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3D Printing Scaffolds

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Journal of
Materials Chemistry B
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REVIEW
Cite this: J. Mater. Chem. B, 2018,
6, 4397
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3D printing of ceramic-based scaffolds for bone
tissue engineering: an overview
Xiaoyu Du,a Shengyang Fua and Yufang Zhu
*ab
Currently, one of the most promising strategies in bone tissue engineering focuses on the development
Received 12th March 2018,
Accepted 16th June 2018
DOI: 10.1039/c8tb00677f
of biomimetic scaffolds. Ceramic-based scaffolds with favorable osteogenic ability and mechanical
properties are promising candidates for bone repair. Three-dimensional (3D) printing is an additive
manufacturing technique, which allows the fabrication of patient-specific scaffolds with high structural
complexity and design flexibility, and gains growing attention. This review aims to highlight advances in
3D printing of ceramic-based scaffolds for bone tissue engineering. Technical limitations and practical
rsc.li/materials-b
challenges are emphasized and design considerations are also discussed.
1. Introduction
Bone tissue engineering has emerged as an innovative and
promising strategy for treating bone defects, in which a threedimensional (3D) porous scaffold can be loaded with tissueinducing factors or specific cells to launch tissue regeneration
in a natural way.1,2 A variety of materials, consisting of either
biometallic materials, bioceramics, biopolymers or biocomposites, have been proposed and used to fabricate scaffolds for bone
tissue engineering over the last few decades, while developing
functions similar to natural bone remains a challenging task.3
Architecture, mechanical properties and osteogenic ability are
considered as the most critical characteristics for an ideal
a
School of Materials Science and Engineering, University of Shanghai for Science
and Technology, 516 Jungong Road, Shanghai 200093, China.
E-mail: [email protected]
b
Shanghai Innovation Institute for Materials, Shanghai 200444, China
scaffold.4 Many ceramic materials have high stiffness and bioactivity (i.e., their similarity to the mineral phase of natural
bone),5,6 which can act as a temporary framework for providing
a suitable environment for cell adhesion, growth, and more
explicitly help bone tissue regeneration.
On the other hand, there is significant interest in the development of fabrication methods for enhancing the function of
scaffolds. Traditional or regular methods used to fabricate 3D
porous scaffolds, such as particle leaching, foaming, or freezedrying, have limitations to precisely control the overall architectures and internal pore connectivity.7,8 Advanced additive
manufacturing techniques, such as 3D printing, can control the
architecture and pore structures precisely and produce customdesigned, computer-controlled tissue scaffolds, overcoming
many limitations of current fabrication methods.9
The most commonly used 3D printing techniques for biomedical applications can be classified into six main groups:
fused deposition modeling (FDM), stereolithography (SLA),
Xiaoyu Du has been studying at the
School of Materials Science and
Engineering, University of Shanghai
for Science and Technology, for her
master’s degree since 2015. Her
research field is 3D printing porous
functional scaffolds for bone tissue
engineering. So far, M. S. Du has
published 6 papers as the first
author or coauthor.
Xiaoyu Du
This journal is © The Royal Society of Chemistry 2018
Shengyang Fu has been studying at
the School of Materials Science and
Engineering, University of Shanghai
for Science and Technology, for
his master’s degree since 2016.
His research field includes the
preparation of polymer-derived
silicon-based ceramics, as well as
the synthesis and characterization
of novel biomaterials by 3D
printing.
Shengyang Fu
J. Mater. Chem. B, 2018, 6, 4397--4412 | 4397
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Table 1
Journal of Materials Chemistry B
Characteristics of various 3D printing techniques for biomedical application
Type
Abbreviation Appliance materials
Accuracy
Cost Advantages
Disadvantages
Fused deposition
modeling
FDM
++ (200–500 mm)
+
High mechanical properties, solvent not required
Need to be formed into a
filament, high temperature
Stereolithography
SLA
+++ (10–30 mm)
++
High resolution, large
molding products
Selective laser
sintering
SLS
Metal, ceramics (a fine
powder form)
Extensive post processing,
inadequate mechanical
property, toxic uncured
resin
Slow, bulky, expensive,
rough surface
Particle binding
Inkjet printing
PB
IP
Ceramics
Droplets
Direct ink writing
DIW
Viscous materials (inorganic/organic composite
paste, hydrogels)
Polymers or polymer/
ceramic composite
materials
Photosensitive polymers
++ (700–1000 mm) +++ Support not required,
process multiple
materials in a single bed
++ (700–1000 mm) ++ High mechanical strength
+ (25–100
+
Multifunctional
picoliters)
++ (200–600 mm) +
Low temperature, cells and
bioactive molecules can be
printed
selective laser sintering (SLS), particle binding (PB), inkjet
printing (IP) and direct ink writing (DIW).10 Briefly, FDM is a
typical heat-using technique for scaffold fabrication. In this
method, a filament of the desired material is fed and melted in
a vessel by heat and extruded from the nozzle, depositing it
layer-by-layer to create a scaffold. The process temperature
depends on the melting temperature of building materials,
which is generally too high for bioactive molecules or cells to
retain their activity.11 SLA employs a single beam laser to
polymerize or crosslink a photosensitive polymer to get thin
layers of the polymer and then stacks the struts layer-bylayer.12,13 SLS is another technique commonly used in scaffold
fabrication; it uses a high-power laser for metal or ceramic
powder sintering to form a scaffold.14 The powders are
irradiated with lasers during the printing process, and they
can be fused into large parts, and the scaffold is made layer-bylayer. Instead of melting particles together using a laser, the PB
printing method uses a liquid binding solution to fuse particles
together within each layer, followed by a high-temperature
Yufang Zhu obtained his PhD
degree on materials physics and
chemistry from Shanghai Institute
of Ceramics, Chinese Academy of
Sciences. He was an Alexander
von Humboldt research fellow
at Technical University Dresden
(Germany) and a postdoctoral
fellow at the National Institute for
Materials Science (Japan) from 2006
to 2011. He then joined the School
of Materials Science and Engineering, University of Shanghai for
Yufang Zhu
Science and Technology, where he
is a full professor. His research interests include 3D printing of
bioceramics for bone tissue engineering and functional mesoporous
nanoparticles for potential cancer therapy.
4398 | J. Mater. Chem. B, 2018, 6, 4397--4412
Need further sintering step
Low mechanical property
Solvent required, easy to
sag or collapse during
printing
sintering step to solidify the final 3D products.15 IP enables
the deposition of very small volumes of individual droplets
from a nozzle onto a printing surface with a goal of forming
structures by post-printing solidification.16 DIW belongs to the
extrusion-based 3D printing methods. Viscous materials
(referred to as a ‘‘paste’’ or an ‘‘ink’’) are extruded through
the nozzles by a compressed gas to form individual lines that
solidify onto a build plate in a layer-by-layer fashion.17 This easy
and fast fabrication method is considered very promising for
biomedical applications, especially for 3D printing ceramicbased bone tissue engineering scaffolds.18–20 The main characteristics of these 3D printing techniques are summarized in
Table 1.
3D-printed bioceramics have broad application prospects in
bone tissue engineering. This review summarizes the most
popular bioceramic materials, as well as 3D printing fabrication
methods and potential clinical application of ceramic-based
scaffolds. Through understanding the advantages and limitations of different 3D-printed ceramic-based scaffolds, new favorable bone implants could be developed, which will eventually
compete with natural bone.
