Review

Journal of Biomaterials Applications

2022, Vol. 36(6) 9 45­–955
Progress of biomaterials for bone ! The Author(s) 2021
Article reuse guidelines:
tumor therapy sagepub.com/journals-permissions
DOI: 10.1177/08853282211035236
journals.sagepub.com/home/jba

Hanzheng Chen1,2 and Yongchang Yao1,2

Abstract
Bone tumors are currently a major clinical challenge. In recent decades, strategies using well-designed versatile bio-
materials for the treatment of bone tumors have emerged and attracted extensive research interest. Suitable bioma-
terials not only facilitate repair for bone defects aroused by surgical intervention but also help deliver antineoplastic
drugs to the target site or provide photothermal/magnetothermal therapy to kill bone tumor cells. Thus, the develop-
ment of biomaterials exhibits a great perspective for future bone tumor treatment.
We summarize the recent progress of versatile biomaterials for bone tumor therapy, with an emphasis on photothermal/
magnetothermal therapy and drug delivery.
With the further understanding and development of biomaterials, multifunctional biomaterials have been proposed for
bone tumor treatment. Through the interdisciplinary cooperation from the fields of biomedicine, clinical medicine and
engineering, multifunctional biomaterials will perfectly match individual bone defects in the clinic with low cost in the
future.

Keywords
Bone tumor, bone regeneration, drug delivery, photothermal therapy, magnetothermal therapy

