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Meng, B. Sun, P. Chen, X. Liu, K. Zhang, X. Yang, J. Peng and S. Lu, Biomater. Sci., 2017, DOI:
10.1039/C7BM00315C.

Volume 4 Number 1 January 2016 Pages 1–196 This is an Accepted Manuscript, which has been through the

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 Page 1 of 32 Biomaterials Science
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DOI: 10.1039/C7BM00315C

3D Printing Porous Ceramic Scaffold for Bone Tissue

Engineering: A Review
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Biomaterials Science Accepted Manuscript

Authors: Yu Wen M.D., Sun Xun M.D., Meng Haoye M.D.,

Sun baichuan M.D., Chen peng M.D., Liu xuejian M.D.,

Zhang kaihong M.D. Yang xuan M.D., Peng Jiang

M.D. ,Ph.D.[corresponding author], Lu Shibi M.D. ,Ph.D.

Name and address of the corresponding author: Jiang Peng,

Orthopedics Research Institute of Chinese PLA, Beijing Key Lab of
Regenerative Medicine in Orthopedics, General Hospital of Chinese
PLA, Fuxing Road 28, Haidian District, Beijing 100853, P. R. China.

This work is supported by grant from National Natural Science

Foundation of China (NSFC 81472092, 31640029, 81572148),

1. Introduction

Bone defects are a difficult orthopedic problem and much

1-10
research has focused on their treatment . A method to

improve the osteogenesis of bone grafts and to reduce the

amount of autologous bone is urgently required. Additive

manufacturing technology for bone tissue engineering has

greatly promoted the research and development of bone

regeneration11-24. The most important additive

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manufacturing techniques include three-dimensional (3D)

printing, stereo lithography, fused deposition modeling and

selective laser sintering. Bioactivity, biodegradability and

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Biomaterials Science Accepted Manuscript

biocompatibility are the main properties sought in an ideal

tissue repair material. Bioceramics have potential market

and social value in the construction of an efficient and safe

material for the repair of bone defects25. Therefore, the

application of tissue engineering technology in bone

regeneration is very promising. This paper describes the

main technologies used in the printing of 3D ceramic

scaffolds and the most popular bioceramic raw materials, as

well as the fabrication and clinical application of ceramic

scaffolds.

2. Material and Methods

A Medline (PubMed) search was performed in duplicate for

studies regarding the application of powder-based 3D

printing for the production of bone tissue engineering

scaffolds. The Medical Subject Heading (MeSH) term

“three-dimensional printing” was used together with the

term “bone defect” applying the following search strategy:

((("2010/01/01"[PDAT] : "2017/02/16"[PDAT]) AND

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(((("printing, three-dimensional"[MeSH Terms] AND (3D[All

Fields] AND ("printing"[MeSH Terms] OR "printing"[All

Fields] OR "print"[All Fields]))) OR (three[All Fields] AND

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Biomaterials Science Accepted Manuscript

dimensional[All Fields] AND ("printing"[MeSH Terms] OR

"printing"[All Fields] OR "print"[All Fields]))) OR (3[All

Fields] AND dimensional[All Fields] AND ("printing"[MeSH

Terms] OR "printing"[All Fields] OR "print"[All Fields]))) OR

("printing, three-dimensional"[MeSH Terms] OR

("printing"[All Fields] AND "three-dimensional"[All Fields])

OR "three-dimensional printing"[All Fields] OR ("3d"[All

Fields] AND "printing"[All Fields]) OR "3d printing"[All

Fields]))) AND bioceramic[All Fields]) AND (((((massive[All

Fields] AND ("bone and bones"[MeSH Terms] OR

("bone"[All Fields] AND "bones"[All Fields]) OR "bone and

bones"[All Fields] OR "bone"[All Fields]) AND defect[All

Fields]) OR (large[All Fields] AND ("bone and bones"[MeSH

Terms] OR ("bone"[All Fields] AND "bones"[All Fields]) OR

"bone and bones"[All Fields] OR "bone"[All Fields]) AND

defect[All Fields])) OR (segmental[All Fields] AND ("bone

and bones"[MeSH Terms] OR ("bone"[All Fields] AND

"bones"[All Fields]) OR "bone and bones"[All Fields] OR

"bone"[All Fields]) AND defect[All Fields])) OR (("bone and

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bones"[MeSH Terms] OR ("bone"[All Fields] AND

"bones"[All Fields]) OR "bone and bones"[All Fields] OR

"bone"[All Fields]) AND defect[All Fields])) OR (("bone and

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Biomaterials Science Accepted Manuscript

bones"[MeSH Terms] OR ("bone"[All Fields] AND

"bones"[All Fields]) OR "bone and bones"[All Fields] OR

("bone"[All Fields] AND "tissue"[All Fields]) OR "bone

tissue"[All Fields]) AND ("engineering"[MeSH Terms] OR

"engineering"[All Fields])))

The online database was searched to find English-language

articles published between 1 January 2010 and 16 February

2017. All in vitro, in vivo or human studies regarding the

use of powder-based 3D printing for the synthesis of bone

tissue engineering scaffolds were considered. No limitations

with regard to sample size or length of follow-up period

were applied.

Systematic reviews and meta-analyses were excluded.

Studies relating to the following topics were excluded:

3D-printed templates for dental implant positioning or

osteotomy design, 3D-printed anatomic templates for

preoperative planning or training.

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2.1 Study selection

The titles and abstracts that were identified by the

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electronic search were, whenever available, independently

Biomaterials Science Accepted Manuscript

screened by two of the authors. Any disagreements were

resolved by a discussion between them. The studies that

were selected were then screened independently by the

same authors. Any disagreements were resolved by

discussion.

