapsulating them into micro- or nano-particles,
205
the delayed release of tissue repair biomolecules or stimulating factors
can be realized. Moreover, multifunctional drugs with tumor-killing
capacity and histogenesis stimulating ability might be preferred. For
example, curcumin, a traditional anticancer and anti-inflammatory
drug isolated from rhizome of turmeric (Curcuma longa),
206
was
reported to have the ability to induce osteogenic differentiation,
which could react throughout the entire anticancer and healing pro-
cess. The simplification of drugs can make it easier to administer drugs
without worrying about drug interactions. However, the resulting
drug resistance is a nonnegligible problem we have to deal with. In
the future drug delivery model, how to control the combination of
drug and single drug based on hydrogel system is a topic worth
exploring.
Third, this review has focused on the hydrogel-based localized
solid tumor treatment, while quite a few patients are diagnosed
according to metastatic carcinoma features, such as CRC.
207
Typically,
the patient's tumor is already in the advanced stage, in which the
accurate targeting capacity of hydrogel would be halved with the
unknown and far-ranging metastatic lesion. Capturing cancerous cells
is a novel train of thought, adding specific signals to the hydrogel
would better track down targeted cancer cells. In a study, researching
on capturing the drug-resistant leukemia cell line K562/adriamycin
(ADM), P-gp antibody-modified GelMA porous hydrogel particles
were successfully applied.
208
The specific binding between P-gp and
drug-resistant cancer cells made capturing accurate, and with this evi-
dence, “tracking down cancerous cells”might be a better option for a
more precise treatment. However, this work is both time-consuming
and laborious, so more in vivo and in vitro experimental evidence is
needed to prove the feasibility of this technology.
Furthermore, the future clinical translation of hydrogel in cancer
treatment still faces challenges. One is that the penetration depth of
NIR is limited.
209,210
For instance, when using 810 nm NIR of less
than 1 W, the tissue penetration depth of NIR is limited to 3 mm,
211
which only supports the treatment of skin cancer or subcutaneous
tumor. In other words, this technique seems hard to function for the
treatment of deep tumors in human body like ovarian cancer and
CRC. This problem also bothers photo-crosslinking hydrogels for the
shallow penetration of visible lights.
212
Besides, although quite a few
researches adopt subcutaneous tumors as in vivo model, in clinical
practice, there are often complicated and essential anatomical struc-
tures
213,214
(arteries, veins, nerves, lymphatics, etc.) around the tumor
that might even be eroded by carcinoma tissue, which need to be put
into consideration in cancer treatment design. What is more, for
patients of different ages, sexes, and various tolerance, hydrogel-
TAN ET AL.15
related systemic studies of metabolism and degradation, immune
response as well as biodistribution in human body are limited. There-
fore, the clinical translation of hydrogel-based cancer therapy still has
a long way to go. To sum up, based on the specific clinical situation
and experience, the multidisciplinary combined treatment strategies
can make tumor treatment more effective and significantly improve
the prognosis of patients.
5|PERSPECTIVE AND CONCLUSION
In this review, we summarized the recent studies on polysaccharide
and synthetic polymers-derived hydrogel therapies in different cancer
treatment (direct treatment and preventing postoperative recurrence
of tumor), and we also discussed the new trend of the application of
hydrogel in killing cancer and tissue repair combined treatment. We
found that PTT and PDT has received preference in cancer therapy
for their controllability and treating accuracy, and hydrogels showed
necessity in this system due to their appropriate loading capacity and
signal-sensitivity. In addition, hydrogel-based therapy is less invasive
and more personalized according to disparate cases, which lay a foun-
dation for precise and individual treatment. Moreover, multifunctional
hydrogels are promising options in killing cancer and tissue repair
therapy. Apart from the anticancer effect, other fascinating functions
such as anti-inflammatory, antibacteria, and tissue regeneration stimu-
lating capacity can improve the healing process, thus acquiring better
outcomes compared with the original treatment. This review has
pointed out a new trend of an integrated therapeutic scheme of
hydrogel applied in tissue engineering after cancer treatment, which
might provide a new way of thinking for the researchers and clinical
doctors.
To date, hydrogel-based cancer therapy is basically still in an
experimental stage, and for the future clinical translation, more works
should be contributed: (a) Create a hydrogel property evaluation sys-
tem for killing cancer and tissue repair therapy, which can make future
researches more normalized and standardized, thus paving the way for
clinical treatment. (b) Attach great importance to multifunctional
hydrogel system, and take advantages of each of these properties and
then put them in a logical order, thus designing a purposeful and effi-
cient schedule. (c) Construct more tumor models with similar structure
and composition to human body, and reveal the molecular mechanism
of tumor reproduction, invasion and recurrence at more levels, so as to
seek potential accurate therapeutic targets. (d) Explore more effective
hydrogel-based comprehensive treatment, including the introduction
of new nanometer and micron materials, the splicing and combination
of functional groups, the combination of physical and chemical therapy.
In summary, researchers from all disciplines and fields should cooper-
ate together, thus providing more opportunities for the next genera-
tion of hydrogel-based therapy platform in cancer-related treatment.
ACKNOWLEDGMENT
This work was financially supported by the National Natural Science
Foundation (31972925), Sichuan Science & Technology Program
(2020YJ0065), Sichuan University Spark Project (2018SCUH0029),
and State Key Laboratory of Oral Diseases Foundation
(SKLOD202016).
CONFLICT OF INTEREST
The authors declare no conflict of commercial or proprietary interest.
REFERENCES
1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A.
Global cancer statistics 2018: GLOBOCAN estimates of incidence
and mortality worldwide for 36 cancers in 185 countries. CA Cancer
J Clin. 2018;68:394-424.
2. White MC, Holman DM, Boehm JE, Peipins LA, Grossman M, Jane
Henley S. Age and cancer risk: a potentially modifiable relationship.
Am J Prev Med; Elsevier. 2014;46:S7-S15.
3. Omofuma OO, Turner DP, Peterson LL, Merchant AT, Zhang J,
Steck SE. Dietary advanced glycation end-products (AGEs) and risk
of breast cancer in the prostate, lung, colorectal and ovarian cancer
screening trial (PLCO). Cancer Prev Res. 2020;13(7):601-610.
4. Berg CJ, Haardörfer R, Lanier A, et al. Tobacco use trajectories in
Young adults: analyses of predictors across systems levels. Nicotine
Tob Res. 2020.
5. Carter AJ, Nguyen CN. A comparison of cancer burden and research
spending reveals discrepancies in the distribution of research
funding. BMC Public Health. 2012;12:526.
6. Sulman EP, Ismaila N, Armstrong TS, et al. Radiation therapy for glio-
blastoma: American Society of Clinical Oncology clinical practice
guideline endorsement of the American Society for Radiation Oncol-
ogy guideline. J Clin Oncol. 2017;35(3):361-369.
7. Paterson C, Thomson MC, Caldwell B, et al. Radiotherapy-induced
xerostomia: a randomised, double-blind, controlled trial of Visco-
ease™oral spray compared with placebo in patients with cancer of
the head and neck. Br J Oral Maxillofac Surg. 2019;57:1119-1125.
8. Gebremedhn EG, Shortland PJ, Mahns DA. The incidence of acute
oxaliplatin-induced neuropathy and its impact on treatment in the
first cycle: a systematic review. BMC Cancer. 2018;18:410.
9. Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with
ipilimumab in patients with metastatic melanoma. N Engl J Med.
2010;363:711-723.
10. Carter J, Lacchetti C, Andersen BL, et al. Interventions to address
sexual problems in people with cancer: American society of clinical
oncology clinical practice guideline adaptation of cancer care
Ontario guideline. J Clin Oncol. 2018;36:492-511.
