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DOI: 10.1039/C9BM00664H
ARTICLE
Biopolymers for bone substitutes: A review
Biomaterials Science Accepted Manuscript

Anastasiia Kashirina a, Yongtao Yao b, Yanju Liu a, Jinsong Leng b†
Received 00th January 20xx, Human bones have unique structure and characteristics, and to replace a natural bone in case of a bone fracture or bone
Accepted 00th January 20xx
diseases is a very complicated problem. The main goal of this paper is to update on the recent researches about polymer
DOI: 10.1039/x0xx00000x materials for bone substitutes and bone repairing. Bone treatment methods, bone substitute materials and their advantages
and drawbacks, and manufacturing methods are reviewed. Biopolymers are the most promising materials in the field of
artificial bones, and using biopolymers with shape memory effect could improve integration of an artificial bone to the
human body by better mimicking the structure and properties of natural bones, decrease invasiveness of surgical procedures
by producing deployable implants. It is shown that applying of rapid prototyping technology for artificial bones allows to
Published on 25 July 2019. Downloaded on 7/26/2019 7:36:23 AM.
customize bone substitutes for a patient and to create artificial bones with complex structure.
Nowadays bone grafting is the most frequent used method of

1. Introduction bone fracture treatment.6,7 Four types of bone grafts exist:
1. Autologous (or autogenous) bone graft is the gold
1.1 The problem of bone fractures
standard of bone grafting. It means using bone taken from
Bones support human bodies during their whole lives. And since the same person who receives the graft. A bone graft can
ancient times people are breaking bones because of accidents be harvested from non-essential bones: the iliac crest,
resulting in serious injuries, extreme sport, traffic accidents, usually in dental and maxillo-facial surgery, from the
aging and bone diseases (low bone density, osteoporosis make mandibular symphysis (chin area), or anterior mandibular
bones weak and easier to break, osteogenesis imperfect makes ramus (the coronoid process). Autogenous bone is the
bones brittle, Paget's disease makes them weak, cancer, most commonly used because of less risk of the bone graft
infections, and other bone diseases caused by insufficient failure due to the graft derived from the individual's own
nutrition, genetics, or bone growth or rebuilding problems).1 body. Disadvantages of autologous bone grafts include the
Pediatric fractures are frequently to be treated conservatively, need for an additional incision, feeling pain after the
only 8% require internal fixation, for older category (≥16 years surgery for a long time and possible increased blood loss
of age) 56% require internal fixation.2 A simple thing such as during the surgery. Even using patient’s own bone cannot
falling can change older adults’ life. Thousands of older people guarantee 100 % of success.
do that every year. For older people, a bone fracture can be the 2. Allograft bone graft is a bone got from cadavers or an
start of serious problems, such as hospitalization, injury, or even individual who have donated his/her bone for treatment
disability.3 According to World Health Organization data, the of other people. In this method failure rate is high
population is quickly aging.4 The amount of people over 60 compared to patient’s own bone using, and to find a
years old is expected to be 2 billion in 2050 compared to 900 suitable bone is very difficult task.8,9
million in 2015 (increase from 12 % to 22 % of the total 3. Xenografts are bone substitutes removed from a donor
population). Thus, serious fractures and bone diseases are very other than human and grafted into a human body (bovine
important problem, especially among elderly people.5 A and porcine bone, natural coral.10 Xenografts are
fracture treatment for elderly and other people from high-risk commonly applied as a calcified matrix. Both allografts and
groups (car drivers, factory workers, sportsmen, etc.) is required. xenografts exclude donor site complications, but some
biological properties (osteogenic and osteoinductive) can
1.2 Bone fractures treatment methods be reduced.11 And a bovine xenograft may not be the most
Bones unlike many other tissue types can regenerate. In view of relevant for foot and ankle surgery.
this, bone grafting is possible for bone fracture treatment. 4. Artificial bone. Commonly studied artificial bone
biomaterials are: titanium alloys,12,13 zirconia,14 steel,15,16
bioceramics (including bioglasses)17,18,19 and polymer
a. Department of Astronautical Science and Mechanics, Harbin Institute of materials for tissue engineering.
Technology, PO Box 301, No. 92 West Dazhi Street, Harbin 150001, China Autogenous bone has optimal biological properties, but donor’s
b. National Key Laboratory of Science and Technology on Advanced Composites in
morbidity (pain, blood tumor, infection, fracture) and limited
Special Environments, Harbin Institute of Technology, No. 2 YiKuang Street,
Harbin 150080, China availability are challenging factors. On the contrary, allogeneic
† Corresponding author. lengjs@hit.edu.cn (J. Leng) (genetically different) and artificial grafts are expensive, may
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ARTICLE Journal Name
have an inflammatory response and transmit disease, 2. Bone substitute rough surface. The surface roughness is an
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producing can be difficult, osteogenic or osteoconductive important factor not only in the initial adhesion, but also
DOI: 10.1039/C9BM00664H
properties have limits.20,21 in the activity and differentiation of osteoblasts.32
Some research reported that several metal ions (from Ni-Ti, Co- 3. Biocompatibility (integration of a bone implant into
Cr-Mo-Ni-Fe, stainless steel, Ti alloys, pure Ti) are released into natural bone tissues or just a human body to intensify the
surrounding tissues because of a wide range of mechanisms tissue repairing process).
including corrosion. Metal ion release is often considered as a 4. Biodegradability (an adjustable rate of degradation over
cause of clinical failure or dermic allergic reaction.22-24 Metal time while bone tissue regeneration occurs).
materials have good mechanical properties, but in most cases 5. Mechanical properties (mechanical properties similar to