2.2 Data extraction

Two of the authors independently extracted and analyzed

the data. The consensus of the other authors was sought at

this point of the process. The following data were registered:

the authors' names, the year of publication, the material

used to produce the scaffolds, and the main features of the

scaffold structure.

3 Present Status of 3D printing Technology

3.1 Mechanism

3D printing is a modern additive manufacturing technology

that emerged in the late 1980s. 3D printing integrates such

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techniques as computer-aided design (CAD),

computer-aided manufacturing, numerical control

techniques, laser techniques, polymers, and 3D computed

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tomography techniques. On the basis of the principle of

discrete/bulk formation, the 3D geometric information is

determined by CAD models of the parts, or by scanning

objects in two dimensions and processing the acquired data

into a 3D model. Then a 3D sample is fabricated from sheet

material or powder [Figure 1]. 3D printing can reduce the

time and cost of making physical models or sample implants,

one at a time or even in small batches. 3D printing also has

other advantages, such as creating personalized implants

and breaking time and space constraints of conventional

methods and exquisite design of scaffold structure. It can

assist the doctor-patient communication and help surgeons

to obtain comprehensive preoperative assessment of the

condition and design more reasonable operation plan24,26.

[figure 1]
Fig. 1. Schematic drawing representing the 3D printing process. Figure from
52
Fielding, G. & Bose, S (Reproduced with permission from Elsevier).

3.2 Introduction of different 3D printing technology(Table 1)

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Tab. 1 Characteristics of several 3D printing techniques in

medical applications
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Biomaterials Science Accepted Manuscript

Accurac Cost advantages disadvantages
y
Stereolithography +++ $$ large molding Low mechanical
(SLA) product strength

Selective laser ++ $$$ large molding high cost, dust

sintering(SLS) product, wide while printing,
range of surface
application for asperities
powders, high
mechanical
strength

Fused deposition ++ $ low cost, high Low processing

modeling(FDM) mechanical speed
strength

Laminated object + $ low cost, large Limitations in

manufacturing(LO product size application for
M) powders

Inkjet printing + $ low cost, high Low mechanical

processing strength
speed,
multifunctional

4 Present Status of Bioceramics

4.1 Definition

Bioceramic refers to a class of ceramic materials with

specific biological or physiological function. Bioceramics can

be used directly in the human body or in applications related

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to the human body, and are used in biological, medical,

biochemical and other research areas. Bioceramics exhibit

many favorable properties, such as biocompatibility,

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Biomaterials Science Accepted Manuscript

mechanical compatibility, excellent surface compatibility,

anti-thrombus effects, bactericidal effects, and good

physical and chemical stability27. Bioceramics can be

divided into bioactive or biologically inert ceramic materials.

The fundamental difference between the two lies in whether

the implant is chemically bonded to the living tissue after

implantation.

4.2 Commonly used bioactive ceramic

4.2.1 Tricalcium phosphate

Tricalcium phosphate(TCP) is crystalline in the solid state.

There are two structures with different atomic

arrangements, α-TCP and β-TCP. The calcium–phosphorus

ratio of TCP is 1.5. This is close to 1.66, the

calcium–phosphorus ratio of natural bone tissue28. Moreover,

TCP has good biocompatibility and combines with bone

tissue without any rejection reaction, making it a good

material for bone repair. After implantation in the bone

defect area, TCP supplies Ca and P ions as materials for new

bone formation. Therefore, research and applications of

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artificial bone material scaffolds based on TCP contribute to

a prosperous field in bone tissue engineering. Besides,

recent research has focused on β-TCP rather than α-TCP.

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Biomaterials Science Accepted Manuscript

α-TCP suffers from excessive solubility and rapid

degradation in the human body. This degradation and

osteogenesis lead to implantation experiment failure29-31.

4.2.2 Calcium sulfate

Calcium sulfate (CaSO4) is an inorganic compound with two

related hydrates, (CaSO4·0.5H2O) and (CaSO4·2H2O). The

two types are obtained by different dehydration methods,

dense type α and porous type β. Calcium sulfate for medical

applications can be in various forms, including medical

gypsum, self-curing cement and ceramic particles. Calcium

sulfate is a better ceramic material than allograft for

residual cavities after tumor resection32. Calcium sulfate

combines with recombinant human bone morphogenetic

protein (rhBMP)-233 or platelet-rich plasma to promote bone

defects repair34.

4.2.3 Hydroxyapatite

Hydroxyapatite (HA), a CaP bioceramic, is an inorganic

composite similar to natural bone tissue. High-purity HA has

been widely investigated by surgeons and engineers for use

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in hard tissue repair. Up to 50% by volume and 70% by

weight of human bone is a modified form of HA known as

bone mineral. HA is not only highly biocompatible but also

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Biomaterials Science Accepted Manuscript

non-toxic and osteoconductive. Studying the binding

processes of HA and bone, Jarhco et al35 found that, by

epitaxial growth, HA formed a strong chemical bond with

bone tissue, known as osseointegration. In clinical

applications the primary objective is that implanted HA will

gradually merge with the natural bone. To enable this,

integration and crosslinking are necessary in the interface

between the implant and the natural bone. HA scaffolds

have the required good porosity for this. Recently, much

attention has been paid to the research and development of

porous HA ceramics, which are fundamentally determined

by the characteristics of bone tissue36-38. Despite pure

hydroxyapatite bioceramic, there are also some

hydroxyapatite bioceramic containing significant amounts

of ion substitution impurities such as Na+, Mg2+, K+,

citrate, HPO2-, carbonate (CO32-), Cl-, F-, etc.