11. Liu Y, Guo J, Huang L. Modulation of tumor microenvironment for
immunotherapy: focus on nanomaterial-based strategies.
Theranostics. 2020;10(7):3099-3117.
12. Rubio K, Castillo-Negrete R, Barreto G. Non-coding RNAs and
nuclear architecture during epithelial-mesenchymal transition in lung
cancer and idiopathic pulmonary fibrosis. Cell Signal. 2020;70:
109593.
13. Quint~
ao NLM, Santin JR, Stoeberl LC, Corrêa TP, Melato J, Costa R.
Pharmacological treatment of chemotherapy-induced neuropathic pain:
PPARγagonists as a promising tool. Front Neurosci. 2019;13:907.
14. Thambi T, Deepagan VG, Yoon HY, et al. Hypoxia-responsive poly-
meric nanoparticles for tumor-targeted drug delivery. Biomaterials.
2014;35:1735-1743.
15. Bahrami B, Hojjat-Farsangi M, Mohammadi H, et al. Nanoparticles
and targeted drug delivery in cancer therapy. Immunol Lett. 2017;
190:64-83.
16. Graham-Gurysh EG, Moore KM, Schorzman AN, et al. Tumor
responsive and tunable polymeric platform for optimized delivery of
paclitaxel to treat Glioblastoma. ACS Appl Mater Interfaces. 2020;12:
19345-19356.
16 TAN ET AL.
17. Khodadadi M, Alijani S, Montazeri M, Esmaeilizadeh N, Sadeghi-
Soureh S, Pilehvar-Soltanahmadi Y. Recent advances in electrospun
nanofiber-mediated drug delivery strategies for localized cancer che-
motherapy. J Biomed Mater Res - Part A. 2020;108(7):1444-1458.
18. Sepantafar M, Maheronnaghsh R, Mohammadi H, et al. Engineered
hydrogels in cancer therapy and diagnosis. Trends Biotechnol. 2017;
35(11):1074-1087.
19. Fan DY, Tian Y, Liu ZJ. Injectable hydrogels for localized cancer ther-
apy. Front Chem. 2019;7:1-11.
20. Naahidi S, Jafari M, Logan M, et al. Biocompatibility of hydrogel-
based scaffolds for tissue engineering applications. Biotechnol Adv.
2017;35(5):530-544.
21. Sun Z, Song C, Wang C, Hu Y, Wu J. Hydrogel-based controlled drug
delivery for Cancer treatment: a review. Mol Pharm. 2020;17:
373-391.
22. Rizwan M, Yahya R, Hassan A, et al. pH sensitive hydrogels in drug
delivery: brief history, properties, swelling, and release mechanism,
material selection and applications. Polymers (Basel). 2017;9(4):137-149.
23. Raman R, Hua T, Gwynne D, et al. Light-degradable hydrogels as
dynamic triggers for gastrointestinal applications. Sci Adv. 2020;6:
eaay0065.
24. Batool SR, Nazeer MA, Ekinci D, Sahin A, Kizilel S. Multifunctional
alginate-based hydrogel with reversible crosslinking for controlled
therapeutics delivery. Int J Biol Macromol. 2020;150:315-325.
25. Hao Y, Liu Y, Wu Y, et al. A robust hybrid nanozyme@hydrogel plat-
form as a biomimetic cascade bioreactor for combination antitumor
therapy. Biomater Sci. 2020;8:1830-1839.
26. Wang C, Zhao N, Yuan W. NIR/thermoresponsive injectable self-
healing hydrogels containing polydopamine nanoparticles for effi-
cient synergistic cancer thermochemotherapy. ACS Appl Mater Inter-
faces. 2020;12:9118-9131.
27. Yu YT, Shi SW, Wang Y, et al. A ruthenium Nitrosyl-functionalized
magnetic Nanoplatform with near-infrared light-controlled nitric
oxide delivery and photothermal effect for enhanced antitumor and
antibacterial therapy. ACS Appl Mater Interfaces. 2020;12:312-321.
28. Fisher DR, Fidel J, Maitz CA. Direct interstitial treatment of solid
tumors using an injectable Yttrium-90-polymer composite. Cancer
Biother Radiopharm. 2020;35:1-9.
29. Yildirim A, Blum NT, Goodwin AP. Colloids, nanoparticles, and mate-
rials for imaging, delivery, ablation, and theranostics by focused
ultrasound (FUS). Theranostics. 2019;9:2572-2594.
30. Koga T, Tomimori K, Higashi N. Transparent, high-strength, and shape
memory hydrogels from thermo-responsive amino acid–derived vinyl
polymer networks. Macromol Rapid Commun. 2020;41:1900650.
31. Trombino S, Servidio C, Curcio F, Cassano R. Strategies for
hyaluronic acid-based hydrogel design in drug delivery. Pharma-
ceutics. 2019;11:1-17.
32. Cirillo G, Spizzirri UG, Curcio M, Nicoletta FP, Iemma F. Injectable
hydrogels for cancer therapy over the last decade. Pharmaceutics.
2019;11(9).
33. Houssami N, Macaskill P, Luke Marinovich M, Morrow M. The asso-
ciation of surgical margins and local recurrence in women with early-
stage invasive breast cancer treated with breast-conserving therapy:
a meta-analysis. Ann Surg Oncol. 2014;21:717-730.
34. Wang Y, Zheng D, Chen T, Zhang J, Yao F, Chen H. Survival predic-
tion and adjuvant chemotherapy based on tumor marker for stage IB
lung adenocarcinoma. Ann Thorac Surg. 2020;109:927-937.
35. Lacroix M, Abi-Said D, Fourney DR, et al. A multivariate analysis of
416 patients with glioblastoma multiforme: prognosis, extent of
resection, and survival. J Neurosurg. 2001;95:190-198.
36. Si R, Gao C, Guo R, Lin C, Li J, Guo W. Human mesenchymal stem
cells encapsulated-coacervated photoluminescent nanodots layered
bioactive chitosan/collagen hydrogel matrices to indorse cardiac
healing after acute myocardial infarction. J Photochem Photobiol B
Biol. 2020;206:111789.
37. Luo Y, Wei X, Wan Y, Lin X, Wang Z, Huang P. 3D printing of hydro-
gel scaffolds for future application in photothermal therapy of breast
cancer and tissue repair. Acta Biomater Acta Materialia Inc. 2019;92:
37-47.
38. Ma H, Zhou Q, Chang J, Wu C. Grape seed-inspired smart hydrogel
scaffolds for melanoma therapy and wound healing. ACS Nano.
2019;13:4302-4311.
39. Luo S, Wu J, Jia Z, et al. An injectable, Bifunctional hydrogel with
Photothermal effects for tumor therapy and bone regeneration.
Macromol Biosci. 2019;19:1-10.
40. Hoffman AS. Hydrogels for biomedical applications. Adv Drug Deliv
Rev. 2002;54(1):3-12.
41. Fujiyabu T, Yoshikawa Y, il CU, Sakai T. Structure-property relation-
ship of a model network containing solvent. Sci Technol Adv Mater.
2006;243(2):212-222.
42. Castillo Diaz LA, Elsawy M, Saiani A, Gough JE, Miller AF. Osteo-
genic differentiation of human mesenchymal stem cells promotes
mineralization within a biodegradable peptide hydrogel. J Tissue Eng.
2016;7:204173141664978.
43. Feng Q, Lin S, Zhang K, et al. Sulfated hyaluronic acid hydrogels with
retarded degradation and enhanced growth factor retention pro-
mote hMSC chondrogenesis and articular cartilage integrity with
reduced hypertrophy. Acta Biomater. 2017;53:329-342.