they do not interact with body cells and are too strong those of the natural bone are necessary for bone grafting
compared to natural bone what can lead to stress shielding and success. The scaffold must provide support during bone
bone loss and bone relaxation.25,26,27 Bioactive ceramics have ingrowth process until the new bone has enough
similar composition to natural bone and show excellent coherence to support itself).33
biocompatibility and bioactivity. However, their typical 6. Positive interaction between bone substitute material and
brittleness and low toughness limit their application in bone body cells is necessary for cell functions (adhesion,
repairing.28 proliferation, differentiation, and gene expression).34,35
In comparison, biopolymers (including natural and synthetic 7. Producing time can be very long, because a patient cannot
polymer based composites) due to good biocompatibility, wait for one or two weeks.
adjustable chemical composition and biodegradation, ability to So far, a material that can meet all requirements to bone
reorganize, are very promising as biomaterials for fabricating of substitutes does not exist. However with the development of
medical products and bone substitutes.29 modern technology, material properties are getting nearer and
The main goal of this paper is to present the recent researches nearer to a natural bone. This review shows recent progress in
in polymer materials for bone implants and bone repairing. material science for bone substitutes, and emphasizes on
creating scaffolds with the natural bone-like structure and
1.3 Requirements to bone substitute materials mechanical properties.
In terms of such a complex biological and sensitive system as a
human body, the requirements to the materials for tissue
2. Review of polymer bone materials in 2015-
engineering are extremely challenging,30 which are detailed as
follows: 2019 years
1. Porosity (bone-like porous structures provide nutrients 2.1 Natural biopolymers
movement, blood circulation, passing of osteogenic cells Collagen materials
and bioactive components that in conjunction promote
Saska et al fabricated nanocomposites based on bacterial
mineralization and blood vessel formation throughout the
cellulose (BC), collagen (COL), apatite (Ap, in situ precipitation
graft). The structure of bones is shown in Figure 1.31
was used to incorporate Ap into BC-COL matrix), and osteogenic
Figure 1 Structural organization of bones from macroscopic to molecular level. Reproduced with permission from reference [31], copyright 2018,
Springer Nature, distributed under the Creative Commons CC BY license.
2 | J. Name., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 20xx

Science
Journal Name ARTICLE
growth peptide (OGP) or its C-terminal pentapeptide [OGP(10- Chitosan/nanohydroxyapatite/zoledronic acid scaffolds View Article were
Online
14)] were incorporated into the (BC-COL)-Ap composite by prepared using in situ precipitation method. 42 That scaffolds
DOI: 10.1039/C9BM00664H
absorption for bone regeneration purpose.36 All composites revealed excellent tumor inhibition properties, antibacterial
showed no cytotoxicity, genotoxicity and mutagenicity effects; activity, and well osteoinductivity. Although the mechanical
they stimulated cell growth at earlier time than the pure properties were not measured in this study,42 in any cases
bacterial cellulose sample. The tensile strength of (BC-COL)-Ap porous CS/nHA/Zol is a promising biomaterial in bone tumor
before (57.7±1.8 MPa) and after gamma radiation sterilization therapy and in bone defect repair.
(45.0±4.0 MPa) were reported. Despite decreased tensile Wu et al described one more problem, what limited the use of
strength of the (BC-COL)-Ap composites compared to the BC, chitosan materials – degradation time.43 It was emphasized that