2. Ceramic scaffolds
Bioceramics refer to a class of ceramic materials with specific
biological or physiological function, and can be used directly
in the human body or in applications related to the human
body.21 Bioceramics applied in bone tissue engineering are
used for the diagnosis and treatment of biological system diseases
and promote or restore the function of bone tissues.22 According to
their bioactivity, bioceramics could be divided into bioinert and
bioactive ceramics.23 The fundamental difference between both
types of bioceramics is whether the bioinert implant is chemically
bonded to the living tissue after implantation.24 The characteristics
of bioinert ceramics are high mechanical strength, outstanding
biocompatibility and chemical stability, while bioactive ceramics
are biodegradable and osteoconductive. Actually, both materials
and scaffolds are two integral parts of bone tissue engineering.
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Table 2
Review
A summary of materials and properties used for 3D printing of ceramic scaffolds
Type
Raw materials
Precursors
Properties
Ref.
Bioinert
ceramic
scaffold
Alumina, alumina/borosilicate
glass, alumina/SiC
Dextrin, urea-formaldehyde, etc.
35–38
Zirconia
Poly(vinyl alcohol), polycaprolactone, etc.
Improved mechanical properties (tensile
strength, flexural strength, compressive
strength); lack of bioactivity
Interconnected architectures; lack of chemical
bonding between tissues
Hydroxyapatite
Poly(acrylic acid), poly(lactic acid),
photo-curable resin, polycaprolactone, etc.
Hydroxypropyl methylcellulose,
polymethacrylate, polyethylenimine, etc.
Silicone polymer, etc.
Bioactive
ceramic
scaffold
Tricalcium phosphate
Calcium silicate
Mesoporous bioactive glasses
13-93 bioactive glass, 6P53B
glass, alkali-free bioactive
glass
Polycaprolactone, poly(lactic
acid), methylcellulose, etc.
Scaffolds are 3D biocompatible structures that can ideally mimic
the properties of a mechanical support, cellular activity and protein
production through biochemical and mechanical interactions.
Also, a 3D scaffold provides a template for cell attachment and
stimulates bone tissue formation in vivo as mentioned above.25,26
To date, much effort has been made to fabricate bioceramic
scaffolds by 3D printing techniques. We will introduce them
according to bioinert and bioactive scaffolds, and thereby highlight
the flexibility of the ceramic scaffolds by 3D printing. Table 2
summarizes the materials and properties used for 3D printing of
ceramic scaffolds.
2.1
Bioinert scaffolds
Bioinert ceramics were evaluated in implant applications due to
their good biocompatibility, corrosion resistance and stability
in the physiological environment in the early 1970s. Alumina
(Al2O3) and zirconia (ZrO2) are two main bioinert ceramics.
Indeed, Al2O3 was the first bioceramic used in clinic widely owing
to its negligible tissue reaction.27 Al2O3-Based bioinert ceramics
have high biocompatibility and chemical inertness, nontoxicity,
high mechanical strength, hardness, and wear resistance. Moreover, Al2O3-based bioinert ceramics could stay for a long time
in vivo and maintain their physical and chemical properties,
which meet the prerequisites for implantation and long-term
service, and thereby make them highly promising as bone
implants.28 ZrO2 has also been commonly used in clinic because
it has the highest toughness among oxide ceramics.29,30 Besides
Al2O3 and ZrO2, other novel bioinert ceramics such as titanium
dioxide (TiO2), silicon carbide (SiC) and carbon materials were
also studied.31–34
Recently, much effort has been made to fabricate Al2O3-based
scaffolds by 3D printing. For instance, Liu et al.35 fabricated
Al2O3 scaffolds with a through-hole structure using 3D printing
and sol–gel technology. The results showed that the biocompatibility of scaffolds is high and favorable, but the mechanical
properties still cannot satisfy the demand. Thus, many researchers
proposed to incorporate other components into Al2O3 to enhance
their mechanical strength. Zhang et al.36 used Al2O3/dextrin
This journal is © The Royal Society of Chemistry 2018
39–42
Superior biocompatibility; capable of cell
adhesion, proliferation and differentiation
50–56
Biocompatibility and degradation ability in
physiological environment; low compressive
strength
Biaxial flexural strength; good cell viability, no
cytotoxicity effect on the cells
Good bioactivity in vitro and in vivo for bone
tissue regeneration
57–64
65–70
72–77
powders as precursor materials for 3D printing, and the
3D-printed scaffolds were sintered at 1600 1C for 2 h to
get alumina/glass composite scaffolds with enhanced mechanical
strength. In addition, the mechanical properties could be improved
by pressureless infiltration with lanthanum-aluminosilicate glass.
Similarly, Cao et al.37 proposed to fabricate Al2O3/borosilicate glass
scaffolds by 3D printing and used urea-formaldehyde (UF) resin as
an in-powder adhesive. Such composite scaffolds exhibited maximal
values for tensile strength, flexural strength, compressive strength,
Young’s modulus, Vickers hardness and fracture toughness
compared to pure Al2O3 scaffolds. Moreover, SiC and Al2O3
scaffolds with flexural strengths of 300 MPa and 230 MPa were
successfully fabricated by direct ink writing.38 Notably, there
are not many studies on 3D printing of Al2O3-based scaffolds
for bone tissue engineering due to the difficulty in shaping the
powder and the biological defects of Al2O3 ceramics.
Similarly, fabrication of bioinert ZrO2 scaffolds has also
been attempted by 3D printing. Zhao et al.39 reported the
fabrication of ZrO2 scaffolds by 3D printing followed by a
sintering process. They mixed ZrO2 powders with poly(vinyl
alcohol) to form a precursor material for 3D printing green
body, and obtained ZrO2 scaffolds after sintering at 1400 1C.
Interestingly, an increase of density and bending strength was
observed with the increase of ZrO2 powder content in the
precursor material. Faes et al.40 prepared ZrO2 ceramic beams
by SLA after UV cross-linking and sintering. ZrO2 ceramic parts
were also successfully printed by a new 3D gel-printing process
with a complex structure.41 Furthermore, Li et al.42 printed
ZrO2 scaffolds using a water-based ink and investigated their
biological properties in vitro. A water-based 70 wt% ink was
prepared for 3D printing green scaffolds, and the 3D-printed
green scaffolds were sintered at 1250 1C for 4 hours. The
fabricated ZrO2 scaffolds had uniform grain and pore size,
and the compressive strength could be 10 MPa at a porosity
of 55%. Also, the interconnected architecture of porous ZrO2
scaffolds was beneficial for cell attachment and proliferation.
Nevertheless, due to the lack of chemical bonding between tissues
and the need for a second operation after the implantation, the
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applications of bioinert ceramic scaffolds as a potential bone
substitute are limited to some extent.