Introduction strength and desirable osteogenic, osteoinductive and

Bone tumors often occur in the bone or its affiliated
tissues (blood vessels, nerves, bone marrow, etc.) and
are likely characterized by pain and bone destruction.1
In the clinic, current treatments are commonly based on
surgical intervention, chemotherapy and radiotherapy.2
Nevertheless, a surgical resection cannot completely
remove tumor cells in certain cases, which likely results
in cancer recurrence and metastasis.3 Simultaneously,
large bone defects caused by a surgical resection require
repair using biomaterials. In addition, chemotherapy
and radiotherapy involve side effects, such as liver dys-
function, heart toxicity and damage to normal tissues.
Some bone tumors, such as Osteosarcoma, is invalid to
radiotherapy and is inclined to resist chemotherapy.4
The above considerations urge the development of bio-
materials for bone tumor therapy.
Biomaterials are biocompatible materials that are
implanted into the human body to enhance or replace
bodily tissues or organs.5 In the past few decades,
efforts have been made to develop biomaterials, includ-
ing bioceramics,6,7 composite biomaterials8 and metal
materials,9,10 with stable biocompatibility, suitable
osteoconductive properties for bone tissue engineering.
In addition to bone defect, biomaterials have recently
been designed for bone tumor diagnosis and treat-
ment.11,12 Early diagnosis and treatment are essential
to enhance the survival rate and increase the quality of
life. Hyperthermic treatments, such as photothermal
therapy and magnetothermal therapy, using biomateri-
als have emerged as a promising candidate method for
bone tumor treatment and obtained encouraging clin-
ical outcomes.13 And drug delivery system based on
biomaterials can avoid systemic side effects by selective
delivery. In recent years, increasing attention has
focused on designing multifunctional biomaterials
1
Department of Joint Surgery, the First Affiliated Hospital of Guangzhou
Medical University, Guangzhou, China
2
Guangdong Key Laboratory of Orthopaedic Technology and Implant
Materials, Guangzhou, China
Corresponding author:
Yongchang Yao, Department of Joint Surgery, the First Affiliated Hospital
of Guangzhou Medical University, Guangzhou 510120, China.
Email: yaoyc@gzhmu.edu.cn
2946 Journal
that can not only eliminate residual bone tumor cells
around defect sites, but also prompt bone regeneration.
Some representative biomaterials for bone tumor treat-
ment were summarized and listed in Table 1.
This review summarizes the recent progress of ver-
satile biomaterials for bone tumor therapy, with an
emphasis on photothermal/magnetothermal therapy
and drug delivery. A critical understanding of multi-
functional biomaterial development will provide fresh
insights for creating novel biomaterials for bone tumor
therapy.
Photothermal therapy for bone tumors
Photothermal therapy mainly uses photothermal
agents to absorb and convert laser energy into local
heat upon near-infrared exposure. The light irradiation
can be controlled to irradiate only the tumor site in
space, which can selectively result in irreversible cell
death and tumor destruction.25–28 Most light-
absorbing materials absorb near-infrared (NIR) light
in the wavelength range of 700–1100 nm, leading to
deep penetration into biological tissue.29,30 Therefore,
compared with the conventional therapeutic
approaches for bone tumors, photothermal therapy
shows the excellent properties of high spatial and tem-
poral resolution with remarkable features as a nonin-
vasive therapy with fewer side effects and no obvious
damage to normal tissues.31–34 To date, many different
kinds of photothermal agents using biomaterials, such
as metal nanomaterials, carbon-based nanoparticles
and scaffolds with 3 D-printing techniques, have been
designed and developed for bone cancer treatment.
Metal nanoparticles as photothermal agents
A large number of nanoparticles with inherent light-
absorbing features and photochemical stability have
been developed for tumor therapy and tissue engineer-
ing. In addition, nanoparticles exhibit a high surface
area ratio, and the ability to penetrate cellular mem-
branes and structural barriers.35 Therefore, these nano-
particles can be used as photothermal agents to destroy
the possibly residual tumor cells.
At present, many metal nanoparticles have been
designed as photothermal agents. Wang et al. developed
trifolium-like platinum nanoparticles (TPNs) by an easy
and green method with a small size (<20 nm in diameter)
and remarkable photothermal conversion perfor-
mance.36 The results from an in vitro study demonstrat-
ed that these TPNs had minimal cytotoxicity to normal
cells in the biocompatibility assay but killed a high per-
centage of cancer cells in the presence of an NIR laser.
Furthermore, these nanoparticles were first confirmed
to effectively suppress tumor growth and osteolysis in a
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bone metastasis model. Subsequently, photothermal
agents with high targeting to bone tissue were developed
to improve the therapeutic efficiency. Dendritic
platinum-copper alloy nanoparticles (DPCNs) were cre-
ated and validated as photothermal agents with a
remarkable photothermal conversion efficiency and