4.2.4 Ca-Si-based ceramics

Akermanite has great potential for bone regeneration

because of its good mechanical properties39 and

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controllable degradation rate40. It contains calcium (Ca),

silicon (Si) and magnesium (Mg). In vitro studies,

comparing with β-TCP, show that akermanite has better

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Biomaterials Science Accepted Manuscript

osteogenic differentiation of bone marrow-derived stromal

cells41 and increased gene expression of osteogenetic

markers in adipose-derived stem cells42. Porous akermanite

implants also improved the rate of new bone formation and

obtained more bone regeneration than β-TCP in rabbit

model43.

4.2.5 Diopside

Diopside (MgCaSi2O6) is a monoclinic pyroxene mineral. It is

a novel energy-saving additive and a ceramic material that

satisfies the requirements of low temperature and fast firing

for building bioceramics. It is a high-performance ceramic

with high value for medical applications. It is characterized

by its lack of amorphous transformation and weight loss

during sintering, as well as its good thermal expansion

properties. Several additives such as calcium oxide,

magnesium oxide and silica can be added simultaneously to

diopside to change inorganic iron to improve angiogenesis

in vivo. Natural properties of diopside enable

low-temperature sintering. Therefore, diopside is a

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bioactive ceramic material with potential for

development44,45.

4.2.6 Bioglass
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Biomaterials Science Accepted Manuscript

Bioactive glasses(BGs) was discoveried by Hench46. Its

main components are Na2O, CaO, SiO2 and P2O5. BGs is

considered to be the most promising biomaterials in bone

tissue engineering. However, BGs causes fast porous

structure collapse because of the inherent brittleness. The

drawback negatively affect new bone ingrowth. Many BGs

have been investigated47. Many bioactive scaffolds have

been explored for enhancing bone repair48,49.

4.3 Biological inert ceramic

After being implanted into the body, inert ceramic material

do not form a chemical bonds with living tissue and has low

fracture toughness. The main inert ceramic materials used

in clinical applications were alumina and zirconia.

4.3.1 Alumina

α-Aluminum oxide (Al2O3) is a crystal with mostly ionic

bonds. Owing to the strong bond force, alumina has a high

melting point (2050°C), hardness, chemical corrosion

resistance and elastic modulus. In medical applications,

alumina is mainly used for artificial joints or teeth. The main

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advantages of bioinert ceramic materials in such

applications are50: (1) wear resistance, can resist abrasive

wear and three-body abrasion; (2) high strength, can meet

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Biomaterials Science Accepted Manuscript

the requirements of material strength of load-bearing parts;

(3) high hardness, no creep phenomenon, structural

stability; (4) crystal structure surface can be highly polished;

(5) good hydrophilicity and excellent lubricating properties;

(6) chemical stability, excellent corrosion resistance, almost

no ion release; (7) biologically inert, less likely to cause a

rejection reaction; (8) a surface that bacteria cannot adhere

easily to. Periodical micrometer-scale micropatterns on

inert alumina ceramics have been shown to mediate

adhesion and to stimulate osteogenic differentiation of

51
human mesenchymal stem cells .

4.3.2 Zirconia

There are three crystal forms of pure zirconia under normal

atmospheric pressure, monoclinic zirconia, tetragonal

zirconia and cubic zirconia. These three crystal forms exist

in different temperature ranges and transform into each

other at certain temperatures. Of the three forms,

tetragonal zirconia polycrystals are used most frequently in

the medical field at present. They are mainly used in

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artificial joints, dental crowns or all-ceramic teeth.

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4.4 3D-printed bioceramics for bone tissue engineering

Biomaterials Science Accepted Manuscript

Every bioceramic has different advantages and

disadvantages; therefore, ideal bone implants can be made

by using two or more raw materials or by optimizing the

microstructure of the scaffolds.

CaP bioceramics, which exhibit excellent osteoconductive

properties due to their chemical similarity to natural bone,

are widely applied to fabricate porous scaffolds for bone

tissue engineering. Properties of CaP scaffolds can be

modified using additives or surface coating treatments to

enhance angiogenesis and osteogenesis.

Using 3D printing, Fielding et al52 fabricated a β-TCP

scaffold doped with silica and zinc oxide that enhanced

osteogenesis and angiogenesis in vivo compared with a

pure β-TCP scaffold. Tarafder et al53 fabricated a

PCL-coated TCP scaffold from which in vivo local

alendronate (AD) delivery could further induce increased

early bone formation. Castilho et al54 printed a new cage for

tibial tuberosity advancement made of calcium phosphate,

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calcium hydrogen phosphate and calcium carbonate using

3D printing. Wang et al55 fabricated a scaffold from HA and

TCP (60/40, wt%) filled with phage nanofibers displaying a

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Biomaterials Science Accepted Manuscript

high-density Arg-Gly-Asp (RGD) peptide, which induced

osteogenesis and angiogenesis. The RGD peptide in the

extracellular matrix regulated the migration and adhesion

of the endothelial cells. Zhang et al56 printed a TCP scaffold

and applied a mesoporous bioactive glass nanolayer to the

surface. This improved osteogenesis compared with the

pure TCP scaffold. Adel-Khattab et al57 developed a novel

porous scaffold by rapid prototyping from silica containing

calcium-alkali-orthophosphate, on which new bone was

formed in vitro. This scaffold had superior mechanical and

biological properties compared with that prepared by the

Schwartzwalder Somers method.

Recently, biodegradable ceramics have been modified

using various other materials, and a variety of new

scaffolds have been developed for bone regeneration.