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2.2
Bioactive scaffolds
A wide range of bioactive ceramics, such as beta-tricalcium
phosphate (b-TCP), hydroxyapatite (HA), bioactive glass (BG)
and calcium silicate (CS), similar in composition to the mineral
phase of bone are of great clinical interest.43 Bioactive ceramic
scaffolds could be implanted into bone defects and selfdegrade in vivo. Importantly, bioactive ceramic scaffolds are
able to react with physiological fluids, resulting in the
formation of strong chemical bonding to bone tissues due to
the formation of bone-like HA layers.44,45 Nowadays, a variety of
studies have reported on the relationships among the chemical
compositions, bioactivity and the fabrication process of scaffolds, their modification and so forth.
HA is a naturally occurring mineral form of calcium phosphate with the formula Ca5(PO4)3(OH), which is the most
popular biomaterial used for bone tissue engineering.46 HA
scaffolds with interconnected and regular structures have been
fabricated by 3D printing followed by a sintering process at
1200–1400 1C.47–49 Normally, a water soluble polymer was used
as a binder for 3D printing. For example, Seitz et al.50 reported
3D printing of HA scaffolds, in which a box was filled with HA
powders. HA scaffolds were printed with a polymer-based
binder solution layer-by-layer, and sintered at 1250 1C in
ambient air. Through changing the printing parameters and
the proportion of the binder, HA scaffolds with controlled
shapes and pore sizes could be easily fabricated. Pires et al.51
fabricated sintered HA scaffolds by 3D printing, and the results
showed that the sintering temperature and powder morphology
were critical factors that influenced the density, porosity and
mechanical strength of HA scaffolds. With the increase of
sintering temperature, the density, compressive strength and
tangent modulus of the scaffolds increased slightly, while the
porosity decreased as expected. Furthermore, HA scaffolds
showed superior biocompatibility compared with b-TCP
scaffolds and BioOsss scaffolds.52
However, the poor mechanical strength of porous HA scaffolds usually limits their application in bone tissue engineering. Microwave sintering can create higher heat conductivity
and a rapid heating rate compared to conventional sintering
methods. Wu et al. proposed to use microwave sintering for the
fabrication of porous HA scaffolds with a lattice-like structure
by 3D printing,53,54 which provided an efficient sintering
method to improve the mechanical strength of bioceramics.
Typically, 3D-printed green scaffolds were heated at 400 1C to
burnout of the organic components, and then rapidly sintered
at 1000–1200 1C holding for 0.5 h. Compared to conventional
sintering, a significant increase in mechanical strength was
achieved (ca. 45.57 MPa at a porosity of scaffolds of 55–60%).
Furthermore, MC3T3-E1 cells were cultured on the fabricated
scaffolds and the in vitro results showed that HA scaffolds were
able to stimulate cell adhesion and proliferation.
Normally, the fabrication of pure bioactive ceramic scaffolds
by 3D printing includes mixing raw ceramic powders with
4400 | J. Mater. Chem. B, 2018, 6, 4397--4412
Journal of Materials Chemistry B
adhesives, 3D printing of green scaffolds, burning out the
organic components and sintering routinely. Recently, a twostep method starting from preceramic polymers was proposed
to fabricate bioceramic scaffolds by 3D printing. For example,
Fiocco et al.55 reported an easy method to fabricate silicabonded apatite scaffolds by negative replica, starting from
poly(lactic acid) (PLA) 3D-printed sacrificial templates. Liquid
preceramic polymers mixed with CaCO3 fillers were used as a
slurry to infiltrate PLA forms and they were treated at 350 1C
and 600 1C to burn out the PLA and form the ceramics,
respectively. The ceramic scaffolds were phosphatized by
immersion in a Na2HPO4 bath to convert calcite into apatite.
The compressive strength of HA scaffolds were 13–16 MPa at a
porosity between 57% and 69%. Lee et al.56 fabricated biomimetic HA ossicles by a two-step 3D printing technology,
which were formed from HA powder and a solidified photocurable resin in a projection-based microstereolithography
system and sintered at 1400 1C, indicating the feasibility of
3D printing artificial bone in future applications.
Besides HA scaffolds, b-TCP scaffolds are another important
bioceramics for bone tissue engineering. Vorndran et al.57
reported for the first time pure b-TCP scaffolds with different
binders by 3D printing, and demonstrated the effect of grain
size on the compressive strength. Much smaller grains will
induce a better sintering behavior, and thereby result in higher
compressive strength. Sa et al.57 prepared an injectable b-TCP
paste with a mixture of b-TCP powders, hydroxypropyl methylcellulose (HPMC), polymethacrylate and polyethylenimine (PEI)
for 3D printing and sintered at 1150 1C. The fabricated b-TCP
scaffolds had biocompatibility and degradation ability in the
physiological environment, but exhibited poor compressive
strength (0.54 MPa) and modulus (32 MPa) at a porosity of
49.5%. Almela et al.58 reported 3D printing of b-TCP scaffolds
that simulated the two distinct cortical and cancellous layers
of the natural bone. The b-TCP scaffolds with a porosity of
61.8 1.4% had high compressive strength (10 MPa) and
Young’s modulus (55.5 MPa) as well as osteoblastic proliferation and differentiation by cell vitality assessment and relatedgene expression analysis.
Generally, the material properties including particle size,
flow ability, roughness and wettability influence the printing
and sintering processes. Butscher et al.59–61 theoretically confirmed the relationships among these factors of materials and
the printing and sintering processes. Miranda et al.62 found
that the compressive strength and modulus of b-TCP scaffolds
were much lower than those of HA scaffolds due to the
formation of micro-cracks in the b-TCP scaffolds during the
sintering process. Fortunately, the mechanical strength of
the 3D-printed b-TCP scaffolds could be enhanced to 10.9 MPa
by microwave sintering, and the scaffolds promote in vivo osteogenesis by SrO and MgO doping.63,64
Calcium silicate is another kind of bioceramic which has
aroused much attention due to its outstanding bioactivity. Calcium
silicates could be divided into binary, ternary and quaternary
systems, and CaO–SiO2, CaO–MgO–SiO2 and SrO–ZnO–CaO–SiO2
are representatives, respectively. Wollastonite (CaO–SiO2) has great
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Journal of Materials Chemistry B
potential for bone repair. Xie et al.65 prepared magnesium-doped
wollastonite porous scaffolds by 3D printing and found that the
magnesium-doping, higher sintering temperature and a two-step
sintering process together improve the strength of wollastonite
scaffolds.65 Interestingly, a facile process for the fabrication of
porous calcium silicate scaffolds by 3D printing has been developed by an approach of polymer-derived ceramics instead of multistep fabrication including powder preparation, 3D printing and
sintering. Preceramic polymers have been considered as powerful
raw materials for the production of bioceramics due to their
advantage in synthesis procedures.66 Elsayed et al.67 developed
wollastonite-diopside scaffolds derived from silicone resin and
inorganic fillers (dolomite and calcium carbonate) by direct ink
writing. Active fillers easily react with the silica derived from the
silicone resin during heat treatments to form wollastonite–
diopside scaffolds.68 Zocca et al.69 fabricated AP40 glassdoped wollastonite scaffolds derived from silicone resin and
calcium carbonate by 3D printing, and the scaffolds possessed
Review
a porosity of 64% with a biaxial flexural strength of about
6 MPa, and showed good cell viability and no cytotoxicity effect
on the cells. Shao et al.70 systematically evaluated the role of
side-wall pore architecture in direct-ink-written bioceramic
scaffolds in their mechanical properties and osteogenic
capacity in rabbit calvarial defects (Fig. 1). They fabricated
dilute Mg-doped calcium silicate scaffolds with different layer
thicknesses and macropore sizes. The results demonstrated
that the side-wall pore architecture in 3D-printed bioceramic
scaffolds is required to optimize for bone repair in calvarial
bone defects, and especially Mg-doped wollastonite is promising
for 3D printing thin-wall porous scaffolds for craniomaxillofacial
bone defect treatment compared to pure calcium silicate.