high drug-loading properties.37 Wang et al. prepared a
bone-targeted nanoparticle using DPCN, which was
modified by an aspartate octapeptide (Asp-DPCN).38
In vitro, Asp-DPCN displayed a higher affinity for
hydroxyapatite and bone fragments than the unmodi-
fied DPCN. In vivo, more Asp-DPCN efficiently accu-
mulated around cancer cells and yielded a higher
temperature. The data indicated that Asp-DPCN-
mediated photothermal therapy not only significantly
inhibited tumor growth but also remarkably suppressed
osteoclastic bone destruction. Likewise, Zhou et al.
modified platinum nanoparticles with phytic acid,
taking advantage of the bone-targeting properties of
phytic acid and the photothermal performance of plat-
inum nanoparticles.22 These composite nanoparticles
enhanced the targeted combination of hydroxyapatite
and their accumulation at the tumor site. An in vivo
therapeutic study revealed that these composite nano-
particles significantly inhibited bone tumor growth and
tumor-associated osteolysis. In another study, a bone-
targeted nanoplatform was developed using gold nano-
rods, which were enclosed inside mesoporous silica
nanoparticles (Au@MSNs) and then combined with
zoledronic acid (ZOL). Owing to the affinity of ZOL
for bone, Au@MSNs activated by NIR irradiation
can effectively inhibit cancer cell growth and the osteo-
clast activity both in vitro and in vivo.39
Metal oxide nanoparticles also exhibit antitumor
activity. It has been reported that black TiO2 nanoma-
terials have good biocompatibility, excellent NIR
absorbance, high photothermal conversion efficiency,
and desirable photothermal stability.40–42 A study by
Zhang et al. demonstrated that a hydrogenated black
TiO2 (H-TiO2) coating showed remarkable and con-
trollable photothermal performance to suppress
tumor cells by controlling the NIR laser irradiation
power and duration time.14 Most importantly, due to
the hierarchical micro/nano-topographies and Ti-OH
groups, the fabricated H-TiO2 coating displayed excel-
lent cytocompatibility and prompted the adhesion, pro-
liferation and osteogenesis of rat bone mesenchymal
stem cells (BMSCs) in vitro, further regenerating the
lost bone defects. This study offers a novel and efficient
method for the treatment of bone tumors.
Carbon-based nanoparticles as photothermal agents
Carbon-based nanocomposites, such as carbon nano-
tubes, carbon nanospheres and graphene, have been
Table 1. Summary of representative biomaterials for bone tumor treatment.
Type Biomaterial Effect
Photothermal therapy Hydrogenated black TiO2 Controllable photothermal per-
coating with biomimetic formance to suppress tumor
hierarchical micro/ cells, hierarchical surface and
nanostructures Ti-OH groups to promote
proliferation and osteogenesis
of BMSCs
Nano-hydroxyapatite/gra- Photothermal effect on killing
phene oxide/chitosan tumor cells and promoting
scaffolds osteogenesis, a good hemo-
static effect
MoS2-modified akerman- Photothermal effect on inhibiting
ite scaffolds tumor cell viability, ionic
products released from scaf-
folds to facilitate bone growth
Elements (Cu, Fe, Mn, Metal elements in BGC to
Co)-doped bioactive endow BGC with both pho-
glass-ceramic (BGC) tothermal effect and bone
scaffolds regeneration ability
Fe-CaSiO3 composite Synergistic effects of photother-
scaffolds mal and ROS tumor therapies
by Fe ions and the ability to
enhance bone regeneration
3D-printed scaffold co- Synergistic photothermal thera-
loaded with black py and chemotherapy to elim-
phosphorus nano- inate tumors promptly,
sheets, doxorubicin sustanined release of osteo-
hydrochloride and genic peptides to improve new
osteogenic peptides bone formation
Magnetothermal therapy Polymethylmethacrylate Superior bone tumor ablation
(PMMA) bone cements without obvious side effects
containing Fe3O4 and strong mechanical support
nanoparticles for bone repair
PMMA bone cements Useful magnetothermal therapy
containing Fe3O4 nano- for bone tumor
particles with different
dimensions
Chen
Additional comment Animal Model Ref.
Chen and
14
The temperature can be adjusted Nude mice
Yao
and Yao
by the laser power and dura-
tion time
15
30% of nano-hydroxyapatite in Nude mice, Sprague-
graphene oxide performed Dawley rats
better
16
The temperature of scaffolds can Nude mice, New Zealand
be controlled by altering the rabbits
MoS2 content, scaffold sizes
and NIR power density
17
The final temperature of scaf- Nude mice
folds can be modulated by
controlling the doping element
categories, contents and laser
power density
18
The scaffold had a high com- Nude mice, New Zealand
pressive strength to meet the rabbits
demand for cortical bone
defect regeneration
19
On-demand photothermal ther- Nude mice, Sprague-
apy can kill tumor cells quickly Dawley rats
whereas localized chemother-
apy at a low concentration can
eliminate bone tumor cells
gradually
20
PMMA bone cement containting New Zealand rabbits
6% Fe3O4 exhibited the best
performance among the
experimental groups
21
The heating capability of cements
strongly depended on the size
of the Fe3O4 nanoparticles
and the conditions of the
applied magnetic fields
(continued)
9473
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widely studied as NIR-absorbing materials due to their