Ma et al58 fabricated a bioceramic scaffold with a uniformly

self-assembled Ca-P/polydopamine nanolayer surface

for treatment of bone defect after resection of bone

tumors[Fig.2]. Castilho et al59 printed another novel β-TCP

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scaffold for tibial tuberosity advancement operation and

osteogenesis was observed after implantation. Chang et al60

fabricated a scaffold made of mixture of calcium carbonate

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Biomaterials Science Accepted Manuscript

and silica(5:95, w/w) , which had good mechanical

properties and cell affinity.Luo et al61 printed a

hollow-struts-packed scaffold from tetraethylorthosilicate,

triethylphosphate, calcium nitrate tetrahydrate, alginate

and poloxamer 407. Compared with a solid-struts-packed

scaffold, more new bone formation was observed, thus the

hollow-struts-packed scaffold is more suitable for

application in bone tissue engineering. Shao et al49

fabricated a scaffold from calcium silicate and bioactive

glass. The pore morphologies of calcium silicate–bioactive

glass scaffolds were Archimedean chord, honeycomb and

parallelogram [Fig.3].

Dadhich et al62 reported a novel method of printing an

eggshell-based scaffold which had good osteoinduction.

Meininger et al63 printed a magnesium phosphates

scaffold which, when doped with strontium ions,

showed superior mechanical properties and good

degradation in vitro.
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[figure 2]
Fig. 2. (a) Photograph of 3D printed pure bioceramics (BC), DOPA-BC (2 mg/mL), DOPA-BC

(4 mg/mL), DOPA-BC (6 mg/mL) scaffolds, respectively; Optical images of pure BC (b) and 4

mg/mL DOPA-BC (c) scaffolds on the top view; Scanning electron microscopy (SEM) images
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of pure BC (d) and 2 mg/mL DOPA-BC (e), 4 mg/mL DOPA-BC (f), 6 mg/mL DOPA-BC (g)

Biomaterials Science Accepted Manuscript

scaffolds, showing a uniform nanolayer composed of polydopamine and amorphous Ca-P

nanoparticles on DOPA-BC surface; Sectional SEM images (h) and sectional linescan EDS

spectrum of 4 mg/mL DOPA-BC (i). DOPA indicates dopamine and BC indicates bioceramic.

Figure from Ma et al58 (Reproduced with permission from Elsevier).

[figure 3]
Fig. 3.The pore morphologies of CSi-BG scaffolds are Archimedean chords, honeycomb and

parallelogram, respectively. Figure from Shao et al49(Reproduced with permission from IOP

Publishing）.

Recently, a scaffold made of tricalcium silicate was

fabricated with a nano surface structure by Yang et al64.

Liu et al65 fabricated a scaffold from akermanite that had

better mechanical properties and higher rate of new

bone formation than pure TCP scaffold. The fabrication

and assessments of the scaffold manufactured in the above

articles are summarized in Table 2. Among the scaffolds

mentioned above, it was observed that bone marrow

mesenchymal stem cells or osteoblast could adhere,

migrate and proliferate on or in scaffold that had good

biocompatibility.
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Tab. 2. Summary of 3D-printed scaffolds fabrication and in

vivo defect model

[tab. 2]
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Author Fielding Miguel Castilho Jianglin Wang Chang, C. H Luo, Y et al Shao, H. et Zhang, Y. et
Gary et et al. et al. et al al. al.

Biomaterials Science Accepted Manuscript

al.
Date 2013 2014 2014 2015 2015 2015 2015
Raw materials TCP, dicalcium biphasic silica Tetraethylorthosilicate calcium mesoporous
bioactive
silica, phosphate calcium (SiO2), ((C2H5O)4Si), silicate, glass,
zinc anhydrous phosphate, calcium Triethylphosphate bioactive β-TCP
oxide carbonate; ((C2H5O)3PO), glass
(DCPA, hydroxyapatite
(CaCO3) calcium nitrate
and β-TCP at a
CaHPO4, tetrahydrate
mass ratio of
(Ca(NO3)2·4H2O),
monetite), 60/40
F-127, alginate
calcium
carbonate
Printer R-1 R&D a Z510 a robotic A bioscaffold printer of 3D writing The 3D
printer spectrum 3DP deposition home-made Fraunhofer IWS equipment plotting
by system device 3D printing (Dresden, Germany) (home-made device
ProMetal (Z-Corporation, (RoboCAD 3.0, machine printing ( designed
Burlington, 3-D Inks, system) by
USA) Stillwater, OK) the
Fraunhofer
Institute for
Materials
Research
and Beam
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Biomaterials Science Page 20 of 32

Technology,
Dresden,

Biomaterials Science Accepted Manuscript

Germany)
Defect model Bicortical Tibia of 8mm long NM Rabbit femoral bone NM Rabbit
defect in defect in the defect calvarial
the distal Rottweiler central radius defect
femur, (weighing 25 of SD rat (8mm
SD rat circular
kg) cycle )

Biological 28.25% 59.2%, 845μm pore size about 34%, 800μm 86%, about 500μm 60%, 630~650 400μm
properties(porosity, (300 μ m 400μm μm
pore size/channel after
size) sintering)
NM indicates not mentioned.