44. Turabee MH, Thambi T, Duong HTT, Jeong JH, Lee DS. A pH- and
temperature-responsive bioresorbable injectable hydrogel based on
polypeptide block copolymers for the sustained delivery of proteins:
in vivo. Biomater Sci. 2018;6:661-671.
45. Grijalvo S, Nieto-Díaz M, Maza RM, Eritja R, Díaz DD. Alginate
hydrogels as scaffolds and delivery systems to repair the damaged
spinal cord. Biotechnol J. 2019;14(12):e1900275.
46. Zhang C, Yang X, Hu W, Han X, Fan L, Tao S. Preparation and char-
acterization of carboxymethyl chitosan/collagen peptide/oxidized
konjac composite hydrogel. Int J Biol Macromol. 2020;149:31-40.
47. Shi W, Hass B, Kuss MA, et al. Fabrication of versatile dynamic
hyaluronic acid-based hydrogels. Carbohydr Polym. 2020;233:
115803.
48. Tan S, Yamashita A, Gao SJ, Kurisawa M. Hyaluronic acid hydrogels
with defined crosslink density for the efficient enrichment of breast
cancer stem cells. Acta Biomater. Acta Materialia Inc. 2019;94:
320-329.
49. Sun M, Sun X, Wang Z, Guo S, Yu G, Yang H. Synthesis and properties
of gelatin methacryloyl (GelMA) hydrogels and their recent applica-
tions in load-bearing tissue. Polymers (Basel).2018;10(11):1290-1010.
50. De France KJ, D'Emilio E, Cranston ED, Geiger T, Nyström G. Dual
physically and chemically crosslinked regenerated cellulose –gelatin
composite hydrogels towards art restoration. Carbohydr Polym.
2020;234:115885.
51. Pellá MCG, Lima-Tenório MK, Tenório-Neto ET, Guilherme MR,
Muniz EC, Rubira AF. Chitosan-based hydrogels: from preparation
to biomedical applications. Carbohydr Polym. 2018;196:233-245.
52. Zhou Y, Shen J, Bai Y, Li T, Xue G. Enhanced degradation of acid red
73 by using cellulose-based hydrogel coated Fe
3
O
4
nanocomposite
as a Fenton-like catalyst. Int J Biol Macromol. 2020;152:242-249.
53. Gisbert Roca F, Lozano Picazo P, Pérez-Rigueiro J, Guinea
Tortuero GV, Monleón Pradas M, Martínez-Ramos C. Conduits
based on the combination of hyaluronic acid and silk fibroin: charac-
terization, in vitro studies and in vivo biocompatibility. Int J Biol
Macromol. 2020;148:378-390.
54. Li Z, Song J, Zhang J, et al. Topical application of silk fibroin-based
hydrogel in preventing hypertrophic scars. Coll Surf B Biointerf. 2020;
186:110735.
TAN ET AL.17
55. Maione S. Polymers and Peptide-Polymer Conjugates as Bioactive
Platforms and Carriers for the Encapsulation of Biomolecules. TDX
(Tesis Dr en Xarxa). 2017;
56. Li J, Illeperuma WRK, Suo Z, Vlassak JJ. Hybrid hydrogels with
extremely high stiffness and toughness. ACS Macro Lett. 2014;3:
520-523.
57. Zhao X. Multi-scale multi-mechanism design of tough hydrogels:
building dissipation into stretchy networks. Soft Matter. 2014;10(5):
672-687.
58. Zhang J, Lu N, Peng H, et al. Multi-triggered and enzyme-mimicking
graphene oxide/polyvinyl alcohol/G-quartet supramolecular hydro-
gels. Nanoscale. 2020;12:5186-5195.
59. Chen M, Feng Z, Guo W, et al. PCL-MECM-based hydrogel hybrid
scaffolds and meniscal Fibrochondrocytes promote whole meniscus
regeneration in a rabbit Meniscectomy model. ACS Appl Mater Inter-
faces. 2019;11:41626-41639.
60. Livingston MK, Morgan MM, Daly WT, et al. Evaluation of PEG-
based hydrogel influence on estrogen-receptor-driven responses in
MCF7 breast Cancer cells. ACS Biomater Sci Eng. 2019;5:6089-6098.
61. Yang H, Lei K, Zhou F, et al. Injectable PEG/polyester thermogel: a
new liquid embolization agent for temporary vascular interventional
therapy. Mater Sci Eng C. 2019;102:606-615.
62. Liu WC, Wang HY, Lee TH, Chung RJ. Gamma-poly glutamate/gelatin
composite hydrogels crosslinked by proanthocyanidins for wound
healing. Mater Sci Eng C.2019;101:630-639.
63. Hong Y, Chen J, Fang H, et al. All-in-one hydrogel realizing adipose-
derived stem cell spheroid production and in vivo injection via “gel-
sol”transition for angiogenesis in hind limb ischemia. ACS Appl Mater
Interfaces. 2020;12:11375-11387.
64. Chyzy A, Tomczykowa M, Plonska-Brzezinska ME. Hydrogels as
potential nano-, micro- and macro-scale systems for controlled drug
delivery. Materials (Basel). 2020;13(1):188-220.
65. Bardajee GR, Khamooshi N, Nasri S, Vancaeyzeele C. Multi-stimuli
responsive nanogel/hydrogel nanocomposites based on
κ-carrageenan for prolonged release of levodopa as model drug. Int J
Biol Macromol. 2020;153:180-189.
66. Zhang J, Wu P, Zhao Y, et al. A simple mechanical agitation method
to fabricate chitin nanogels directly from chitin solution and subse-
quent surface modification. J Mater Chem B. 2019;7:2226-2232.
67. Chang S, Finklea F, Williams B, et al. Emulsion-based encapsulation
of pluripotent stem cells in hydrogel microspheres for cardiac differ-
entiation. Biotechnol Prog. 2020;36(4):e2986.
68. Winter RL, Tian Y, Caldwell FJ, et al. Cell engraftment, vasculariza-
tion, and inflammation after treatment of equine distal limb wounds
with endothelial colony forming cells encapsulated within hydrogel
microspheres. BMC Vet Res. 2020;16:43.
69. Gu D, O'Connor AJ, Qiao GGH, Ladewig K. Hydrogels with smart
systems for delivery of hydrophobic drugs. Expert Opin Drug Deliv.
2017;14(7):879-895.
70. Wang Q, Li X, Wang P, et al. Bionic composite hydrogel with a
hybrid covalent/noncovalent network promoting phenotypic main-
tenance of hyaline cartilage. J Mater Chem B. 2020;8:4402-4411.
71. Wang Y, Xu Z, Lovrak M, et al. Biomimetic strain-stiffening self-
assembled hydrogels. Angew Chemie - Int Ed. 2020;59:4830-4834.
72. Wang H, Biswas SK, Zhu S, et al. Self-healable electro-conductive
hydrogels based on core-shell structured nanocellulose/carbon nan-
otubes hybrids for use as flexible supercapacitors. Nanomaterials.
2020;10(1):112-133.
73. Ma M, Zhong Y, Jiang X. Thermosensitive and pH-responsive
tannin-containing hydroxypropyl chitin hydrogel with long-lasting
antibacterial activity for wound healing. Carbohydr Polym. 2020;236:
116096.
74. Shriky B, Kelly A, Isreb M, et al. Pluronic F127 thermosensitive
injectable smart hydrogels for controlled drug delivery system devel-
opment. J Colloid Interface Sci. 2020;565:119-130.