Ref.
22

23

24
excellent NIR absorbance and attractive NIR-heat
conversion efficiency for the therapy of tumors.43–45
Carbon aerogel (CA), a carbon-based nano-biomateri-
al, was coated on a beta-tricalcium phosphate (b-TCP)

Sprague-Dawley rats
scaffold via a series of reactions, which formed a novel
multifunctional b-TCP bioceramic platform.46 The
Animal Model

results indicated that complete ablation of osteosarco-

Nude mice

ma tumors can be achieved by the efficient hyperther-

mia generated after irradiation with an 808 nm laser.
Moreover, surface coating with CA can improve pro-
tein recruitment capabilities and osteogenesis due to
the increased roughness and higher surface area. All
these data suggested the potential bio-applications of
Genistein, daidzein, and glycitein
thermal performance of plati-

in 5:4:1 ratio was adopted to

gered by the pH, Ca2þ con-

mimic their original propor-

CA for the treatment of osteosarcoma.

The drug release can be trig-
phytic acid and the photo-
Bone-targeting properties of

num nanoparticles were

Lin et al. successfully fabricated multi-walled carbon

centration and thermal

tion in soy isoflavones

nanotubes (MWNTs) and suggested their effectiveness

Additional comment

in photothermal therapy.47 This study revealed that

MWNTs raised the temperature and inhibited tumor
growth in a dose- and irradiation time-dependent
therapy

manner. Therefore, optimizing the NIR irradiation

utilized

time and the dose of photothermal agent can achieve

a complete elimination of cancer cells and enhance the
therapeutic effects. In a subsequent study, a bi-
functional scaffold was developed with MWNTs and
Fe3O4 magnetite nanoparticles integrated into a nano-
osteogenic and anti-inflamma-
tory ability for bone repair

composite scaffold consisting of gelatin/akermanite

High drug encapsulation, low
tumor growth and tumor-
Significant inhibition of bone

Improved chemopreventive,

(Gel/Akr), which exerted hyperthermal treatment to

cytotoxicity and good
associated osteolysis

effectively kill tumor cells and showed great potential

in tissue regeneration.48 Ma et al. developed a multi-
biocompatibility

functional nano-hydroxyapatite/graphene oxide/chito-

san scaffold, which could not only kill tumor cells
through photothermally controlled ablation, but also
promote osteogenesis and achieve a good hemostatic
Effect

effect.15

Photothermal agents by 3 D-printing techniques

A triple-stimuli-responsive

scaffolds co-loaded with

works and supramolec-

genistein, daidzein and

Phytic acid-capped plati-

ular pseudorotaxanes

Many 3 D-printed scaffolds with specially designed

metal–organic frame-

Tricalcium phosphate
num nanoparticles

compositions and structures have been prepared with

system combining

remarkable physicochemical and biological effects.

3 D-printed scaffolds with photothermal performance
Biomaterial

have attracted increasing attention. Recent studies

glycitein

have demonstrated that these scaffolds possess the

simultaneous capabilities of bone tissue regeneration
and bone tumor therapy.
A bifunctional bioceramic scaffold with MoS2 nano-
sheets grown on the strut surface was produced suc-
cessfully by means of 3 D printing and hydrothermal
Drug delivery system
Table 1. Continued

methods.16 The photothermal effects of this scaffold

were significant and controllable by altering the
MoS2 concentrations, scaffold sizes and NIR power
density. The in vivo study results indicated the effects
of this bifunctional scaffold on the inhibition of tumor
Type

cell viability and the facilitation of bone growth.