(continued)
Adel-Khattab, Dadhich, P., Liu, A., et al. Ma, H., et al. Meininger, S., et al. Castilho, Yang, C., et
D., et al. et al. M., et al. al
2016 2016 2016 2016 2016 2017 2017
calcium alkali eggshell akermanite Ca7Si2P2O16, strontium-incorporated TCP bioactive
orthophosphate polydopamine magnesium phosphate Ca3SiO5
(main crystalline nanolayer cements
phase surface
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Ca2NaK(PO4)2),
magnesium

Biomaterials Science Accepted Manuscript

potassium
phosphate, silica
R1 Series ExOne Fused desktop 3D direct NM a Z510 spectrum a Z510 3D printing
(PROMETAL, deposition ceramic ink writing printer spectrum equipment
USA) machine equipment(specific 3D developed
(RapMan 3.2, machine not printer by
BFB) mentioned) Fraunhofer
IWS
(Dresden,
Germany)
NM Rabbit a critical size (Ø6x 5 x 8 mm NM NM 6 x 10 mm
subcutaneous 6 mm) circular critical-sized critical-sized
area defect of rabbit rabbit rabbit
femoral condyle femoral
defect
model
SSM scaffold: 54.5~60.7%, 50%, 280μm 200-400μm 15-25%, 4.5-25μm 20-46% ~61%, ~200 μ
86.9%, mostly ~750μm m
200-600μm;
RP scaffolds: 50%;
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5. Conclusion

The shapes of bone defects caused by trauma, tumors or

disease are often irregular. There are only limited sources of

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traditional autogenous bone. The production cycle is long

and the size and shape of autogenous bone cannot always

match that of bone defects, resulting in unsatisfactory

surgical outcomes. Individualization and precision is the

current direction of medical development. Application of

3D-printing technology in the field of medicine has greatly

advanced the progress of medicine. 3D-printing technology

has reduced the reliance on traditional factory production.

3D-printing allows convenient, fast, and individualized

implants and shortens the production period. Together with

modern imaging and computer aided manufacturing

technologies, 3D printing can facilitate doctor–patient

communication. These technologies are more intuitive and

help clinicians make comprehensive preoperative

assessments of the condition. They can also help clinicians

to design more reasonable operation plans that reduce

operation time, as well as blood loss and other

complications, leading to significant clinical benefits.

However, 3D printing is a new technology and it is still

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expensive and technically challenging. The raw materials

required in the printing process require good

biocompatibility and biomechanical properties. In addition,

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Biomaterials Science Accepted Manuscript

this technology requires clinicians to master not only

medical skills but also knowledge of 3D reconstruction and

CAD technology. The development of new bioceramic

materials, creative combinations of different ceramic

materials, or combinations of natural and synthetic

materials is an important research direction for bone

regeneration. The 3D-printed composite porous ceramic

scaffold is well suited to use in bone repair-for example, in

in situ bone regeneration or in tissue engineering.

3D-printing technology is ideally suited to fabricate a wide

range of inorganic ceramic structures with controlled pore

architecture and mechanical properties. A novel scaffold for

bone-regeneration has excellent pore structure and high

mechanical strength, and drugs could be easily loaded.

Acronyms

3DP three-dimensional printing

AM additive manufacturing

BMP bone morphogenic protein

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CAD/CAM computer-aided design and computer-aided

manufacturing

CaP calcium phosphate

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Biomaterials Science Accepted Manuscript

FDM fused deposition modeling

HA hydroxyapatite

SEM scanning electron microscope

SLA stereolithography

SLS selective laser sintering

TCP tricalcium phosphate

Acknowledgements

This study was supported by National Natural Science

Foundation of China (NSFC 81472092, 31640029,

81572148), People's Liberation Army 13th five-year plan

period (Key Program) (16CXZ044), National Key Research

Special Program (2016YFC1102100) and High Technology

Research and Development Program of Beijing

(Z161100005016059). Dr. Wen Yu thanks my wife Xiaojuan

Su for her wholehearted support.

Disclosure Statement

No competing financial interests exist.

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References:
1 Boschetti, F., Tomei, A. A., Turri, S., Swartz, M. A. & Levi, M. Design, fabrication, and
characterization of a composite scaffold for bone tissue engineering. The International
journal of artificial organs 31, 697-707 (2008).
2 Al-Munajjed, A. A. et al. Development of a biomimetic collagen-hydroxyapatite scaffold for
Published on 23 June 2017. Downloaded by University of California - San Diego on 23/06/2017 12:41:35.

bone tissue engineering using a SBF immersion technique. Journal of biomedical materials

Biomaterials Science Accepted Manuscript

research. Part B, Applied biomaterials 90, 584-591 (2009) doi:10.1002/jbm.b.31320.
3 Athanasiou, V. T. et al. Histological comparison of autograft, allograft-DBM, xenograft, and
synthetic grafts in a trabecular bone defect: an experimental study in rabbits. Medical science
monitor : international medical journal of experimental and clinical research 16, Br24-31
(2010).
4 Andric, T., Wright, L. D. & Freeman, J. W. Rapid mineralization of electrospun scaffolds for
bone tissue engineering. Journal of biomaterials science. Polymer edition 22, 1535-1550,
(2011) doi:10.1163/092050610x514241.
5 Alge, D. L. et al. Poly(propylene fumarate) reinforced dicalcium phosphate dihydrate cement
composites for bone tissue engineering. Journal of biomedical materials research. Part A 100,
1792-1802 (2012) doi:10.1002/jbm.a.34130.
6 Abdal-hay, A., Sheikh, F. A. & Lim, J. K. Air jet spinning of hydroxyapatite/poly(lactic acid)
hybrid nanocomposite membrane mats for bone tissue engineering. Colloids and surfaces. B,
Biointerfaces 102, 635-643 (2013) doi:10.1016/j.colsurfb.2012.09.017.
7 Abou Neel, E. A., Chrzanowski, W. & Knowles, J. C. Biological performance of titania
containing phosphate-based glasses for bone tissue engineering applications. Materials
science & engineering. C, Materials for biological applications 35, 307-313 (2014)
doi:10.1016/j.msec.2013.10.029.
8 Ambre, A. H., Katti, D. R. & Katti, K. S. Biomineralized hydroxyapatite nanoclay composite
scaffolds with polycaprolactone for stem cell-based bone tissue engineering. Journal of
biomedical materials research. Part A 103, 2077-2101 (2015) doi:10.1002/jbm.a.35342.
9 Abdullah, W. A. Evaluation of bone regenerative capacity in rats claverial bone defect using
platelet rich fibrin with and without beta tri calcium phosphate bone graft material. The Saudi
dental journal 28, 109-117 (2016) doi:10.1016/j.sdentj.2015.09.003.
10 Ahlfeld, T. et al. Design and Fabrication of Complex Scaffolds for Bone Defect Healing:
Combined 3D Plotting of a Calcium Phosphate Cement and a Growth Factor-Loaded Hydrogel.
Annals of biomedical engineering 45, 224-236 (2017) doi:10.1007/s10439-016-1685-4.
11 Costa, P. F. et al. Biofabrication of customized bone grafts by combination of additive
manufacturing and bioreactor knowhow. Biofabrication 6, 035006 (2014)
doi:10.1088/1758-5082/6/3/035006.
12 Gur, Y. Additive Manufacturing of Anatomical Models from Computed Tomography Scan Data.
Molecular & cellular biomechanics : MCB 11, 249-258 (2014).
13 Hengsbach, S. & Lantada, A. D. Rapid prototyping of multi-scale biomedical microdevices by
combining additive manufacturing technologies. Biomedical microdevices 16, 617-627 (2014)
doi:10.1007/s10544-014-9864-2.
14 Hofmann, D. C. et al. Developing gradient metal alloys through radial deposition additive
manufacturing. Scientific reports 4, 5357 (2014) doi:10.1038/srep05357.
 Biomaterials Science Page 26 of 32
View Article Online
DOI: 10.1039/C7BM00315C