75. Feki A, Hamdi M, Jaballi I, Zghal S, Nasri M, Ben Amara I. Conception
and characterization of a multi-sensitive composite chitosan-red
marine alga-polysaccharide hydrogels for insulin controlled-release.
Carbohydr Polym. 2020;236:116046.
76. Sun J, Zhou F, Hu H, et al. Photocontrolled Thermosensitive
Electrochemiluminescence hydrogel for Isocarbophos detection.
Anal Chem. 2020;92:6136-6143.
77. Araiza-Verduzco F, Rodríguez-Velázquez E, Cruz H, et al. Photo-
crosslinked alginate-methacrylate hydrogels with modulable
mechanical properties: effect of the molecular conformation and
electron density of the methacrylate reactive group. Materials
(Basel). 2020;13(3):534-548.
78. Gao Z, Li Y, Shang X, Hu W, Gao G, Duan L. Bio-inspired adhesive
and self-healing hydrogels as flexible strain sensors for monitoring
human activities. Mater Sci Eng C. 2020;106:110168.
79. Chen YN, Jiao C, Zhao Y, Zhang J, Wang H. Self-assembled polyvinyl
alcohol-tannic acid hydrogels with diverse microstructures and good
mechanical properties. ACS Omega. 2018;3:11788-11795.
80. Wei Z, Chen Y, Wijaya W, Cheng Y, Xiao J, Huang Q. Hydrogels
assembled from ovotransferrin fibrils and xanthan gum as
dihydromyricetin delivery vehicles. Food Funct. 2020;11:1478-1488.
81. Yan B, Ma C, Gao J, Yuan Y, Wang N. An ion-Crosslinked Supramo-
lecular hydrogel for ultrahigh and fast uranium recovery from seawa-
ter. Adv Mater. 2020;32:1906615.
82. Song X, Zhang Z, Zhu J, et al. Thermoresponsive hydrogel induced
by dual Supramolecular assemblies and its controlled release prop-
erty for enhanced anticancer drug delivery. Biomacromolecules.
2020;21:1516-1527.
83. Mohammed AA, Pinna A, Li S, Sang T, Jones JR. Auto-catalytic redox
polymerisation using nanoceria and glucose oxidase for double net-
work hydrogels. J Mater Chem B. 2020;8:2834-2844.
84. Liu HY, Greene T, Lin TY, Dawes CS, Korc M, Lin CC. Enzyme-
mediated stiffening hydrogels for probing activation of pancreatic
stellate cells. Acta Biomater. 2017;48:258-269.
85. Jiang Z, Shaha R, McBride R, et al. Crosslinker length dictates step-
growth hydrogel network formation dynamics and allows rapid on-
chip photoencapsulation. Biofabrication. 2020;12:035006.
86. Ahmadi M, Seiffert S. Thermodynamic control over energy dissipa-
tion modes in dual-network hydrogels based on metal-ligand coordi-
nation. Soft Matter. 2020;16:2332-2341.
87. Ribeiro VP, da Silva Morais A, Maia FR, et al. Combinatory approach
for developing silk fibroin scaffolds for cartilage regeneration. Acta
Biomater. 2018;72:167-181.
88. Huang B, Hu R, Xue Z, et al. Continuous liquid interface production
of alginate/polyacrylamide hydrogels with supramolecular shape
memory properties. Carbohydr Polym. 2020;231:115736.
89. Qian C, Asoh TA, Uyama H. Osmotic squat actuation in stiffness
adjustable bacterial cellulose composite hydrogels. J Mater Chem B.
2020;8:2400-2409.
90. Donnelly PE, Chen T, Finch A, Brial C, Maher SA, Torzilli PA. Photo-
crosslinked tyramine-substituted hyaluronate hydrogels with tunable
mechanical properties improve immediate tissue-hydrogel interfacial
strength in articular cartilage. JBiomaterSciPolymEd. 2017;28:582-600.
91. Mukerji R, Schaal J, Li X, et al. Spatiotemporally photoradiation-
controlled intratumoral depot for combination of brachytherapy and
photodynamic therapy for solid tumor. Biomaterials. 2016;79:79-87.
92. Lee HJ, Ahn J, Jung CR, et al. Optimization of 3D hydrogel microen-
vironment for enhanced hepatic functionality of primary human
hepatocytes. Biotechnol Bioeng. 2020;117:1864-1876.
93. Zhan L, Hou Z, Huang G. Agarose hydrogel-enhanced paper spray
ionization mass spectrometry for metabolite detection in raw urine.
Analyst. 2020;145:2118-2124.
94. Bao W, Li M, Yang Y, et al. Advancements and frontiers in the high
performance of natural hydrogels for cartilage tissue engineering.
Front Chem. 2020;8:53-71.
18 TAN ET AL.
95. Alvarez-Lorenzo C, Grinberg VY, Burova TV, Concheiro A. Stimuli-
sensitive cross-linked hydrogels as drug delivery systems: impact of
the drug on the responsiveness. Int J Pharm. 2020;579:119157.
96. Van Vlierberghe S, Dubruel P, Schacht E. Biopolymer-based hydro-
gels as scaffolds for tissue engineering applications: a review. Bio-
macromolecules. 2011;12(5):1387-1408.
97. Liu S, Zhao M, Zhou Y, et al. A self-assembling peptide hydrogel-
based drug co-delivery platform to improve tissue repair after
ischemia-reperfusion injury. Acta Biomater. 2020;103:102-114.
98. Hekmatimoghaddam S, Iman M, Shahdadi Sardo H, Jebali A. Gelatin
hydrogel containing cerium oxide nanoparticles covered by
interleukin-17 aptamar as an anti- inflammatory agent for brain
inflammation. J Neuroimmunol. 2019;326:79-83.
99. Farag RK, Labena A, Fakhry SH, Safwat G, Diab A, Atta AM. Antimi-
crobial activity of hybrids terpolymers based on magnetite hydrogel
nanocomposites. Materials (Basel). 2019;12(21):3604-3617.
100. Wei H, Zhao Z, Wang Y, Zou J, Lin Q, Duan Y. One-step self-
assembly of multifunctional DNA Nanohydrogels: An enhanced and
harmless strategy for guiding combined antitumor therapy. ACS Appl
Mater Interfaces. 2019;11:46479-46489.
101. Jang H, Zhi K, Wang J, Zhao H, Li B, Yang X. Enhanced therapeutic
effect of paclitaxel with a natural polysaccharide carrier for local
injection in breast cancer. Int J Biol Macromol. Elsevier B.V. 2020;
148:163-172.
102. Kretlow JD, Young S, Klouda L, Wong M, Mikos AG. Injectable bio-
materials for regenerating complex craniofacial tissues. Adv Mater.
2009;21:3368-3393.
103. Gutkin PM, Fernandez-Pol S, Horst KC. Erythema of the skin after
breast radiotherapy: it is not always recurrence. Int Wound J. 2020;
17(4):910-915.
104. Zhang B, Wan S, Peng X, et al. Human serum albumin-based doxoru-
bicin prodrug nanoparticles with tumor pH-responsive aggregation-
enhanced retention and reduced cardiotoxicity. J Mater Chem B.
2020;8:3939-3948.
105. Critchlow AK. Introduction to Robotics. New York: Macmillan; 1985.
106. Li Q, Liu C, Wen J, Wu Y, Shan Y, Liao J. The design, mechanism and
biomedical application of self-healing hydrogels. Chinese Chem Lett;
Chinese Chemical Society. 2017;28:1857-1874.
107. Yu Z, Xiao Z, Shuai X, Tian J. Local delivery of sunitinib and Ce6 via
redox-responsive zwitterionic hydrogels effectively prevents osteo-
sarcoma recurrence. J Mater Chem B. 2020;8(30):6418-6428.