Chen
Chen and
and Yao
Yao
In addition, bioactive glass (BG) is usually used for
bone tissue engineering owing to its great bone-forming
activity. For the first time, Wu’s group applied semi-
conductor CuFeSe2 nanocrystals to BG using both 3 D
printing and solvothermal strategies.49 The data con-
firmed the great photothermal performance of the scaf-
folds, as evidenced by their precise location at the
tumor sites and the effective ablation of the tumor
cells in vitro and in vivo. The scaffolds also exhibited
the excellent effects on the promotion of osteogenesis
of rabbit BMSCs and new bone formation with the
release of ions, including Ca, Si, P, Fe, Cu, and Se
from the scaffolds. In a subsequent study, this group
further explored the effects of various elements, includ-
ing Cu, Fe Mn and Co, on the photothermal perfor-
mance and osteogenesis ability. They prepared Cu-,
Fe-, Mn- and Co-doped BG ceramics (BGCs) respec-
tively by a 3 D printing technique and reported the
trend of photothermal performance as follows:
5Cu-BGC > 5Fe-BGC > 5Mn-BGC > 5Co-BGC.
Additionally, it was demonstrated that among the pre-
pared scaffolds, the 5Fe-BGC and 5Mn-BGC scaffolds
displayed significant effects on bone regeneration, thus
suggesting their great potential to realize the dual func-
tions of photothermal treatment of bone tumors and
bone regeneration.17
Recently, various studies have focused on further
developing versatile biomaterials via 3 D printing tech-
niques.50 To satisfy the higher requirement of bioma-
terials for cortical bone repair, Wu et al. fabricated
Fe-CaSiO3 composite scaffolds by means of a 3 D
printing technique.18 The photothermal effects of Fe
and reactive oxygen species therapies induced by the
Fenton reaction between Fe ions and H2O2 in tumor
cells synergistically improved the tumor therapeutic
effects. Such composite scaffolds have high compres-
sive strength as well as good degradation performance
in the presence of CaSiO3. Thus, they could meet the
demand for cortical bone defect regeneration. All of
these properties exhibit the promising potential for
the future treatment of bone cancer and cortical bone
regeneration. In another study, considering the impor-
tant role of angiogenesis in nutrient transmission
during the process of bone regeneration, researchers
prepared b-TCP scaffolds with a 3 D printing device
and then modified the strut surface of TCP scaffolds
with copper-coordinated tetrakis (4-carboxyphenyl)
porphyrin (Cu-TCPP) nanosheets via a solvothermal
reaction.51 In addition to the significant photothermal
effects of tumor ablation by the Cu-TCPP nanosheets,
the Cu-TCPP-TCP scaffolds could effectively enhance
bone regeneration. Most importantly, the results from
the in vitro and in vivo experiments indicated that the
scaffolds facilitated the attachment of human umbilical
vein endothelial cells (HUVECs) and induced the
9495
expression of angiogenesis-specific genes in HUVECs,
thus suggesting the angiogenic activity of the prepared
multifunctional scaffolds through the released Cu ions.
This study provided fresh insight into the design of
multifunctional biomaterials in bone tissue engineering.
Another novel scaffold with multiple functional ele-
ments was created based on cryogenic 3 D printing
technique. The contents of water-in-oil polyester emul-
sion inks included b-TCP, 2 D black phosphorus
nanosheets, low-dose doxorubicin hydrochloride and
high-dose osteogenic peptide. Thus, the final prepared
scaffold could not only eliminate tumors promptly and
suppress tumor recurrence in the long-term by the syn-
ergistic photothermal therapy and chemotherapy but
also enhance new bone formation by the sustained
release of osteogenic peptides.19
Magnetite (Fe3O4)-based materials for
bone tumor treatment
Magnetite-based materials are attracting increasing
attention for bone tumors due to their potential effi-
ciency in cancer diagnosis and bone tumor treatment.
An improved magnetic resonance imaging (MRI) agent
was synthesized in large quantities using quasi-cubic
magnetite/silica core-shell nanoparticles, which could
extend the shelf life, improve the stability in biological
fluids and enhance the contrast during cancer imag-
ing.52 In addition, magnetic hyperthermia, produced
by the transformation of electromagnetic energy to
heat under a proper external alternating magnetic
field by magnetite, provides a promising alternative
for bone tumor ablation.53,54 This strategy exhibits
high heat efficiency and averts biological barriers,
which are effective for both superficial and deep
organs/tissues.55,56 A low content of Fe3O4 nanopar-
ticles in b-tricalcium phosphate bioceramic scaffolds,
which were regulated by coating times, promoted the
super hyperthermal effects of the scaffolds, which could
cause the death of most of osteosarcoma cells.57
Another study also found that the accommodation of
both Co2þ and Fe3þ in b-tricalcium phosphate could
not only improve the hyperthermal effects, but also
induce obvious antibacterial efficacy.58
In addition, there is great potential for hydroxyap-
atite modified with Fe3O4 for bone tumor treatment.59
Collagen/hydroxyapatite with 1 or 2% magnetite con-
tent produced insufficient hyperthermia, while compos-
ite scaffolds with a magnetite content of 5% could act
as regenerative scaffolds with hypothermic anti-
tumoral effects.60 Additionally, Li et al. successfully