Bioactive glass (BG) has been one of the most promising
bioceramics with good bioactivity in vitro and in vivo for bone
tissue engineering since the breakthrough invention in 1969 by
Hench et al..22,71 The original BG named 45S5 consists of Na2O
24.5 wt%, CaO 24.5 wt%, P2O5 6.0 wt% and SiO2 45 wt%. Since
Fig. 1 Construction of a calvarial defect model and Mg-doped calcium silicate scaffold implantation, and optical images of specimens at different
implantation times. (A) Schematic diagram of the bone repair area in a rabbit. (B) Schematic diagram of the porous scaffold implanted into the calvarial
defect area. (C and D) The bone defects and implantation of the ceramic scaffolds in rabbit skull defects. (E) The optical images of the specimens and
blank implanted in vivo at 4, 8 and 12 weeks, respectively. Scale bars represent 4 mm. The image is printed with permission from ref. 70. Copyright 2017
IOP Publishing Group.
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Review
then, other bioactive glasses with different proportions of composition or additional components have been developed.45 In
general, BG scaffolds should be fabricated in three steps: the
preparation of BG powders by sol–gel or solid-reaction methods,
3D printing of scaffolds, and sintering for densification. For
example, 13-93 BG scaffolds have been successfully produced by
indirect selective laser sintering (SLS).72,73 The 13-93 BG scaffold
was prepared by a melting process and quenching in water, and
then the 13-93 BG powders were mixed with stearic acid as a
binder, which helped fuse the powders during the SLS process.
Finally, 13-93 BG scaffolds with different structures could be
obtained after printing and sintering. On the other hand, the
printing laser power, printing scanning speed, heating rate and
sintering temperatures had influence on the mechanical
strength, and a maximal compressive strength of 23.6–41 MPa
was achieved for the 13-93 BG scaffolds. Seidenstuecker et al.74
fabricated BG, b-TCP and BG/b-TCP composite scaffolds by 3D
powder printing. BG and b-TCP powders were granulated in a
spray dryer at 220 1C using PVA as a binder. The powder was
mixed with 10–15 wt% dextrin and then produced with an inkjet
3D printer. After that, all green scaffolds were sintered. The
results show that all scaffolds can support MG-63 cells and the
70/30 BG/b-TCP scaffold proved to be superior in terms of
biocompatibility and mechanical strength.
In addition, direct ink writing is another common 3D
printing technology for fabricating BG scaffolds. Fu et al.75,76
fabricated 6P53B BG scaffolds by direct ink writing using a
mixture of BG particles and F127. The compressive strength
reached 136 MPa with a porosity of 60% and 77 MPa was retained
after immersion in SBF for 3 weeks, which met the requirements
of the compressive strength and porosity of human cortical bone
(100–150 MPa) and trabecular bone (50–90%).75,76 An alkali-free
FastOssBG scaffold in a diopside–fluorapatite–tricalcium phosphate system with composition 38.49 SiO2, 36.07 CaO, 19.24 MgO,
5.61 P2O5, and 0.59 CaF2 (in mol%) has also been fabricated by
robocasting, which used hydroxypropyl methylcellulose (HPMC)
as a binder and Aristoflexs TAC as a gelling agent.77 The excellent
processing and sintering ability resulted in compressive strength
values comparable to that of cancellous bone essential for 3D
porous scaffolds intended for bone regeneration and tissue
engineering applications.
3. Ceramic-based composite scaffolds
Much progress has been made in 3D printing of pure ceramics
and polymers in recent years. However, the development
of composite inks quickly emerged as the technology grew,
especially due to the development of direct ink writing printers.
The main goal of using composite inks is to enhance ink
properties such as processability, printability, mechanics
(stiffness) and bioactivity (to enhance cellular function and tissue
integration).78 HA, b-TCP and BG are widely used as inorganic
biomaterials due to their excellent osteoconductivity.79 Organic
biomaterials used for bone tissue engineering applications are
usually biocompatible polymers (such as poly(lactic acid) (PLA),
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polycaprolactone (PCL) and poly(lactic-co-glycolic acid) (PLGA)) or
natural hydrogels (such as collagen, chitosan and alginate).80
Next, the most commonly printed ceramic-based composite scaffolds for bone tissue engineering are summarized (Table 3), which
include ceramic/polymer composite scaffolds, ceramic/hydrogel
composite scaffolds, ceramic/ceramic composite scaffolds and
functional ceramic-based scaffolds.
3.1
Ceramic/polymer composite scaffolds
Biodegradable ceramic/polymer composite scaffolds have
recently attracted much attention as bone tissue mimics. Their
main advantage is that altering the organic/inorganic material
composition or ratio can change the properties of the composite
scaffolds to satisfy the requirements for bone tissue engineering.
PLA, PCL, PLGA and so on are common biocompatible polymers
used for bone tissue engineering applications. Generally, these
polymers can act as binders during the printing process. They
need to be dissolved in a rapidly evaporating organic solvent,
such as dichloromethane, tetrahydrofuran or dimethyl sulfoxide
that can rapidly dissipate upon extrusion. Bioceramic powders
are combined with the polymer solution homogeneously to form
a viscous paste which has sufficiently low viscosity to facilitate
printing at moderate to low pressure and is shear-thinnable to
prevent clogging and facilitate flow.10 Notably, the printed struts
must dry in times of seconds to minutes in order to maintain
shape integrity and the solvent needs to be completely removed.
Beyond these, the mechanical and degradation properties of the
composite scaffolds can be tailored as well.
There have been lots of attempts to combine HA with synthetic
polymers to simulate natural bone. Trachtenberg et al.81 fabricated hydroxyapatite/poly(propylene fumarate) (HA/PPF) composite scaffolds with robust compressive mechanical properties.
This work demonstrated the feasibility of using extrusion-based
printing techniques to control the spatial deposition of HA
nanoparticles on a 3D composite scaffold, and provided insight
into the proper fabrication and characterization of composite
scaffolds containing particle gradients and showed the suitability
of these scaffolds for potential clinical applications. Malayeri
et al.82 combined the merits of synthetic degradable polymer
PLA with osteoconductive HA to print custom-shaped PLA/HA
composite scaffolds. Michna et al.83 produced a highly concentrated HA paste for direct printing of periodic scaffolds
potentially useful for bone tissue engineering. By carefully
tailoring the viscoelastic properties, they fabricated selfsupporting HA scaffolds from HA inks with minimal organic
content (o1 wt%). Notably, binder properties are a key factor
that determine the quality of bone scaffolds fabricated using 3D
powder printing. Wei et al.84 used molecular dynamics simulation and experimental methods to study the cohesive energy
density, mechanical properties, bonding behavior, and surface
morphology of three polymer binders (PVP, PAM and PVA)
employed in the 3D printing of HA scaffolds. It was a reflection
of the mechanical properties of scaffolds being a comprehensive
reflection of the basic materials and their bonding effect. Conclusions from this work can be used to forecast the properties of
three commonly used polymer binders and provide a theoretical
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Table 3
Review
A summary of composite materials used for 3D printing of ceramic-based composite scaffolds and the improved properties
Type
Raw materials
Enhancement of properties
Ref.