108. de Souza NM, Liu Y, Chiti A, et al. Strategies and technical chal-
lenges for imaging oligometastatic disease: recommendations from
the European Organisation for Research and treatment of cancer
imaging group. Eur J Cancer. 2018;91:153-163.
109. Zhang M, Wang R, Wu Y, et al. Micro-ultrasound imaging for accu-
racy of diagnosis in clinically significant prostate cancer: a meta-
analysis. Front Oncol. 2019;9:1368.
110. Gonçalves M, Mignani S, Rodrigues J, Tomás H. A glance over doxo-
rubicin based-nanotherapeutics: from proof-of-concept studies to
solutions in the market. J Control Release. 2020;317:347-374.
111. Carvalho C, Santos R, Cardoso S, et al. Doxorubicin: the good, the
bad and the ugly effect. Curr Med Chem. 2009;16:3267-3285.
112. Mei L, Xu K, Zhai Z, He S, Zhu T, Zhong W. Doxorubicin-reinforced
supramolecular hydrogels of RGD-derived peptide conjugates for
pH-responsive drug delivery. Org Biomol Chem. 2019;17:3853-
3860.
113. Farjadian F, Rezaeifard S, Naeimi M, et al. Temperature and pH-
responsive nano-hydrogel drug delivery system based on lysine-
modified poly (vinylcaprolactam). Int J Nanomedicine. 2019;14:6901-
6915.
114. Cao D, Zhang X, Akabar MD, et al. Liposomal doxorubicin loaded
PLGA-PEG-PLGA based thermogel for sustained local drug delivery
for the treatment of breast cancer. Artif cells, Nanomedicine Bio-
technol. Taylor & Francis. 2019;47:181-191.
115. Kampan NC, Madondo MT, McNally OM, Quinn M, Plebanski M.
Paclitaxel and its evolving role in the management of ovarian cancer.
Biomed Res Int. 2015;2015:413076.
116. Hyun H, Park MH, Jo G, Kim SY, Chun HJ, Yang DH. Photo-cured
glycol chitosan hydrogel for ovarian cancer drug delivery. Mar Drugs.
2019;17:1-12.
117. Yang DH, Seo DI, Lee DW, et al. Preparation and evaluation of
visible-light cured glycol chitosan hydrogel dressing containing dual
growth factors for accelerated wound healing. J Ind Eng Chem. 2017;
53:360-370.
118. Klemm D, Kramer F, Moritz S, et al. Nanocelluloses: a new family of
nature-based materials. Angew Chemie - Int Ed. 2011;50(24):5438-
5466.
119. Ning L, You C, Zhang Y, Li X, Wang F. Synthesis and biological evalu-
ation of surface-modified nanocellulose hydrogel loaded with pacli-
taxel. Life Sci Elsevier Inc. 2020;241:117137.
120. Chakraborty P, Dastidar P. An easy access to topical gels of an anti-
cancer prodrug (5-fluorouracil acetic acid) for self-drug-delivery
applications. Chem Commun Royal Soc Chem. 2019;55:7683-7686.
121. Hosseinifar T, Sheybani S, Abdouss M, Hassani Najafabadi SA,
Shafiee AM. Pressure responsive nanogel base on alginate-
Cyclodextrin with enhanced apoptosis mechanism for colon cancer
delivery. J Biomed Mater Res - Part A. 2018;106:349-359.
122. Martínez-Garcia M,
Alvarez-Linera J, Carrato C, et al. SEOM clinical
guidelines for diagnosis and treatment of glioblastoma (2017). Clin
Transl Oncol. 2018;20:22-28.
123. Ganipineni LP, Danhier F, Préat V. Drug delivery challenges and
future of chemotherapeutic nanomedicine for glioblastoma treat-
ment. J Control Release. 2018;281:42-57.
124. Turabee MH, Jeong TH, Ramalingam P, Kang JH, Ko YT. N,N,N-
trimethyl chitosan embedded in situ pluronic F127 hydrogel for the
treatment of brain tumor. Carbohydr Polym; Elsevier Ltd. 2019;203:
302-309.
125. Mirani B, Pagan E, Shojaei S, et al. A 3D bioprinted hydrogel mesh
loaded with all-trans retinoic acid for treatment of glioblastoma. Eur
J Pharmacol. Elsevier BV. 2019;854:201-212.
126. Zhao M, Danhier F, Bastiancich C, et al. Post-resection treatment of
glioblastoma with an injectable nanomedicine-loaded photo-
polymerizable hydrogel induces long-term survival. Int J Pharm.
Elsevier. 2018;548:522-529.
127. Breugom AJ, Swets M, Bosset JF, et al. Adjuvant chemotherapy
after preoperative (chemo)radiotherapy and surgery for patients
with rectal cancer: a systematic review and meta-analysis of individ-
ual patient data. Lancet Oncol. 2015;16:200-207.
128. Lin JT, Ye QB, Yang QJ, Wang GH. Hierarchical bioresponsive
nanocarriers for codelivery of curcumin and doxorubicin. Coll Surf B
Biointerf. Elsevier. 2019;180:93-101.
129. Shi H, Chi H, Luo Z, et al. Self-healable, fast responsive poly(ω-pen-
tadecalactone) thermogelling system for effective liver cancer ther-
apy. Front Chem. 2019;7:1-16.
130. Koppe MJ, Boerman OC, Oyen WJG, Bleichrodt RP. Peritoneal car-
cinomatosis of colorectal origin: incidence and current treatment
strategies. Ann Surg. 2006;243(2):212-222.
131. Ren Y, Li X, Han B, et al. Improved anti-colorectal carcinomatosis
effect of tannic acid co-loaded with oxaliplatin in nanoparticles
encapsulated in thermosensitive hydrogel. Eur J Pharm Sci Elsevier
BV. 2019;128:279-289.
132. Yu S, Wei S, Liu L, et al. Enhanced local cancer therapy using a
CA4P and CDDP co-loaded polypeptide gel depot. Biomater Sci
Royal Soc Chem. 2019;7:860-866.
133. Pal S, Medatwal N, Kumar S, et al. A localized chimeric hydrogel
therapy combats tumor progression through alteration of
Sphingolipid metabolism. ACS Cent Sci. 2019;5:1648-1662.
134. Barbarisi M, Iaffaioli RV, Armenia E, et al. Novel nanohydrogel of
hyaluronic acid loaded with quercetin alone and in combination with
TAN ET AL.19
temozolomide as new therapeutic tool, CD44 targeted based, of
glioblastoma multiforme. J Cell Physiol. 2018;233:6550-6564.
135. Yao X, Yang P, Jin Z, et al. Multifunctional nanoplatform for photo-
acoustic imaging-guided combined therapy enhanced by CO
induced ferroptosis. Biomaterials. 2019;197:268-283.
136. Sun T, Han J, Liu S, Wang X, Wang ZY, Xie Z. Tailor-made semicon-
ducting polymers for second near-infrared photothermal therapy of
orthotopic liver cancer. ACS Nano. 2019;13(6):7345-7354.
137. Lee C, Lim K, Kim SS, et al. Near infrared light-responsive heat-
emitting hemoglobin hydrogels for photothermal cancer therapy.
Colloids Surf B Biointerf; Elsevier. 2019;176:156-166.
138. Tao ZQ, Shi A, Lu C, Song T, Zhang Z, Zhao J. Breast Cancer: epide-
miology and etiology. Cell Biochem Biophys. 2015;72:333-338.