produced hydroxyapatite composite poly(lactic-co-
glycolic acid) scaffolds with osteogenic effects. They
further verified that these composite scaffolds modified
6950 Journal
with magnetic nanoparticles had good magnetic and
thermal properties in vivo to inhibit tumor growth
and enhance bone formation after resection.61
Furthermore, a rabbit bone tumor model demon-
strated that polymethylmethacrylate bone cement con-
taining 6% Fe3O4 exhibited the best performance
among the materials tested, as evidenced by superior
bone tumor ablation after treatment with magnetic
heat without obvious side effects, while maintaining
strong mechanical support for bone repair.20 Another
study reported that the size of the Fe3O4 nanoparticles
in polymethylmethacrylate bone cement played an
important role in heating capability.21 The data
showed that cement containing Fe3O4 with a mean
diameter of approximately 35 nm exhibited the highest
heating capability in alternating current magnetic fields
of 120 and 300 Oe at 100 kHz while cement with a mean
diameter of approximately 11 nm exhibited the opti-
mum heating capability in AC magnetic fields of
40 Oe at 600 kHz. Additionally, a series of borosilicate
BG scaffolds loaded with varying amounts (5–15 wt%)
of Fe3O4 nanoparticles were investigated in vitro. The
in vitro results indicated that the greater the amounts
of Fe3O4 nanoparticles in the scaffolds, the better
observed osteogenesis. An in vivo study demonstrated
that scaffolds with 15% Fe3O4 nanoparticles strongly
promoted bone regeneration compared with pure
scaffolds.62
Drug delivery system for bone tumors
With a further understanding of material science,
researchers have devoted to developing and designing
biomaterials for the delivery of antineoplastic drugs
aside from applying them as scaffolds in tissue engi-
neering. Here, we mainly discuss their applications in
drug delivery from the following aspects.
Increasing the efficacy of a drug delivery system
Alendronate has been proven to be an effective anti-
cancer drug and is often used to treat bone-related
diseases, especially osteosarcoma.63 However, due to
its low bioavailability, high doses of alendronate are
needed, which results in increased toxicity and side
effects. Recently, Ravanbakhsh et al. proposed altering
the negative surface charge of mesoporous bioactive
glass (MBG) from negative to positive by introducing
an amine group to MBG (AMBG) so that the positive
surface charge can enhance the drug attachment and
improve drug loading efficiency.64 The results validated
the speculation. Moreover, the data demonstrated that
local release of alendronate from AMBG, even at low
concentrations, could potently suppress tumor cell
growth.
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Another group took advantage of the properties of
cyclodextrins polymers to functionalize the surface of
hydroxyapatite.65 The cell vitality assay supported the
excellent cytocompatibility of this prepared biomateri-
al, while the drug release test indicated an improved
drug loading capacity and extended release duration.
This drug delivery system can control local drug
administration and avoid systemic toxicity. Similarly,
adriamycin (ADM), an antineoplastic drug, was
encapsulated in poly(lactic-co-glycolic acid) (PLGA)
nanoparticles followed by loading onto a nanohydrox-
yapatite/collagen (NHAC) scaffold.66 The formed
ADM-PLGA-NHAC scaffold exhibited excellent bio-
compatibility and a long release profile. The in vivo
data demonstrated that the scaffold had a higher anti-
tumor efficacy with fewer adverse effects than direct
administration of ADM.
Targeting bone-localized tumors with a drug delivery
system
In recent decades, nanoparticles have been regarded as
promising carriers to deliver drugs, based on the
enhanced permeability and retention effect (EPR
effect).67 Thereinto, hydroxyapatite nanoparticles
exhibited a high affinity for bone tissue due to the pres-
ence of the phosphate and hydroxyl groups of hydroxy-
apatite, thus, these nanoparticles have been applied for
delivering drugs to bone-localized tumors.68,69
In addition, many studies have reported that bone-
targeting agents, such as bisphosphonates and phytic
acid, have been used in anticancer drug delivery
vehicles to improve their specific binding to bone
tumor cells. Alendronate has been widely used as a
bone-targeting ligand since it can chelate calcium
ions in bone tissue. Studies in which polymeric
nanoparticles fabricated by various means70–73 were
functionalized with alendronate demonstrated their
bone-homing ability with decreased toxic off-target
effects. The strong binding affinity between alendro-
nate and the bone tumor led to a longer retention
time of the nanoparticles at target site and thus
enhanced the therapeutic effect.70,71
Another study reported that the modification of
platinum nanoparticles with phytic acid, which had
both bone-targeting capability and anticancer activity,
not only exhibited a high affinity towards hydroxyap-
atite in vitro and in vivo but also maintained the inher-
ent anticancer ability of phytic acid and the
photothermal effect of platinum nanoparticles.22 The
modification of DPCN with an ASP had a much
higher affinity for bone fragments in vitro and
showed improved efficiency to accumulate around
bone tumors in vivo compared to the DPCNs without
modification. Thus, the delivery of nu using
Chen
Chen and
and Yao
Yao 9517