Ceramic/polymer
composite scaffolds
Hydroxyapatite/poly(propylene fumarate)
Hydroxyapatite/poly(lactic acid)
Hydroxyapatite/polycaprolactone/poly(lacticco-glycolic acid)
Beta-tricalcium phosphate/polycaprolactone
Beta-tricalcium phosphate/poly(1,8octanediol-co-citrate)
Mesoporous bioactive glasses/
polycaprolactone
Mesoporous bioactive glasses/poly(3hydroxybutyrate-co-3-hydroxyhexanoate)
Improved compressive mechanical properties
Good osteoconductive properties
With hyperelastic property
81
82
85
Promising mechanical properties and good hydrophilic behavior
With high compressive modulus (50–75 MPa) and good drug
delivery performance
Improved mechanical strength, higher molding capability, and
effective in vitro bone forming bioactivity
Fast apatite-forming ability and stimulated bone regeneration
capability
86
87
Bioactive glass/hydroxyapatite/poly(ethylene
glycol) dimethacrylate
Mesoporous bioactive glasses/poly(vinyl
alcohol)
Strontium-containing mesoporous bioactive
glass/poly(vinyl alcohol)
The capacity for both soft and hard tissue engineering
95
Improved compressive strengths
96
Exhibited sustained drug delivery behavior and good apatiteforming ability
Bioactive glass/alginate
Bioactive glass/poly(vinyl alcohol)/alginate/
dexamethasone
Beta-tricalcium phosphate/collagen
Hydroxyapatite/gelatin/chitosan
Increased porosity and decreased shrinkage ratios
Increased bone ingrowth in vivo and better control of degradation
rate.
Improved compressive strengths
Improved bioactivity and roughness and wettability on the scaffolds
surface
Improved strength and biocompatibility
Improved strength and reduced brittleness
97
and
98
101
102
Ceramic/hydrogel
composite scaffolds
Hydroxyapatite/alginate/gelatin
Tricalcium phosphate/alginate/phosphoric
acid
Ceramic/ceramic
composite scaffolds
Hydroxyapatite/beta-tricalcium phosphate
Beta-tricalcium phosphate/silica/zinc oxide
Bioactive glass/akermanite
Beta-tricalcium phosphate/bioactive glass
Magnesium-doped wollastonite/betatricalcium phosphate
Mesoporous bioactive glass/calcium sulfate
Tricalcium silicate/mesoporous bioactive
glass
Pearl/calcium sulfate
Functional ceramicbased scaffolds
Beta-tricalcium phosphate/polycaprolactone
(coating)
Nagel and Ca–P/polydopamine nanolayer
(coating)
Beta-tricalcium phosphate/mesoporous
bioactive glass (coating)
Hydroxyapatite/chitosan/collagen with
rhBMP-2-delivery microspheres (coating)
Mesoporous bioactive glasses/mesoporous
silica nanoparticles
Tricalcium silicate
Magnetic Fe3O4 containing mesoporous
bioactive glass/polycaprolactone
b-TCP/Fe3O4 nanoparticles/graphene oxide
Akermanite/alginic acid sodium/Pluronic
F127/molybdenum disulfide
Bioactive glass/CuFeSe2 nanocrystals
Bioactive glass/black phosphorus
nanosheets
Enhanced cell proliferation compared to scaffolds with HA or TCP
alone
Enhanced osteogenesis and angiogenesis in vivo
Regulate the migration and adhesion of the endothelial cells
Bioresorption properties
Ultrahigh mechanical strength
91
103
104
105
106
107
108
109
110
111
Enhance new bone formation in calvarial defects compared to pure 126
calcium sulfate scaffolds
Stimulate the attachment, proliferation and differentiation of
127
hBMSCs with increasing MBG component
Improved bone-implant contact index
128
Effectiveness for controlled alendronate release and increased early
bone formation
A remarkable capability for both cancer therapy and bone
regeneration
Improved osteogenesis significantly compared with the pure TCP
scaffold
Simultaneously achieved localized long-term controlled release of
rhBMP-2 and bone regeneration
Combined the merits of osseous regeneration and local multi-drug
therapy
Loaded with two model drugs and had controllable nanotopography
on the surface to improve bone regeneration in vivo
Endow excellent magnetic heating ability and significantly stimulated proliferation
Super paramagnetic behavior and hyperthermia effects
Photothermal therapeutic potential and bone growth promoting
effect
Excellent photothermal performance and significantly inhibited
bone tumor growth in vivo
Ability of both photothermal ablation of osteosarcoma and the
subsequent material-guided bone regeneration
basis for the choice of polymer binders in the production of
DIW-fabricated scaffolds.
Many ceramic-based scaffolds exhibit enhanced compressive strength, while lacking elasticity. Adam et al.85 3D-printed a
This journal is © The Royal Society of Chemistry 2018
89
129
130
131
132
133
134
135
136
137
138
139
new synthetic osteoregenerative biomaterial, hyperelastic ‘‘bone’’
(HB), which is composed of 90 wt% HA and 10 wt% PCL or PLGA.
The resulting 3D-printed HB exhibited excellent elastic mechanical properties (B32 to 67% strain to failure, B4 to 11 MPa elastic
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Fig. 2 HB mechanical properties. (A) Photograph series showing the compression and recovery of a 1 cm-diameter 3D-printed HAPLGA cylinder over a
single compression cycle. (B) Digital representation of average adult human femur and corresponding femoral midshaft section longitudinal and axial
views. Axial (C) and longitudinal (D) views of 3D-printed HB femoral midshaft constructed using the digital file shown in (B). (E) Longitudinal compressive
loading profile of HB femoral midshaft (D) and corresponding photographs at the indicated percent strain points. Plastic deformation of HB femoral
midshaft begins at 2 (10.3% strain) and proceeds to buckle and barrel (3 and 4). Cyclic compression loading profile (10 cycles) of HB femoral midshaft
loaded in the axial direction (C) in strain domain (F) and time domain (G). (H) Photograph series of a single axial compression cycle displayed in (F) and (G)
and the corresponding percent strain. The image is printed with permission from ref. 85. Copyright 2016 Science Translation Medicine Publishing Group.
modulus) (Fig. 2). Beyond these, HB became vascularized, quickly
integrated with surrounding tissues, and underwent rapid
ossification and supported new bone growth without the need
for added biological factors when implanted in vivo.
Similarly to HA, tricalcium phosphates have been studied
with polymeric additives aiming to improve the binding properties of the final scaffolds. Davila et al.86 fabricated PCL/b-TCP
scaffolds by 3D mini-screw extrusion printing, a novel additive
manufacturing process, which makes use of an extrusion head
coupled to a 3D printer based on [email protected] equipment. They
found that the scaffolds with a porosity of 55% and a pore size
of 450 mm showed promising mechanical properties and good
hydrophilic behavior. Gao et al.87 fabricated beta-tricalcium
4404 | J. Mater. Chem. B, 2018, 6, 4397--4412
phosphate/poly(1,8-octanediol-co-citrate) (b-TCP/POC) composite scaffolds by a 3D printing technique based on a free-form
fabrication system with micro-droplet jetting, and the 3Dprinted b-TCP/POC scaffolds had a high compressive modulus
(50–75 MPa) and good drug delivery performance, which might
be a promising candidate for bone defect repair.