139. Jiang YW, Gao G, Hu P, et al. Palladium nanosheet-knotted inject-
able hydrogels formed: via palladium-sulfur bonding for synergistic
chemo-photothermal therapy. Nanoscale Royal Soc Chem. 2020;12:
210-219.
140. Zheng Y, Wang W, Zhao J, et al. Preparation of injectable
temperature-sensitive chitosan-based hydrogel for combined hyper-
thermia and chemotherapy of colon cancer. Carbohydr Polym;
Elsevier. 2019;222:115039.
141. Shu M, Long S, Huang Y, Li D, Li H, Li X. High strength and
antibacterial polyelectrolyte complex CS/HS hydrogel films for
wound healing. Soft Matter. 2019;15:7686-7694.
142. Wang B, Wu S, Lin Z, et al. A personalized and long-acting local ther-
apeutic platform combining photothermal therapy and chemother-
apy for the treatment of multidrug-resistant colon tumor. Int J
Nanomed. 2018;13:8411-8427.
143. Chen R, Zheng X, Qian H, Wang X, Wang J, Jiang X. Combined near-
IR photothermal therapy and chemotherapy using gold-
nanorod/chitosan hybrid nanospheres to enhance the antitumor
effect. Biomater Sci. 2013;1:285-293.
144. Ouyang B, Liu F, Ruan S, et al. Localized free radicals burst triggered
by NIR-II light for augmented low-temperature photothermal ther-
apy. ACS Appl Mater Interf Am Chem Soc. 2019;11:38555-38567.
145. Mallidi S, Anbil S, Bulin AL, Obaid G, Ichikawa M, Hasan T. Beyond
the barriers of light penetration: strategies, perspectives and possi-
bilities for photodynamic therapy. Theranostics. 2016;6:2458-
2487.
146. Zhou TJ, Xing L, Fan YT, Cui PF, Jiang HL. Inhibition of breast cancer
proliferation and metastasis by strengthening host immunity with a
prolonged oxygen-generating phototherapy hydrogel. J Control
Release. Elsevier. 2019;309:82-93.
147. Pan W, Dai C, Li Y, et al. PRP-chitosan thermoresponsive hydrogel
combined with black phosphorus nanosheets as injectable biomate-
rial for biotherapy and phototherapy treatment of rheumatoid
arthritis. Biomaterials. 2020;239:119851.
148. Chang G, Zhang H, Li S, Huang F, Shen Y, Xie A. Effective photody-
namic therapy of polymer hydrogel on tumor cells prepared using
methylene blue sensitized mesoporous titania nanocrystal. Mater Sci
Eng C; Elsevier. 2019;99:1392-1398.
149. Wang HH, Fu ZG, Li W, et al. The synthesis and application of nano
doxorubicin-indocyanine green matrix metalloproteinase-responsive
hydrogel in chemophototherapy for head and neck squamous cell
carcinoma. Int J Nanomedicine. 2019;14:623-638.
150. Meng Z, Zhou X, Xu J, et al. Light-triggered in situ gelation to enable
robust photodynamic-immunotherapy by repeated stimulations. Adv
Mater. 2019;31:1-12.
151. Leach DG, Dharmaraj N, Piotrowski SL, et al. STINGel: controlled
release of a cyclic dinucleotide for enhanced cancer immunotherapy.
Biomaterials. 2018;163:67-75.
152. Chen Q, Wang C, Zhang X, et al. In situ sprayed bioresponsive
immunotherapeutic gel for post-surgical cancer treatment. Nat
Nanotechnol. 2019;14:89-97.
153. De Groot CJ, Cadée JA, Koten JW, Hennink WE, Den Otter W.
Therapeutic efficacy of IL-2-loaded hydrogels in a mouse tumor
model. Int J Cancer. 2002;98:134-140.
154. Wu H, Liu L, Song L, Ma M, Gu N, Zhang Y. Enhanced tumor syner-
gistic therapy by injectable magnetic hydrogel mediated generation
of hyperthermia and highly toxic reactive oxygen species. ACS Nano.
2019;13:14013-14023.
155. Jiguet Jiglaire C, Baeza-Kallee N, Denicolaï E, et al. Ex vivo cultures
of glioblastoma in three-dimensional hydrogel maintain the original
tumor growth behavior and are suitable for preclinical drug and radi-
ation sensitivity screening. Exp Cell Res. Elsevier. 2014;321:99-108.
156. Gonçalves DPN, Rodriguez RD, Kurth T, et al. Enhanced targeting of
invasive glioblastoma cells by peptide-functionalized gold nanorods
in hydrogel-based 3D cultures. Acta Biomater. 2017;58:12-25.
157. Nguyen DT, Fan Y, Akay YM, Akay M. TNP-470 reduces glioblas-
toma angiogenesis in three dimensional gel MA microwell platform.
IEEE Trans Nanobiosci. 2016;15:683-688.
158. Partridge M, Li SR, Pateromichelakis S, et al. Detection of minimal
residual cancer to investigate why oral tumors recur despite seem-
ingly adequate treatment. Clin Cancer Res. 2000;6:2718-2725.
159. Saha RN, Vasanthakumar S, Bende G, Snehalatha M.
Nanoparticulate drug delivery systems for cancer chemotherapy.
Mol Membr Biol. 2010;27(7):215-231.
160. Pàez-Ribes M, Allen E, Hudock J, et al. Antiangiogenic therapy elicits
malignant progression of tumors to increased local invasion and dis-
tant metastasis. Cancer Cell. 2009;15:220-231.
161. Gilliam LAA, Clair DK. Chemotherapy-induced weakness and fatigue
in skeletal muscle: the role of oxidative stress. Antioxidants Redox
Signal. 2011;15(9):2543-2563.
162. Roy S, Lahiri D, Maji T, Biswas J. Recurrent Glioblastoma: where we
stand. South Asian J Cancer. 2015;4:163-173.
163. Smoll NR, Schaller K, Gautschi OP. Long-term survival of patients
with glioblastoma multiforme (GBM). J Clin Neurosci. 2013;20:
670-675.
164. Bastiancich C, Bianco J, Vanvarenberg K, et al. Injectable
nanomedicine hydrogel for local chemotherapy of glioblastoma after
surgical resection. J Control Release. 2017;264:45-54.
165. Zhao M, Bozzato E, Joudiou N, et al. Codelivery of paclitaxel and
temozolomide through a photopolymerizable hydrogel prevents
glioblastoma recurrence after surgical resection. J Control Release.
2019;309:72-81.
166. Lei N, Gong C, Qian Z, et al. Therapeutic application of injectable
thermosensitive hydrogel in preventing local breast cancer recur-
rence and improving incision wound healing in a mouse model.
Nanoscale. 2012;4:5686-5693.
167. Li Q, Wen J, Liu C, et al. Graphene-nanoparticle-based self-healing
hydrogel in preventing postoperative recurrence of breast cancer.
ACS Biomater Sci Eng; American Chemical Society. 2019;5:768-779.
168. Gao F, Xie W, Miao Y, et al. Magnetic hydrogel with optimally adap-
tive functions for breast cancer recurrence prevention. Adv Healthc
Mater. 2019;8:1-14.
169. Zhang K, Fang Y, He Y, et al. Extravascular gelation shrinkage-
derived internal stress enables tumor starvation therapy with
suppressed metastasis and recurrence. Nat Commun. Springer
US. 2019;10:1-17.
170. Pua VSC, Huilgol S, Hill D. Evaluation of the treatment of non-
melanoma skin cancers by surgical excision. Australas J Dermatol.
2009;50:171-175.
171. Wang Y, Xie R, Li Q, et al. A self-adapting hydrogel based on
chitosan/oxidized konjac glucomannan/AgNPs for repairing irregular
wounds. Biomater Sci. 2020;8:1910-1922.