ug nt
Dr me
ch
ta
at
Main constituents
Imitative
of bone such as
hierarchical
hydroxyapatite,
structures of
collagen & calcium
native bone by
means of 3D-
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l
em na
st tio
technology

s y unc
tif
ul
M
Surgical Stimuli
Implantation Repairing
resection action

Combined
therapies (e.g.
photothermal/
magnetothermal
therapy)
Ultrasound
pH
Enzyme

Temperature Light Drug

release
Lonic Magnetic
strength field
Redox
potential

Bone tumor Residual tumor cell Biomimetic Bone-targeted Multifunctional Various stimuli
bone scaffold nanoparticle system
Bone defect Antineoplastic drug

Figure 1. Schematic diagram for bone tumor treatment by multifunctional system.

ASP-DPCN enhanced the photothermal therapy
effects with higher temperature in bone tumors.38
Releasing drugs in a controlled manner with
stimuli-responsive systems
To improve the efficacy of drug release and lower the
undesirable side effects in healthy tissues, many stimuli-
responsive systems have been designed. Such systems
generally take advantage of internal stimuli, such as the
more acidic pH at the tumoral matrix and the over-
expression of redox potential in tumor cells, and exter-
nal stimuli, such as the generation of heat and the use
of light and ultrasounds.74,75
Recently, an inorganic-organic system hybridizing
calcium phosphate and phosphorylated adenosine was
fabricated and had a high doxorubicin loading capacity
due to its porous and hollow structure.75 This hybrid
system also exhibited a pH-responsive drug release pro-
file in which more doxorubicin accumulated at pH 4.5
and 6.0 than at the physiological pH of 7.4. It also had
significant therapeutic effects on six osteosarcoma cell
lines in vitro and on osteosarcoma subcutaneous
tumors in a mouse model. Similarly, another smart
drug release system was prepared via modification of
chitosan, a pH-sensitive polymer, onto the surface of
polyetheretherketone to realize the controlled release
of doxorubicin according to the pH change.76
Mesoporous bio-glass nanoparticles loaded with
Imatinib were synthesized using a facile sol-gel
method and reached maximum cumulative drug release
at pH 4.4.77 All these studies substantiated that pH-
responsive drug delivery systems can facilitate smart
drug release in acidic tumoral microenvironments
while alleviating the adverse effects on normal tissues.
Recent studies have developed multi-stimuli-
responsive drug delivery systems to obtain more pre-
cisely controlled drug release. Xue et al.78 fabricated
BG nanoparticles with mussel-inspired surfaces,
which can control the release of doxorubicin via both
pH and NIR stimuli. A triple-stimuli-responsive system
combining metal–organic frameworks and supramolec-
ular pseudorotaxanes was further established by
Yang’s group.23 The results indicated that this system
not only possessed high drug encapsulation and excel-
lent biocompatibility but also triggered drug release by
the pH and Ca2þ concentration since in bone tumor
tissues, the pH is more acidic and the Ca2þ
8952 Journal
concentration is increased due to osteolysis.
Furthermore, this system can control drug release via
thermal therapy. This multifunctional biomaterial
opens up a prospective for the future of bone tumor
therapy.
Delivering multiple drugs with a drug delivery system
An increasing number of studies have reported the
approach to design biomaterials for the delivery of
two or more drugs to the bone tumor site, which has
been shown to be more advantageous than mono-drug
delivery.79 Multi-drug delivery systems can improve
therapeutic efficacy, alleviate drug resistance and lead
to synergistic effects.80
Hess et al. developed a hydroxyapatite matrix scaf-
fold with calcium phosphate beads as drug carriers via
freeze gelation.81 The scaffold was successful in co-
delivering cis-diamminedichloroplatinum (CDDP) and
doxorubicin hydrochloride (DOX) in the long-term.
The results demonstrated that synergistic effects from
the co-delivery of CDDP and DOX by this scaffold
were achieved, evidenced by the enhanced toxicity
towards MG-63 osteosarcoma cells compared to the
single-loaded composites.
The most recent work constructed 3 D-printed tri-
calcium phosphate scaffolds with multimodal porosity
and co-loaded genistein, which can inhibit cancer
growth without harming healthy cells; daidzein,
which is believed to facilitate bone mineral density;
and glycitein.24 The obtained data verified that the
scaffolds not only promoted the proliferation of osteo-
blasts and suppressed the viability of MG-63 osteosar-
coma cells in vitro but also exhibited anti-inflammatory