15 Fuller, S. C. & Moore, M. G. Additive manufacturing technology in reconstructive surgery.

Current opinion in otolaryngology & head and neck surgery 24, 420-425 (2016)
doi:10.1097/moo.0000000000000294.
16 Sing, S. L., An, J., Yeong, W. Y. & Wiria, F. E. Laser and electron-beam powder-bed additive
manufacturing of metallic implants: A review on processes, materials and designs. Journal of
orthopaedic research : official publication of the Orthopaedic Research Society 34, 369-385
Published on 23 June 2017. Downloaded by University of California - San Diego on 23/06/2017 12:41:35.

(2016) doi:10.1002/jor.23075.

Biomaterials Science Accepted Manuscript

17 Studart, A. R. Additive manufacturing of biologically-inspired materials. Chemical Society
reviews 45, 359-376 (2016) doi:10.1039/c5cs00836k.
18 Zadpoor, A. A. & Malda, J. Additive Manufacturing of Biomaterials, Tissues, and Organs.
Annals of biomedical engineering 45, 1-11 (2017) doi:10.1007/s10439-016-1719-y.
19 Youssef, A., Hollister, S. J. & Dalton, P. D. Additive manufacturing of polymer melts for
implantable medical devices and scaffolds. Biofabrication 9, 01200 (2017)
doi:10.1088/1758-5090/aa5766.
20 Hirt, L., Reiser, A., Spolenak, R. & Zambelli, T. Additive Manufacturing of Metal Structures at
the Micrometer Scale. Advanced materials (Deerfield Beach, Fla.),
doi:10.1002/adma.201604211 (2017).
21 Elomaa, L. & Yang, Y. P. Additive Manufacturing of Vascular Grafts and Vascularized Tissue
Constructs. Tissue engineering. Part B, Reviews, doi:10.1089/ten.TEB.2016.0348 (2017).
22 Cicala, G. et al. Engineering thermoplastics for additive manufacturing: a critical perspective
with experimental evidence to support functional applications. Journal of applied
biomaterials & functional materials 15, 0, doi:10.1016/j.dental.2016.11.012
10.5301/jabfm.5000343 (2017).
23 Wang, X. et al. Topological design and additive manufacturing of porous metals for bone
scaffolds and orthopaedic implants: A review. Biomaterials 83, 127-141 (2016)
doi:10.1016/j.biomaterials.2016.01.012.
24 Bose, S., Vahabzadeh, S., Ke, D. & Bandyopadhyay, A. Additive Manufacturing of Ceramics.
(2015).
25 Trombetta, R., Inzana, J. A., Schwarz, E. M., Kates, S. L. & Awad, H. A. 3D Printing of Calcium
Phosphate Ceramics for Bone Tissue Engineering and Drug Delivery. 45, 23-44 (2017)
doi:10.1007/s10439-016-1678-3.
26 Lee, S. J., Lee, H. P., Tse, K. M., Cheong, E. C. & Lim, S. P. Computer-aided design and rapid
prototyping-assisted contouring of costal cartilage graft for facial reconstructive surgery.
Craniomaxillofacial trauma & reconstruction 5, 75-82 (2012) doi:10.1055/s-0031-1300964.
27 Ebrahimi, M., Botelho, M. G. & Dorozhkin, S. V. Biphasic calcium phosphates bioceramics
(HA/TCP): Concept, physicochemical properties and the impact of standardization of study
protocols in biomaterials research. Materials science & engineering. C, Materials for
biological applications 71, 1293-1312 (2017) doi:10.1016/j.msec.2016.11.039.
28 Raynaud, S., Champion, E., Lafon, J. P. & Bernache-Assollant, D. Calcium phosphate apatites
with variable Ca/P atomic ratio III. Mechanical properties and degradation in solution of hot
pressed ceramics. Biomaterials 23, 1081-1089 (2002).
29 Detsch, R., Mayr, H. & Ziegler, G. Formation of osteoclast-like cells on HA and TCP ceramics.
Acta biomaterialia 4, 139-148 (2008) doi:10.1016/j.actbio.2007.03.014.
30 Detsch, R. et al. In vitro: osteoclastic activity studies on surfaces of 3D printed calcium
 Page 27 of 32 Biomaterials Science
View Article Online
DOI: 10.1039/C7BM00315C

phosphate scaffolds. Journal of biomaterials applications 26, 359-380 (2011)

doi:10.1177/0885328210373285.
31 Tarafder, S., Balla, V. K., Davies, N. M., Bandyopadhyay, A. & Bose, S. Microwave-sintered 3D
printed tricalcium phosphate scaffolds for bone tissue engineering. Journal of tissue
engineering and regenerative medicine 7, 631-641 (2013) doi:10.1002/term.555.
32 Yang, Y. et al. A comparative study of calcium sulfate artificial bone graft versus allograft in
Published on 23 June 2017. Downloaded by University of California - San Diego on 23/06/2017 12:41:35.