172. Townsend JM, Sali G, Homburg HB, et al. Thiolated bone and ten-
don tissue particles covalently bound in hydrogels for in vivo cal-
varial bone regeneration. Acta Biomater. 2020;104:66-75.
20 TAN ET AL.
173. Obregon-Miano F, Fathi A, Rathsam C, Sandoval I, Deheghani F,
Spahr A. Injectable porcine bone demineralized and digested extra-
cellular matrix—PEGDA hydrogel blend for bone regeneration.
J Mater Sci Mater Med. Springer US. 2020;31(2):21-35.
174. Antich C, de Vicente J, Jiménez G, et al. Bio-inspired hydrogel com-
posed of hyaluronic acid and alginate as a potential bioink for 3D
bioprinting of articular cartilage engineering constructs. Acta
Biomater. 2020;106:114-123.
175. Schaeffer C, Pfaff BN, Cornell NJ, et al. Injectable microannealed
porous scaffold for articular cartilage regeneration. Ann Plast Surg.
2020;84:S446-S450.
176. Bour RK, Sharma PR, Turner JS, et al. Bioprinting on sheet-based
scaffolds applied to the creation of implantable tissue-engineered
constructs with potentially diverse clinical applications: tissue-
engineered muscle repair (TEMR) as a representative testbed. Con-
nect Tissue Res. 2020;61:216-228.
177. Wang C, Chen C, Guo M, Li B, Han F, Chen W. Stretchable collagen-
coated polyurethane-urea hydrogel seeded with bladder smooth
muscle cells for urethral defect repair in a rabbit model. J Mater Sci
Mater Med. 2019;30:135.
178. Negrini NC, Celikkin N, Tarsini P, Farè S, Święszkowski W. Three-
dimensional printing of chemically crosslinked gelatin hydrogels for
adipose tissue engineering. Biofabrication. 2020;12(2):025001.
179. Kennedy S, Lace R, Carserides C, et al. Poly-ε-lysine based hydrogels
as synthetic substrates for the expansion of corneal endothelial cells
for transplantation. J Mater Sci Mater Med. 2019;30:102.
180. Anderson DEJ, Truong KP, Hagen MW, Yim EKF, Hinds MT. Biomi-
metic modification of poly(vinyl alcohol): encouraging
endothelialization and preventing thrombosis with antiplatelet mon-
otherapy. Acta Biomater. 2019;86:291-299.
181. Keselowsky BG, Collard DM, García AJ. Integrin binding specificity
regulates biomaterial surface chemistry effects on cell differentia-
tion. Proc Natl Acad Sci U S A. 2005;102:5953-5957.
182. Zeng M, Xie J, Li M, Lin S, Su W, Hu Y. Design and evaluation of
poly (lactic-co-glyclic acid)/poly (vinyl alcohol)/nano-hydroxyapatite
hydrogels for cartilage tissue engineering in vitro. Int J Clin Exp Med.
2016;9:9817-9827.
183. Lutolf MP, Weber FE, Schmoekel HG, et al. Repair of bone defects
using synthetic mimetics of collagenous extracellular matrices. Nat
Biotechnol. 2003;21:513-518.
184. Cao J, Wang P, Liu Y, Zhu C, Fan D. Double crosslinked HLC-CCS
hydrogel tissue engineering scaffold for skin wound healing. Int J
Biol Macromol. 2020;155:625-635.
185. Morais JM, Papadimitrakopoulos F, Burgess DJ. Biomaterials/tissue
interactions: possible solutions to overcome foreign body response.
AAPS J. 2010;12(2):188-196.
186. Guillier D, Campisi C, Krähenbühl SM, Raffoul W, di Summa PG.
Bipedicled distally based medial plantar artery perforator flap for
forefoot reconstruction: a case report. Microsurgery. 2020;40:
497-500.
187. Otsu U, Fukui N, Iki M, Moriwaki S, Kiyokane K. Case of cutaneous
malignant melanoma surviving 16 years with late recurrence.
J Dermatol. 2009;36:598-603.
188. Ousey K, Cutting KF, Rogers AA, Rippon MG. The importance of
hydration in wound healing: reinvigorating the clinical perspective.
J Wound Care. 2016;25:122-130.
189. Liu R, Dai L, Si C, Zeng Z. Antibacterial and hemostatic hydrogel via
nanocomposite from cellulose nanofibers. Carbohydr Polym. 2018;
195:63-70.
190. Jing C, Wang Z, Lou R, et al. Nedaplatin reduces multidrug resis-
tance of non-small cell lung cancer by downregulating the expres-
sion of long non-coding RNA MVIH. J Cancer. 2020;11:559-569.
191. Zhou L, Xi Y, Xue Y, et al. Injectable self-healing antibacterial bioac-
tive polypeptide-based hybrid Nanosystems for efficiently treating
multidrug resistant infection, skin-tumor therapy, and enhancing
wound healing. Adv Funct Mater. 2019;29:1-11.
192. Agarwal R, García AJ. Biomaterial strategies for engineering implants
for enhanced osseointegration and bone repair. Adv Drug Deliv Rev.
2015;94:53-62.
193. Li D, Nie W, Chen L, et al. Self-assembled hydroxyapatite-graphene
scaffold for photothermal cancer therapy and bone regeneration.
J Biomed Nanotechnol. 2018;14:2003-2017.
194. Wu J, Cao L, Liu Y, et al. Functionalization of silk fibroin electrospun
scaffolds via BMSC affinity peptide grafting through oxidative self-
polymerization of dopamine for bone regeneration. ACS Appl Mater
Interfaces. 2019;11:8878-8895.
195. Ghorbani F, Zamanian A, Behnamghader A, Joupari MD. A facile
method to synthesize mussel-inspired polydopamine nanospheres
as an active template for in situ formation of biomimetic hydroxyap-
atite. Mater Sci Eng C. 2019;94:729-739.
196. Nishiguchi A, Kurihara Y, Taguchi T. Underwater-adhesive micropar-
ticle dressing composed of hydrophobically-modified Alaska Pollock
gelatin for gastrointestinal tract wound healing. Acta Biomater;
Elsevier Ltd. 2019;99:387-396.
197. Golmohammadi R, Najar-Peerayeh S, Tohidi Moghadam T,
Hosseini SMJ. Synergistic antibacterial activity and wound healing
properties of selenium-chitosan-Mupirocin Nanohybrid system: An
in vivo study on rat diabetic Staphylococcus aureus wound infection
model. Sci Rep. 2020;10:1-10.
198. Kong F, Fan C, Yang Y, Lee BH, Wei K. 5-Hydroxymethylfurfural-
embedded poly (vinyl alcohol)/sodium alginate hybrid hydrogels
accelerate wound healing. Int J Biol Macromol. Elsevier BV. 2019;
138:933-949.
199. Llopis-Grimalt MA, Arbós A, Gil-Mir M, et al. Multifunctional proper-
ties of quercitrin-coated porous Ti-6Al-4V implants for orthopaedic
applications assessed in vitro. J Clin Med. 2020;9:855.
200. Aran S, Zahri S, Asadi A, Khaksar F, Abdolmaleki A. Hair follicle stem
cells differentiation into bone cells on collagen scaffold. Cell Tissue
Bank. Springer Netherlands. 2020;21:181-188.
201. Salehi M, Ehterami A, Farzamfar S, Vaez A, Ebrahimi-Barough S.
Accelerating healing of excisional wound with alginate hydrogel con-
taining naringenin in rat model. Drug Deliv Transl Res. 2020. https://
doi.org/10.1007/s13346-020-00731-6
202. Qiao Y, Liu X, Zhou X, et al. Gelatin Templated polypeptide co-
cross-linked hydrogel for bone regeneration. Adv Healthc Mater.