the (BC-COL)-Ap-OGP or OGP(10-14) may be considered as a degradation time of many biodegradable natural polymers such
potential material for bone repairing due to their good as collagen, hyaluronic acid and chitosan, is still not long enough
biocompatibility. for clinician-suggested period of 4-6 months. In this study
One of the key mechanisms of bone substitutes is providing a chitosan nanofiber membranes were obtained by
“template” for new bone ingrowth. Ren et al investigated electrospinning, and then the surface of nanofibers was
mineralized collagen/glycosaminoglycan (MC-GAG) scaffolds. modified by butyrylation. The modification prolonged the
Animal (rabbit) experiments showed that MC-GAG implant had degradation time of the obtained chitosan membranes, so the
better ability to support bone repairing of cranial defects than modification of material surface may be useful for creating a
non-mineralized collagen/glycosamineglycan scaffolds.37 chitosan based bone repair material.
Although MC-GAG scaffolds have increased healing ability even Elkholy et al developed β-chitosan/nano-hydroxyapatite
without addition of ex vivo cultures with bone marrow-derived composites.44 The optimum mechanical properties were
mesenchymal stem cells (BMSCs) or exogenous growth factor, obtained on the composites with 30 wt % of β-chitosan (the
compressive strength was 13.05 MPa). The animal experiments
the authors consider that the scaffold strength is still less than
revealed enhanced bone regeneration and blood vessels
native rabbit bone, and stiffness is 50~80% of natural bone.
incorporation. The total weight loss during experiments in citric
Zhang et al fabricated crosslinked sponge-like
acid and liquid ionomer glass cement solution at room
collagen/hydroxyapatite composites by liophilization followed
temperature was reached for 8 weeks, so that composite
by dehydrothermal process.38 The composites showed similar
material is very promising as a solid-shaped implant for
with the cony bone spectra, and animal experiments on rabbits relatively healthy patients without bone diseases and for non-
showed induced bone repair effect at defects with sizes critical size defects.
exceeding the critical size for self-recovering. The mechanical Silk materials
tests revealed the tensile strength in range of about 0.1~0.38 One of the most exploring natural polymers for bone
MPa, Young modulus in range of 2900 ~ 8700 MPa, the sample regeneration is silk.45 It is a natural protein fiber and is produced
with ratio collagen:HA 5:5 was too soft. The decomposition time by insect larvae to form cocoons (mulberry silkworm Bombyx
in a tris buffered saline solution at 37 °C was in range from 180 mori larvae are the most known to obtain silk cocoons).46 Spider
to 5640 min. Thus, it can be suggested that MC-GAG and silk is light and has outstanding mechanical properties, but it’s
COL:HA composites may be used in non-bearing applications to using has restricted due to its limited availability.45 As Meinel et
induce bone repair process. al47 said using silk materials may trigger antigenic reaction.45
However creating composite materials with silk and applying
Chitosan composites cutting-edge technologies can help to overcome that drawback.
Chitosan (CS) is a linear polysaccharide commonly produced by The silkworm cocoon consists mainly of two proteins: silk sericin
partial deacetylation of chitin.39 CS is in widespread used in (SS) and silk fibroin (SF). Pure SS is not applied due to low
bone tissue engineering due to its osteoconductivity to enhance mechanical properties, but mitogenic ability of SS makes it
bone formation, good biodegradability, antibacterial activity, beneficial for bone regeneration (to stimulate the formation of
and excellent biocompatibility.40 The composites of chitosan bone-like hydroxyapatite). Thus, it has to be considered to use
and hydroxyapatite is intensively tested, and the compressive SS-based composites.48 In addition to composites with chitosan
strength of such a composite could reach 119.86 MPa, however and hydroxyapatite,39 silk sericin can be used for biomimetic
the aquatic environment can significantly decrease mechanical mineralization and regenerative medicine in a form of
properties of a chitosan/hydroxyapatite composite material.41 microcapsules. The mineralized sericin microcapsules with
Chen et al prepared chitosan-silk sericin/hydrohyapatite (CS- hydroxyapatite shell on the surface showed good
SS/HA) composites using in situ precipitation.39 The mechanical cytocompatibility, and may be used in drug delivery.49
properties of the composites with organic component less than In case of silk fibroin materials, silk fibroin films and ultrathin
50% were not sufficient, the best combination of elastic films could approach the range of mechanical strength a natural
modulus and compressive strength was shown by the bone has: Young’s modulus could reach the amount of 6~8 GPa
composites with 60 and 70 % of organic part due to brittleness and ultimate strength of 100 MPa for nonporous films, however
of HA. The CS-SS/HA composites could promote osteoblast silk films still are brittle and their breaking strain is in the range
attachment and proliferation during experiments with culturing of 0.5~5.5 %.50 The researchers attempt to overcome the lack of
of osteoblast cells on the samples. mechanical strength by creating composite materials.51
This journal is © The Royal Society of Chemistry 20xx J. Name., 2013, 00, 1-3 | 3