the reconstruction of bone defect after tumor curettage. BioMed research international 127,

Biomaterials Science Accepted Manuscript

3092-3097 (2014) doi:10.1155/2014/250958.
33 Qi, Y. et al. Combined mesenchymal stem cell sheets and rhBMP-2-releasing calcium
sulfate-rhBMP-2 scaffolds for segmental bone tissue engineering. Cell transplantation 21,
693-705 (2012) doi:10.3727/096368911x623844.
34 Chen, H. et al. Effects of Calcium Sulfate Combined with Platelet-rich Plasma on Restoration
of Long Bone Defect in Rabbits. Chinese medical journal 129, 557-561 (2016)
doi:10.4103/0366-6999.176981.
35 Jarcho, M. & Bolen, C. H. Hydroxylapatite synthesis and characterization in dense
polycrystalline. Mater Sci 11, 2027-2035 (1976).
36 Woodard, J. R. et al. The mechanical properties and osteoconductivity of hydroxyapatite bone
scaffolds with multi-scale porosity. Biomaterials 28, 45-54 (2007)
doi:10.1016/j.biomaterials.2006.08.021.
37 Warnke, P. H. et al. Ceramic scaffolds produced by computer-assisted 3D printing and
sintering: characterization and biocompatibility investigations. Journal of biomedical
materials research. Part B, Applied biomaterials 93, 212-217(2010) doi:10.1002/jbm.b.31577.
38 Wang, Y., Wei, Q., Pan, F., Yang, M. & Wei, S. Molecular dynamics simulations for the
examination of mechanical properties of hydroxyapatite/ poly alpha-n-butyl cyanoacrylate
under additive manufacturing. Bio-medical materials and engineering 24, 825-833 (2014)
doi:10.3233/bme-130874.
39 Wu, C. & Chang, J. A novel akermanite bioceramic: preparation and characteristics. Journal of
biomaterials applications 21, 119-129 (2006) doi:10.1177/0885328206057953.
40 Wu, C. & Chang, J. Degradation, bioactivity, and cytocompatibility of diopside, akermanite,
and bredigite ceramics. Journal of biomedical materials research. Part B, Applied biomaterials
83, 153-160 (2007) doi:10.1002/jbm.b.30779.
41 Sun, H., Wu, C., Dai, K., Chang, J. & Tang, T. Proliferation and osteoblastic differentiation of
human bone marrow-derived stromal cells on akermanite-bioactive ceramics. Biomaterials
27, 5651-5657 (2006) doi:10.1016/j.biomaterials.2006.07.027.
42 Liu, Q. et al. A comparative study of proliferation and osteogenic differentiation of
adipose-derived stem cells on akermanite and beta-TCP ceramics. Biomaterials 29, 4792-4799
(2008) doi:10.1016/j.biomaterials.2008.08.039.
43 Huang, Y. et al. In vitro and in vivo evaluation of akermanite bioceramics for bone
regeneration. Biomaterials 30, 5041-5048 (2009) doi:10.1016/j.biomaterials.2009.05.077.
44 Wu, C., Ramaswamy, Y. & Zreiqat, H. Porous diopside (CaMgSi(2)O(6)) scaffold: A promising
bioactive material for bone tissue engineering. Acta biomaterialia 6, 2237-2245 (2010)
doi:10.1016/j.actbio.2009.12.022.
45 Kumar, J. P. et al. Synthesis and characterization of diopside particles and their suitability
along with chitosan matrix for bone tissue engineering in vitro and in vivo. Journal of
 Biomaterials Science Page 28 of 32
View Article Online
DOI: 10.1039/C7BM00315C

biomedical nanotechnology 10, 970-981 (2014).

46 Gauthier, O., Bouler, J. M., Aguado, E., Pilet, P. & Daculsi, G. Macroporous biphasic calcium
phosphate ceramics: influence of macropore diameter and macroporosity percentage on
bone ingrowth. Biomaterials 19, 133-139 (1998).
47 Tadic, D. & Epple, M. A thorough physicochemical characterisation of 14 calcium
phosphate-based bone substitution materials in comparison to natural bone. Biomaterials 25,
Published on 23 June 2017. Downloaded by University of California - San Diego on 23/06/2017 12:41:35.

987-994 (2004).