2020;9:1-7.
203. Hanna DH, Lotfy VF, Basta AH, Saad GR. Comparative evaluation
for controlling release of niacin from protein- and cellulose-chitosan
based hydrogels. Int J Biol Macromol. 2020;150:228-237.
204. Lee JK, Huwe LW, Paschos N, et al. Tension stimulation drives tissue
formation in scaffold-free systems. Nat Mater. 2017;16:864-873.
205. Hu Y, Niemeyer CM. Designer DNA-silica/carbon nanotube
nanocomposites for traceable and targeted drug delivery. J Mater
Chem B. 2020;8:2250-2255.
206. Theodoro LH, Ferro-Alves ML, Longo M, et al. Curcumin photody-
namic effect in the treatment of the induced periodontitis in rats.
Lasers Med Sci. 2017;32:1783-1791.
207. Hu Z, Ding J, Ma Z, et al. Quantitative evidence for early meta-
static seeding in colorectal cancer. Nat Genet. 2019;51(7):1113-
1122.
208. Ma X, Zhao Z, Wang H, et al. P-glycoprotein antibody decorated
porous hydrogel particles for capture and release of drug-resistant
tumor cells. Adv Healthc Mater. 2019;8:1-8.
209. Cao J, Zhu B, Zheng K, et al. Recent Progress in NIR-II contrast
agent for biological imaging. Front Bioeng Biotechnol. 2019;7:487.
210. Liu TM, Conde J, Lipi
nski T, Bednarkiewicz A, Huang CC. Revisiting
the classification of NIR-absorbing/emitting nanomaterials for
in vivo bioapplications. NPG Asia Mater. 2016;8:e295.
TAN ET AL.21
211. Nakamura YA, Okuyama S, Furusawa A, et al. Near-infrared photo-
immunotherapy through bone. Cancer Sci. 2019;110(12):3689-
3694.
212. Rapp TL, DeForest CA. Visible light-responsive dynamic biomate-
rials: going deeper and triggering more. Adv Healthc Mater. 2020;9:
e1901553.
213. Nagakawa Y, Yi SQ, Takishita C, et al. Precise anatomical re-
section based on structures of nerve and fibrous tissue around the
superior mesenteric artery for mesopancreas dissection in
pancreaticoduodenectomy for pancreatic cancer. J Hepatobiliary
Pancreat Sci. 2020;27(6):342-351.
214. Acosta-Torres S, Fader AN. Laparoscopic splenectomy for second-
ary cytoreduction of ovarian cancer in a woman with localized
splenic recurrence. Gynecol Oncol. 2020;156:744-745.
215. Chen G, Li J, Cai Y, et al. A glycyrrhetinic acid-modified curcumin
supramolecular hydrogel for liver tumor targeting therapy. Sci Rep;
Nature Publishing Group. 2017;7:1-8.
216. Zhu X, Zhang Y, Huang H, Zhang H, Hou L, Zhang Z. Functionalized
graphene oxide-based thermosensitive hydrogel for near-infrared
chemo-photothermal therapy on tumor. J Biomater Appl. 2016;30:
1230-1241.
217. Raza F, Zhu Y, Chen L, et al. Paclitaxel-loaded pH responsive hydro-
gel based on self-assembled peptides for tumor targeting. Biomater
Sci. 2019;7:2023-2036.
218. Hou M, Liu W, Zhang L, et al. Responsive agarose hydrogel incorpo-
rated with natural humic acid and MnO2 nanoparticles for effective
relief of tumor hypoxia and enhanced photo-induced tumor therapy.
Biomater Sci; Royal Society of Chemistry. 2020;8:353-369.
219. Liang Y, Hao Y, Wu Y, et al. Integrated hydrogel platform for
programmed antitumor therapy based on near infrared-triggered
hyperthermia and vascular disruption. ACS Appl Mater Interf; Ameri-
can Chemical Society. 2019;11:21381-21390.
220. Wu W, Dai Y, Liu H, et al. Local release of gemcitabine via in situ
uv-crosslinked lipid-strengthened hydrogel for inhibiting osteosar-
coma. Drug Deliv; Taylor & Francis. 2018;25:1642-1651.
221. Dalwadi C, Patel G. Thermosensitive nanohydrogel of 5-fluorouracil
for head and neck cancer: preparation, characterization and cytotox-
icity assay. Int J Nanomedicine. 2018;13:31-33.
222. Huang Z, Xiao H, Lu X, Yan W, Ji Z. Enhanced photo/chemo combi-
nation efficiency against bladder tumor by encapsulation of DOX
and ZnPC into in situ-formed thermosensitive polymer hydrogel. Int
J Nanomedicine. 2018;13:7623-7631.
223. Peng D, Gao H, Huang P, et al. Host-guest supramolecular hydrogel
based on nanoparticles: co-delivery of DOX and siBcl-2 for
synergistic cancer therapy. J Biomater Sci Polym Ed; Taylor & Francis.
2019;30:877-893.
224. Gao F, Zhang T, Liu X, et al. Nonmagnetic hypertonic saline-based
implant for breast cancer postsurgical recurrence prevention by
magnetic field/pH-driven thermochemotherapy. ACS Appl Mater
Interf; American Chemical Society. 2019;11:10597-10607.
225. Liu H, Shi X, Wu D, et al. Injectable, biodegradable, thermosensitive
nanoparticles-aggregated hydrogel with tumor-specific targeting,
penetration, and release for efficient postsurgical prevention of
tumor recurrence. ACS Appl Mater Interfaces. 2019;11:19700-
19711.
226. Schiapparelli P, Zhang P, Lara-Velazquez M, et al. Self-assembling
and self-formulating prodrug hydrogelator extends survival in a glio-
blastoma resection and recurrence model. J Control Release; Elsevier
BV. 2020;319:311-321.
227. Wang T, Wang D, Yu H, et al. A cancer vaccine-mediated postopera-
tive immunotherapy for recurrent and metastatic tumors. Nat
Commun Springer US. 2018;9:1-12.
228. Wang X, Wang J, Wu W, Li H. Vaginal delivery of carboplatin-loaded
thermosensitive hydrogel to prevent local cervical cancer recurrence
in mice. Drug Deliv. 2016;23:3544-3551.
229. Wu Y, Wang H, Gao F, Xu Z, Dai F, Liu W. An injectable supramolec-
ular polymer nanocomposite hydrogel for prevention of breast can-
cer recurrence with Theranostic and Mammoplastic functions. Adv
Funct Mater. 2018;28:1-12.
230. Wang X, Ma B, Xue J, Wu J, Chang J, Wu C. Defective black nano-
titania thermogels for cutaneous tumor-induced therapy and healing.
Nano Lett; American Chemical Society. 2019;19:2138-2147.
231. Fenn SL, Charron PN, Oldinski RA. Anticancer therapeutic alginate-
based tissue sealants for lung repair. ACS Appl Mater Interfaces.
2017;9:23409-23419.
232. Wang X, Zhang J, Li J, et al. Bifunctional scaffolds for the
photothermal therapy of breast tumor cells and adipose tissue
regeneration. J Mater Chem B; Royal Society of Chemistry. 2018;6:
7728-7736.
How to cite this article: Tan B, Huang L, Wu Y, Liao J.
Advances and trends of hydrogel therapy platform in localized
tumor treatment: A review. J Biomed Mater Res. 2020;1–22.
https://doi.org/10.1002/jbm.a.37062
22 TAN ET AL.