Bhattacharjee et al reinforced nonmulberry tasar silk obtained in silk fibroin composites.58 The addition of β-TCPView particles to
Article Online
from Antheraea mylitta by poly-vinyl alcohol.52 The electrospun the silk scaffolds increased compressive strength of the
DOI: 10.1039/C9BM00664H
nanobibers were 177~193 nm in diameter. The elongation at composite materials not significantly (under 0.6 MPa for
break was in the range of 14.5~23.6 % (what is higher than in pristine SF scaffolds obtained by freeze-drying, 0.71~0.72 MPa
the work of Koh et al50), the ultimate tensile strength of for SF/β-TCP hybrid composites), and the addition of β-TCP did
4.87~12.55 MPa, but that amount was still lower than the not influence on fibroblast growth in vitro, however SF/β-TCP
elongation at break for the silk composite prepared using samples showed faster bone regeneration in rat calvarial
similar electrospinning process (recombinant silk fibroin defects in comparison to the pure SF samples.
produced with HFA-hydrate as a spinning solvent).53 The highest mechanical properties within silk materials were

In the study of Behera et al silk fibroin (obtained from tropical found by Melke et al51 by reviewing the articles of Perez-
nonmulberry tasar silkworm Antheraea mylitta) scaffolds were Rigueiro et al.59,60 The silk samples obtained by forced reeling of
reinforced by fibroin-hydroxyapatite nanoparticles prepared by Bombyx mori silkworms showed high mechanical strength
chemical precipitation method.54 The porous scaffolds (pore (Table 1), however forced silking is a time-consuming process
size 41~95 µm) had only 18.89 MPa of Young’s modulus, and it is not suitable for high-volume production.
whereas the scaffolds supported cell proliferation over time, Due to low mechanical strength of silk materials, but great
but without significant difference between the studied scaffolds biocompatibility, some attempts to use silk fibroin as a
and the commercial hydroxyapatite reinforced fibroins in terms supporting material were done. Gentamicin-loaded silk fibroins
of cellular growth and proliferation. (SFGM) were used to decrease risks of postoperative infections
In the other article of Bhattacharjee et al to approach and improve the biological functionality of porous Co-Cr-Mo
requirements for bone substitute materials, poly(ε- scaffolds.61 The Co-Cr-Mo metal scaffold was fabricated by
caprolactone) was blended with silk fibroins (obtained from selective laser melting, and then electrophoretic deposition
Antheraea mylitta) and nanofibrous mats were fabricated using technique was applied to coat SFGM onto the Co-Cr-Mo alloy
electrospinning method.55 Ultimate strength and elongation at sample. With the average pore size 625.0±54.1 µm and
break increased compared to the parameters of electrospun compressive properties ~75 GPa for compressive strength and
PCL (4.94~5.21 MPa and 19.32~29.1 % for SF/PCL compared to ~2.6 GPa for elastic modulus inspite that characteristics (~70
2.98 MPa and 14.1 % for PCL respectively). GPa and ~2.4 GPa respectively) for non-coated Co-Cr-Mo, the
Sahu et al prepared nonmulberry Antheraea mylitta (Am, SFGM is suggested as promising coating for biomaterials.
silkworms did not feed on mulberry leaves) silk fibroin scaffolds Gelatin scaffolds
and Bombyx mori (Bm) silk fibroins.56 Am fibroin scaffolds Bioactive nanoparticles (BP)/gelatin scaffolds were used to
showed good bone regeneration in rat cranial defects, repair femoral defects in rabbits.62 The bioactive nanoparticles
promoted proliferation of osteoprogenitor cells compared to (produced by surface modification on colloidal silica particles by
Bm. Both scaffolds were porous (60 % for Bm, 66,66 % for Am Ca(OH)2)63 proved to be promising additives for bone repair
with average pore size 73 and 76 µm respectively), but their materials. The obtained scaffolds accelerated bone repairing
degradation rate had differences. Am scaffolds had no signs of (the bone defect was most filled with new bone 8 weeks after
degradation up to 12 months, whereas in contrast Bm samples surgery compared to 12 weeks postoperative for rabbits
gradually degraded within 3 months. Also, Bm samples did not without implants). The mechanical properties of the porous
support bone formation well. As the authors mentioned, too composite materials (Figure 2) after 8 weeks after surgery were
fast degradation can lead to mechanical graft failure and higher, but close to the ones of cancellous bone.
insufficient bone regeneration, so Am scaffolds were suggested
as a better candidate for bone tissue repair material, mainly for
non-bearing applications (cranial defects).
Ding et al prepared demineralized bone matrix (DBM)
powder/silk fibroin (SF) porous scaffolds using solvent casting-
salt leaching method.57 The results of culturing of rBMSCs on
the samples showed that the composite with 20 % of DBM
powder provided a better cell proliferation and promoted cell
attachment and growth. Using SF as a carrier for DBM powder
helped to overcome some drawbacks of DBM: difficulties in Figure 2 The bioactive nanoparticles/gelatin scaffolds: A - 3D model, B - the freeze-
handling, the migration from graft sites, and the lack of stability dried sample. Reprinted by permission from [62], ©Springer Nature, 2017.
after surgery. However, the results of mechanical properties