Bioactive glass (BG), being suggested of potential use in
bone tissue engineering recently, has good apatite formation
ability. Moreover, compared to conventional nonporous BG,
mesoporous bioactive glass (MBG) has significantly increased
surface area and the unique pore structure allows it to load
drugs or osteogenic agents for enhancing the bioactivity.88
Constructing suitable MBG-based composite scaffolds through
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a 3D printing approach for bone tissue engineering is promising. Yun et al.89 mixed PCL with different amounts of MBG
powders and developed viscous pastes for 3D printing. The
fabricated MBG/PCL composite scaffolds possessed improved
mechanical strength, higher molding capability, and effective
in vitro bone forming bioactivity.
Beyond these commonly used polymer binders, poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx) as a member
of the poly(hydroxyalkanoates) (PHA) family has been developed for
drug delivery matrices, injectable implant systems, biodegradable
sutures, and artificial nerve conduits due to its proven biodegradability, biocompatibility and better elastomeric properties.90 Zhao
et al.91 chose PHBHHx as the organic component for 3D printing
MBG/PHBHHx composite scaffolds. Compared to the reported
polymer-bonded MBG scaffolds (i.e. MBG/PVA as a control), the
incorporation of the biocompatible PHBHHx polymer as a
binder enhanced their bioactive and osteogenic properties,
including fast apatite-forming ability and the promoted human
bone marrow-derived mesenchymal stem cell (hBMSC) adhesion,
proliferation and differentiation. Also, MBG/PHBHHx scaffolds
were demonstrated to stimulate bone regeneration in calvarial
defects after 8 weeks of implantation and found to have largely
repaired them from the analysis of micro-CT, sequential fluorescence labeling and histology.
3.2
Ceramic/hydrogel composite scaffolds
Hydrogels are three-dimensional polymer networks with the
ability to hold a large quantity of water.10 Hydrogels can provide
excellent ‘‘soft material’’ systems to mimic native extracellular
matrix (ECM) microenvironments due to their tunable degradation, mechanics and functionality.92 Extrusion-based 3D
printing systems are the most suitable methods to print
ceramic/hydrogel composite scaffolds. The classical approach
to design ceramic/hydrogel composite scaffolds is to formulate
a hydrogel solution firstly and incorporate ceramic powders
into the hydrogel matrix that forms a network immediately
after printing. The network could be physically or chemically
cross-linked in response to an external stimulus (i.e. light,
temperature, or ion concentration).93
There are a limited number of suitable hydrogels that can
act as a binder, and tuning their properties remains a challenge.
In general, common hydrogels for 3D printing are made from
natural polymers such as alginate, gelatin, agar, cellulose,
collagen, silk fibroin, hyaluronic acid, or from synthetic polymers
such as poly(vinyl alcohol) (PVA), polyacrylamide, poly(ethylene
glycol) (PEG), or a synthetic–natural mixture. Their gelation
method and physicochemical properties can be tuned through
chemical, physical and enzymatic mechanisms or modulated by
thermal/pH sensitivity.94 Gao et al.95 proposed to evaluate bioactive ceramic nanoparticles on stimulating osteogenesis of bone
marrow-derived human mesenchymal stem cells (hMSCs) in
printed poly(ethylene glycol) dimethacrylate (PEGDMA) scaffolds.
hMSCs suspended in PEGDMA were co-printed with BG or HA
nanoparticles under simultaneous polymerization to obtain
PEGDMA/HA scaffolds and PEGDMA/BG scaffolds. Biochemical
analysis showed the highest collagen production and alkaline
This journal is © The Royal Society of Chemistry 2018
Review
phosphatase activity as well as gene expression in the PEGDMA/
HA group. Importantly, this technology demonstrated the
capacity for both soft and hard tissue engineering with biomimetic structures. Wu et al.96 used PVA as a binder for MBG
particles to prepare injectable pastes, and the 3D-printed
scaffolds exhibited largely improved compressive strengths
(about 200 times that of polyurethane template ones). Zhang
et al.97,98 fabricated strontium-containing mesoporous bioactive
glass scaffolds by 3D printing. Sr–MBG powders were prepared by
sol–gel methods and then printed after being added to an
aqueous 10% PVA solution. Sr–MBG scaffolds exhibited a slower
ion dissolution rate and more significant potential to stabilize the
pH environment with increasing Sr substitution. Furthermore,
Sr–MBG scaffolds exhibited good apatite-forming ability and
stimulated proliferation and differentiation of osteoblast cells.
Interestingly, MBG scaffolds exhibited sustained drug delivery
behavior due to their mesoporous structure.
Alginate is biocompatible and biodegradable, which is the
most commonly used material in tissue engineering, cell and
growth factor delivery.99 Furthermore, the sol–gel transition of
alginate induced by multivalent cations, such as Ca2+, under
mild conditions has been successfully developed as a novel
stabilization method for 3D printing, which would be convenient
for encapsulating bioactive proteins or cells in the 3D-printed
scaffolds.100 Guilin Luo and co-workers101 successfully prepared
bioactive glass/sodium alginate (BG/SA) composite scaffolds with
mass ratios of 0 : 4, 1 : 4, 2 : 4, and 4 : 4. As the BG/SA mass ratio
increased, the pore size and porosity also increased, but the
shrinkage ratios decreased. Furthermore, the 3D-printed scaffolds exhibited in vitro apatite mineralization, the release
of bioactive ions (Ca2+ and SiO42 ) and a weakly alkaline pH
environment, and further promoted the attachment, proliferation and osteogenic differentiation of rat mesenchymal stem
cells (rBMSCs) on scaffolds. Luo et al.102 prepared a mixed
solution of water-soluble PVA and alginate combined with BG
nanoparticles and dexamethasone. After printing, the scaffolds
were solidified by chemically cross-linking the alginate hydrogel
with a calcium chloride solution. The flexibility of this formulation
allowed for tailoring of the mechanical properties by changing the
BG ratios within the ink. The hollow struts combined with BG
nanoparticles led to increased bone ingrowth in vivo and better
control of the degradation rate. Other natural hydrogels such as
gelatin, collagen and silk fibroin are also investigated widely. Bian
et al.103 fabricated and characterized b-TCP/collagen scaffolds with
a bio-inspired design by ceramic stereolithography and gel casting.
Lee et al.104 designed hydroxyapatite/gelatin/chitosan composite
scaffolds by 3D printing. The scaffolds were treated with oxygen
plasma to improve the bioactivity, roughness and wettability
on the scaffold surface, and thereby promote cell responses
to the scaffolds.