effects in vivo.
Conclusions
With the development of biomaterials in recent years,
their applications in bone tumor diagnosis and treat-
ment, apart from bone defect repair, exhibit great
potential. The use of the photothermal or magnetother-
mal properties of biomaterials can induce excellent
elimination of tumor cells without obvious side effects
or damage to healthy cells. Additionally, more efficient
drug delivery systems for antineoplastic drugs have
been designed and fabricated based on biomaterials.
This review summarizes the recent progress of versatile
biomaterials for bone tumor therapy based on the
abovementioned aspects. Current research can pave a
new path towards the effective translation of these bio-
materials into the clinic.
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Perspectives
In recent decades, researchers have attempted to create
biomaterials that possess the capacity to simultaneous-
ly regenerate the large bone defects induced by surgical
resection and eliminate the residual tumor cells. Studies
on these bifunctional biomaterials, such as hybrid
hydrogel with good photothermal and bone-forming
properties,82 have achieved encouraging outcomes.
On the one hand, an ideal scaffold for bone defect res-
toration should mimic normal bone tissue in terms of
the hierarchical structure, chemical composition and
biomechanical properties. Additionally, an increasing
number of biomaterials for bone regeneration have
been designed with enough mechanical support and
desirable osteogenic, osteoinductive and osteoconduc-
tive properties. On the other hand, researchers believe
that the combination of various therapies, such as pho-
tothermal therapy, chemotherapy, and magnetic thera-
py, in biomaterials will enhance the efficiency of bone
tumor treatment. Studies have suggested that although
photothermal therapy could effectively kill bone tumor
cells via a high photothermal temperature, damage to
normal bone tissue and other side effects, such as
inflammation, could also emerge. However, combina-
tional chemotherapy and photothermal therapy could
ablate bone tumor cells at a moderate temperature
under the decreased dosages of photothermal and
chemical agents, which could reduce adverse
effects.83–85 A new approach combining bio-imaging
and efficient tumor eradication exhibits promising
potential for the early diagnosis and synergistic treat-
ment of osteosarcoma.86 In current bone tissue engi-
neering, efforts are also focusing on incorporating
drugs, including antitumor or pro-bone forming
drugs, into scaffolds through biomaterial modification.
Thus, the drugs can be precisely delivered to the target
sites and released in a sustained and controlled way,
which can further enhance the therapeutic outcome and
alleviate the harmful effects on healthy cells.87
With the further understanding and development of
biomaterials, multifunctional biomaterials have been
proposed for bone tumor treatment.88 These innovative
studies will promote the development of more promis-
ing multifunctional biomaterials. 3 D-printing technol-
ogy has emerged as a powerful tool to more precisely
fabricate biomimetic scaffolds that imitate native bone
with hierarchical structures consisting of macro-,
micro-, and nanostructures as well as chemical compo-
sitions, thereby promoting more effective bone forma-
tion, although there are still many issues to be
addressed. Effective targeted drugs need to be further
developed and more efficiently delivered by their spe-
cific binding with biomaterials. Future work should
also optimize the method of combining the various
Chen
Chen and
and Yao
Yao
therapies to obtain synergistic effects for better bone
tumor treatment and realize more accurate control of
antineoplastic drug release by stimuli-responsive sys-
tems (Figure 1). Of course, convincing tests using
large animal models should be carried out to verify
the multiple functions of biomaterials in one animal
model. We believe that through interdisciplinary coop-
eration from the fields of biomedicine, clinical medicine
and engineering, multifunctional biomaterials will per-
fectly match individual bone defects in the clinic with
lower cost and higher efficiency in the future.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
Funding
The author(s) disclosed receipt of the following financial sup-
port for the research, authorship, and/or publication of this
article: This work was supported by Science and Technology
Program of Guangzhou, China (Grant No.: 201804010479).
ORCID iD
Yongchang Yao https://orcid.org/0000-0002-4338-2606
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