Biomaterials Science Accepted Manuscript

48 Baino, F. & Vitale-Brovarone, C. Three-dimensional glass-derived scaffolds for bone tissue
engineering: current trends and forecasts for the future. Journal of biomedical materials
research. Part A 97, 514-535, doi:10.1002/jbm.a.33072 (2011).
49 Shao, H. et al. Bioactive glass-reinforced bioceramic ink writing scaffolds: sintering,
microstructure and mechanical behavior. Biofabrication 7, 035010,
doi:10.1088/1758-5090/7/3/035010 (2015).
50 Oonishi, H. et al. Clinical experience with ceramics in total hip replacement. Clinical
orthopaedics and related research, 77-84 (2000).
51 Lauria, I. et al. Inkjet printed periodical micropatterns made of inert alumina ceramics induce
contact guidance and stimulate osteogenic differentiation of mesenchymal stromal cells. Acta
biomaterialia 44, 85-96 (2016) doi:10.1016/j.actbio.2016.08.004.
52 Fielding, G. & Bose, S. SiO2 and ZnO dopants in three-dimensionally printed tricalcium
phosphate bone tissue engineering scaffolds enhance osteogenesis and angiogenesis in vivo.
Acta biomaterialia 9, 9137-9148 (2013) doi:10.1016/j.actbio.2013.07.009.
53 Tarafder, S. & Bose, S. Polycaprolactone-coated 3D printed tricalcium phosphate scaffolds for
bone tissue engineering: in vitro alendronate release behavior and local delivery effect on in
vivo osteogenesis. ACS applied materials & interfaces 6, 9955-9965 (2014)
doi:10.1021/am501048n.
54 Castilho, M. et al. Application of a 3D printed customized implant for canine cruciate ligament
treatment by tibial tuberosity advancement. Biofabrication 6, 025005,
doi:10.1088/1758-5082/6/2/025005 (2014).
55 Wang, J. et al. Phage nanofibers induce vascularized osteogenesis in 3D printed bone
scaffolds. Advanced materials (Deerfield Beach, Fla.) 26, 4961-4966 (2014)
doi:10.1002/adma.201400154.
56 Zhang, Y. et al. Mesoporous bioactive glass nanolayer-functionalized 3D-printed scaffolds for
accelerating osteogenesis and angiogenesis. Nanoscale 7, 19207-19221,
doi:10.1016/j.jmbbm.2015.09.012
10.1039/c5nr05421d (2015).
57 Adel-Khattab, D. et al. Development of a synthetic tissue engineered 3D printed
bioceramic-based bone graft with homogenously distributed osteoblasts and mineralizing
bone matrix in vitro. Journal of tissue engineering and regenerative medicine,
doi:10.1016/j.biomaterials.2016.10.005
10.1002/term.2362 (2016).
58 Ma, H. et al. 3D printing of biomaterials with mussel-inspired nanostructures for tumor
therapy and tissue regeneration. Biomaterials 111, 138-148,
doi:10.1016/j.jmbbm.2016.08.036
10.1016/j.biomaterials.2016.10.005 (2016).
 Page 29 of 32 Biomaterials Science
View Article Online
DOI: 10.1039/C7BM00315C

59 Castilho, M. et al. Computational design and fabrication of a novel bioresorbable cage for
tibial tuberosity advancement application. ACS applied materials & interfaces 65, 344-355,
doi:10.1021/acsami.6b14297
10.1016/j.jmbbm.2016.08.036 (2017).
60 Chang, C. H. et al. 3D Printing Bioceramic Porous Scaffolds with Good Mechanical Property
and Cell Affinity. PloS one 10, e0143713, doi:10.1371/journal.pone.0143713 (2015).
Published on 23 June 2017. Downloaded by University of California - San Diego on 23/06/2017 12:41:35.

61 Luo, Y. et al. Three-Dimensional Printing of Hollow-Struts-Packed Bioceramic Scaffolds for

Biomaterials Science Accepted Manuscript

Bone Regeneration. ACS applied materials & interfaces 7, 24377-24383,
doi:10.1021/acsami.5b08911 (2015).
62 Dadhich, P. et al. A Simple Approach for an Eggshell-Based 3D-Printed Osteoinductive
Multiphasic Calcium Phosphate Scaffold. ACS applied materials & interfaces 8, 11910-11924,
doi:10.1016/j.actbio.2016.08.039
10.1021/acsami.5b11981 (2016).
63 Meininger, S. et al. Strength reliability and in vitro degradation of three-dimensional powder
printed strontium-substituted magnesium phosphate scaffolds. Acta biomaterialia 31,
401-411, doi:10.1021/acsami.5b11981
10.1016/j.actbio.2015.11.050 (2016).
64 Yang, C. et al. 3D-Printed Bioactive Ca3SiO5 Bone Cement Scaffolds with Nano Surface
Structure for Bone Regeneration. doi:10.1021/acsami.6b14297 (2017).
65 Liu, A. et al. Three-dimensional printing akermanite porous scaffolds for load-bearing bone
defect repair: An investigation of osteogenic capability and mechanical evolution. Journal of
biomaterials applications 31, 650-660, doi:10.1002/term.2362 (2016).
 Biomaterials Science Page 30 of 32
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Fig. 1. Schematic drawing representing the 3D printing process. Figure from Fielding, G. & Bose, S52.
modified.

27x19mm (600 x 600 DPI)

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Fig. 2. (a) Photograph of 3D printed pure bioceramics (BC), DOPA-BC (2 mg/mL), DOPA-BC (4 mg/mL),
DOPA-BC (6 mg/mL) scaffolds, respectively; Optical images of pure BC (b) and 4 mg/mL DOPA-BC (c)
scaffolds on the top view; Scanning electron microscopy (SEM) images of pure BC (d) and 2 mg/mL DOPA-
BC (e), 4 mg/mL DOPA-BC (f), 6 mg/mL DOPA-BC (g) scaffolds, showing a uniform nanolayer composed of
polydopamine and amorphous Ca-P nanoparticles on DOPA-BC surface; Sectional SEM images (h) and
sectional linescan EDS spectrum of 4 mg/mL DOPA-BC (i). DOPA indicates dopamine and BC indicates
bioceramic. Figure from Ma et al58.

53x67mm (600 x 600 DPI)

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Fig. 3.The pore morphologies of CSi-BG scaffolds are Archimedean chords, honeycomb and parallelogram,
respectively. Figure from Shao et al49.

19x10mm (600 x 600 DPI)