Although hydrogels are used to fabricate scaffolds, their
mechanical properties may be insufficient. To improve the
strength of hydrogel scaffolds, Wust et al.105 developed a
special hydrogel, which combined alginate and gelatin through
a two-step gelation process. Furthermore, HA was added to the
hydrogel at various ratios for 3D printing scaffolds with tunable
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mechanical strength. Alternatively, a powder binding method
employing the mixtures of b-TCP and alginate powders combined with phosphoric acid as the binding solvent has been
used to 3D print scaffolds with improved strength and reduced
brittleness.106 Scaffolds containing b-TCP and 2.5% alginate
showed increased mechanical strength as well as improved
MG63 osteoblastic cell compatibility and proliferation compared to pure b-TCP controls.
The use of natural polymers reduced the chances of side
effects associated with some synthetic polymers such as harmful
biodegraded products and thereby decreased cell responses.
However, it is worth noting that the fast swelling of hydrogels
in the presence of water is likely to result in a loose structure,
diminished stability and even breaking off for the whole scaffold
when implanted in vivo.
3.3
Ceramic/ceramic composite scaffolds
Bioceramics, like HA, BG and b-TCP, are not mutually exclusive
and can be printed jointly simply by mixing the powder forms
together within the printing bed or ink. For example, Detsch
et al.107 prepared pure HA and b-TCP as well as a biphasic
scaffolds by 3D printing and measured cell proliferation and
cell viability. These biphasic ceramic scaffolds have been found
to have similar cell viability and enhanced cell proliferation
compared to scaffolds with HA or b-TCP alone.
Moreover, the combination of two or more bioceramics can
compensate for the disadvantage of mono-component materials.
Using 3D printing, Fielding et al.108 fabricated a b-TCP scaffold
doped with silica and zinc oxide that enhanced osteogenesis and
angiogenesis in vivo compared with a pure b-TCP scaffold. Wang
et al.109 employed material extrusion 3D-printing followed by a
pressureless sintering process to fabricate high-strength bioactive glass/akermanite composite porous scaffolds with
compressive strength (similar to 36 MPa) ten times higher than
those of pure akermanite porous ceramics, which showed good
potential for the repair of load-bearing segmental bone defects.
Bergmann et al.110 developed a composite of b-TCP and BG to
manufacture customized implants via a 3D printing process,
which combined the bioresorption properties of b-TCP, the
capability to act as bone cement, and the adjustability of BG
from being inert to bioresorbable. Thus, it is possible to print
the tailored bone implants using a bioactive b-TCP/BG composite. Shao et al.111 combined magnesium-doped wollastonite
(CSi-Mg10) with b-TCP to fabricate bioceramic scaffolds using
direct ink writing. The introduction of b-TCP led to mechanical
decay by nearly 50%, but the bone regeneration and repair
models in a critical sized calvarial defect model in rabbits
showed that the CSi-Mg10/TCP15 scaffolds displayed markedly
higher osteogenic capability than the CSi-Mg10 and b-TCP
scaffolds after 8 weeks, and reached B35% of new bone tissue
regeneration at 12 weeks postoperatively.
Bioactive bone cements could fill any site of bone defect
with different shapes and provide a support for cell adhesion,
which are promising candidates for bone tissue engineering.112,113
The major bioactive bone cements include calcium sulfate
cements (CSCs), calcium phosphate cements (CPCs) and calcium
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Journal of Materials Chemistry B
silicate cements (CSCs).114–119 The fabrication of cement scaffolds has a hydration step that improves the physical, chemical
and biological behaviors.120–122 Resorbable di-calcium phosphate bone substitutes and magnesium phosphate cement scaffolds were successfully fabricated by 3D powder printing by
Gbureck et al.123,124 Akkineni et al.125 prepared calcium phosphate cement (CPC) scaffolds loaded with growth factors by 3D
printing and the scaffolds were aged in a water-saturated atmosphere for hydration. Asadi-Eydivand et al.120 fabricated calcium
sulfate cement scaffolds by inkjet-based 3D printing, and the
heat treatment at higher than 1200 1C produced calcium oxide
caused by partial decomposition of calcium sulfate, which was
responsible for the considerable improvements in cell viability.
Although bone cements have been employed due to their
short curing time, rapid resorption and good biocompatibility,
clinical applications of mono bone cement materials have been
limited due to their poor bioactivity, very rapid resorption rate
and the unstable environment generated in vivo. As a consequence, much effort has been made to fabricate composite
cements by combining with other bioactive materials to tailor
the setting time and injection ability, reduce inflammation,
as well as improve bioactivity and decrease resorption rate.
Qi et al.126 incorporated MBG into a calcium sulfate matrix to
fabricate porous bone cement scaffolds, and these composite
cement scaffolds could significantly enhance new bone
formation in calvarial defects compared to pure calcium sulfate
cement scaffolds. Similarly, tricalcium silicate/mesoporous
bioactive glass (C3S/MBG) cement scaffolds were successfully
fabricated by 3D printing with a curing process, which combined
the hydraulicity of C3S with the excellent biological properties of
MBG.127 In vivo results showed that both C3S and C3S/MBG
scaffolds could induce new bone formation, but the C3S/MBG
scaffolds significantly improved the osteogenic capacity compared to pure C3S scaffolds. Du et al.128 combined pearl powders
with calcium sulfate to print composite cement scaffolds.
Critical-sized rabbit femoral condyle defects were implanted
with the scaffolds, and the pearl/CaSO4 scaffolds exhibited
osteogenic capacity, and the bone-implant contact index was
significantly higher for the pearl/CaSO4 scaffold implant than for
the CaSO4 scaffold implant.
3.4
Functional ceramic-based scaffolds
Generally, the hierarchical structure, surface and interface of
biomaterials are important factors that influence their biological properties. Porous bioceramic scaffolds have been
widely used for bone tissue engineering by optimizing their
chemical composition and pore structure. Recently, biodegradable ceramics have been modified using various functional
materials, and a variety of functional scaffolds have been
developed for bone tissue engineering.
There are many reports on coating bioceramic scaffolds to
get different functionality. Tarafder et al.129 fabricated a b-TCP
scaffold by 3D printing followed by PCL coating. PCL coating
showed its effectiveness for controlled alendronate release, and
in vivo local alendronate delivery could further induce increased
early bone formation. Ma et al.130 fabricated a bioceramic
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Ca7Si2P2O16 scaffold with a uniformly self-assembled Ca–P/polydopamine nanolayer surface, which exhibited remarkable capability for both cancer therapy and bone regeneration. Zhang
et al.131 printed b-TCP scaffolds and created a mesoporous
bioactive glass nanolayer with a thickness of 100 nm on the
surface of scaffolds by spin coating, which improved osteogenesis
significantly compared with pure b-TCP scaffolds. Porous HA
scaffolds were developed by coating rhBMP-2-delivery microspheres with collagen.132 The coating of rhBMP-2/collagen microspheres facilitated the adhesion of hMSCs, and the scaffolds can
simultaneously achieve localized long-term controlled release of
rhBMP-2 and bone regeneration, which provided a promising
route for improving the treatment of bone defects.
Drug loading and release properties are some of the most
important functions of ideal bone tissue engineering scaffolds.133
Zhu et al.134 printed macro/meso-porous composite scaffolds. High
dosages of isoniazid/rifampin anti-osteoarticular tuberculosis (TB)
drugs were loaded into chemically modified mesoporous bioactive
glass and mesoporous silica nanoparticles in advance, which were
then bound with a polymer binder through a 3D printing
procedure (Fig. 3). The composite scaffolds showed greatly
prolonged drug release time compared to commercial calcium
phosphate scaffolds either in vitro or in vivo, which combined
the merits of osseous regeneration and local multi-drug
therapy. In addition, micro-CT evaluations and histology
results also indicated partial degradation of the composite
scaffolds and new bone growth in the cavity. Yang et al.135
demonstrated successful preparation of uniform 3D-printed
tricalcium silicate bone cement scaffolds with a controllable
3D structure at room temperature. These scaffolds were loaded
with two model drugs, showing a loading location controllable
Review
drug-release profile. Additionally, they developed a surface
modification process to create controllable nanotopography
on the surface of the pore wall of the scaffolds, which showed
activity to enhance rat bone-marrow stem cell (rBMSC) attachment, proliferation, and ALP activities and improve bone
regeneration in vivo.
The treatment of malignant bone tumors is a significant
clinical challenge because it not only requires the simultaneous
removal of tumor tissues but also the regeneration of bone
defects, and bifunctional 3D porous scaffolds that function in
both tissue regeneration and tumor therapy are expected to
address this need. Therefore, some functional materials were
incorporated into or combined with bioceramic scaffolds to
fulfill more functionalities, such as magnetic hyperthermia and
photothermal therapeutic properties. In Zhang’s study,136 they
fabricated magnetic Fe3O4 nanoparticle incorporated mesoporous bioactive glass/polycaprolactone (Fe3O4/MBG/PCL)
composite scaffolds by 3D printing. The incorporation of
magnetic Fe3O4 nanoparticles into MBG/PCL scaffolds did not
influence the apatite mineralization ability, but resulted in excellent
magnetic heating ability and significantly stimulated cell proliferation and differentiation. Moreover, using doxorubicin (DOX) as a
model anticancer drug, Fe3O4/MBG/PCL scaffolds exhibited a
sustained drug release for use in local drug delivery therapy.
Therefore, the 3D-printed Fe3O4/MBG/PCL scaffolds had
potential multifunctionality for enhanced osteogenic activity,
local anticancer drug delivery and magnetic hyperthermia.
In another study, Zhang et al.137 successfully prepared a
3D-printed b-TCP bioceramic scaffold with surface modification of Fe3O4 nanoparticles/graphene oxide nanocomposite
layers which endowed them with super paramagnetic behavior
Fig. 3 (A) 3D-printed hierarchical scaffold for localized isoniazid/rifampin drug delivery and osteoarticular tuberculosis therapy. (B) Release percentage
curves of INH (a) and RFP (b) in SBF at 37 1C from CaP scaffolds and MPHS scaffolds. (C) Transverse micro-CT images of femoral defects at 1 day and
12 weeks post-implantation of control CaP scaffolds or MPHS scaffolds (scale bar: 2 mm). The image is printed with permission from ref. 134. Copyright
2015 Elsevier Publishing Group.
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Journal of Materials Chemistry B
Fig. 4 Schematic illustrations of the in situ growth of MoS2 nanosheets on 3D-printed bioceramic scaffolds (a); near-infrared (NIR) thermal images (b);
heating curves (c) of tumor-bearing mice post-implanted with MoS2-modified akermanite (MS-AKT) and AKT scaffolds under 808 nm laser irradiation
taken at different time intervals; the whole-body fluorescence imaging (d) of tumor after various different treatments at day 0 (left) and day 7 (right);
(e) relative tumor volume in four groups with increasing days (n = 5). The image is printed with permission from ref. 138. Copyright 2016 Nature Publishing
Group.
and hyperthermia effects. The results demonstrated that the
excellent hyperthermia effect of b-TCP–Fe–GO scaffolds induced
more than 75% cell death for osteosarcoma cells (MG-63)
in vitro. Wang et al.138 combined Akermanite (AKT) powder with
alginic acid sodium and Pluronic F127 solution to get a homogeneous paste and then 3D printed AKT bioceramic scaffolds.
A facile hydrothermal method was applied to fabricate molybdenum
disulfide (MoS2) modified AKT composite scaffolds (MS-AKT).
During the hydrothermal process, MoS2 nanosheets were grown
in situ on the strut surface of bioceramic scaffolds, endowing
them with photothermal therapeutic potential. Under nearinfrared (NIR) irradiation, the temperature of the MS-AKT scaffolds could rapidly increase, thus decreasing the viability of
osteosarcoma cells and breast cancer cells and inhibiting tumor
growth in vivo (Fig. 4). On the other hand, the MS-AKT scaffolds
supported the attachment, proliferation and osteogenic differentiation of bone mesenchymal stem cells and induced bone regeneration in vivo (Fig. 4). Dang et al.139 managed to prepare BG
scaffolds functionalized with CuFeSe2 nanocrystals (BG-CFS) by
combining the 3D printing technique with a solvothermal method
to endow BG scaffolds with excellent photothermal performance.
4408 | J. Mater. Chem. B, 2018, 6, 4397--4412
The results showed that the BG-CFS scaffolds could effectively
ablate bone tumor cells (Saos-2 cells) in vitro and significantly
inhibit bone tumor growth in vivo. Yang et al.140 3D printed
bioactive glass scaffolds and functionalized them with black
phosphorus (BP) nanosheets. The in situ phosphorus-driven,
calcium-extracted biomineralization of the intra-scaffold BP
nanosheets enables both photothermal ablation of osteosarcoma
and the subsequent material-guided bone regeneration, which
provides a feasible countermeasure for efficient localized treatment of osteosarcoma.
4. Conclusions and perspectives
The shapes of bone defects caused by trauma, tumors or
disease are often irregular. There are only limited sources for
traditional autogenous bone, and the production cycle is long
and the size and shape of autogenous bone cannot always
match those of bone defects, resulting in unsatisfactory surgical
outcomes. Together with modern imaging and computer aided
manufacturing technologies, 3D printing can fabricate specially
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shaped scaffolds rapidly and conveniently. Customized implants
for bone replacement are a great help for a surgeon to remodel
maxillofacial or craniofacial defects in an esthetical way, and to
significantly reduce operation times.
However, 3D printing of biomaterials is a new technology and it
is still expensive and technically challenging. Raw materials for 3D
printing require good mechanical properties and excellent biocompatibility. Additionally, the scaffolds should be similar to the
true bone (i.e. porosity, degradation rate, osteogenic ability). Given
the limited number of commercially available materials, it may be
challenging to control degradation, mechanical properties, pore
size, and surface properties of bone tissue engineering scaffolds.
Combining bioceramics with polymers and adequate porosity by
the 3D printing technique has the potential to create good artificial
scaffolds that may one day compete with autologous bone
implants.
In conclusion, application of the 3D printing technique has
greatly advanced the progress of bone tissue engineering.
Further developments in additive manufacturing in bone tissue
engineering will require scaffold design optimization, better
knowledge of cell and organ physiology and most importantly,
new biomaterials that can be 3D-printed and also emulate the
compositional, structural, and functional complexities of
human natural bone.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
The authors gratefully acknowledge the support by grants from
the Science and Technology Commission of Shanghai Municipality
(No. 17060502400) and the University of Shanghai for Science and
Technology (No. 16KJFZ011, 2017KJFZ010).
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