showed that the most promising composite 20% DBM/SF had To mimic the chemical composition of natural bones, Gupta et
only 1.12±0.16 MPa of compressive strength, 2.41±0.51 MPa of al used gelatin, carboxymethyl chitin (CMC), and hydroxyapatite
compressive modulus, thus, there is an opportunity to use this to prepare a gel. -COO- groups in CMC interact with positive ions
material only for non-bearing repair. in natural/simulated body fluid and with Ca2+ from HA, what is
β-TCP (β-tricalcium phosphate) is well-known reinforcing beneficial for cell proliferation and osteogenesis.64 Such a
material for biocomposites due to its great osteoconductivity material could be applied as a filler for small bone non-load
and biocompatibility. In the study of Park et al β-TCP was used

Science
bearing defects, or as an addition to a strength scaffold for of the natural-origin polymers still consists in their possible
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enhancing osteoconductivity. batch variation, so to prevent these issues recombinant
DOI: protein
10.1039/C9BM00664H
Alginate composites technology has to be used to control monodispersity and
Alginic acid, also called alginate or algin, is an anionic precisely define polymer properties.80
polysaccharide wide-spread in cell walls of brown seaweed.65,66 A lot of newly developed polymers for medical application are
Venkatesan et al claim that alginate materials can be considered based on combinations of natural and synthetic polymers, in
as a materials for bone tissue repairing due to its good scaffold- order to combine great biocompatibility of natural polymers
forming property, biocompatibility, source abundance, and and mechanical strength of synthetic ones. A residue of
biodegradability.67 Alginate materials are widely fabricating in initiators, other compounds or impurities in synthetic polymers

form of microcarriers68,69, foams70 and gels68, 71,72. Popescu et al can interrupt cell growth. However the most of synthetic
mixed alginate with pullulan and Si-Ca-P-Cu-O bioglass to polymers have better mechanical properties and thermal
enhance cell viability and antibacterial effect and to create a stability compared to natural ones, also synthetic polymers can
biocompatible hydrogel for support of bone regeneration.73 be easier processed into a wide range of shapes whereas some
In the study of Coathup et al the attempt to enhance bone forms are not easy to obtain for natural polymers because of
formation of granular HA was done, however the results destroying of structure during high-temperature
showed the opposite: the presence of alginate gel impeded processing.81,82,83
formation of new bone and bone-HA scaffold contact.68 Polyethylene materials
For improving of mechanical strength and degradation rate In the work of Ai et al a composite material based on ultra-high-
poly(L-lactide) was added to algin and crosslinking was molecular-weight polyethylene (UHMWPE) was investigated.
processed.74 Shaheen et al fabricated VEGF was loaded on the surface of UHMWPE by silk fibroin (SF)
alginate/chitosan/hydroxyapatite/nanocrystalline cellulose coating to achieve a controlled release delivery.84 The modified
scaffolds using freeze-drying method and dicationic crosslinking UHMWPE exhibited a better proliferation performance than the
by CaCl2.75 The obtained scaffolds had porosity over 90 %, pore raw UHMWPE: enhanced angiogenesis and osseointegration
size 103~230 µm, and increased compressive yield strength between the modified UHMWPE and the host bone. Due to the
(0.48~0.54 MPa compared to 0.35 MPa for chitosan/alginate chain scission of macromolecules during modification process
samples and 0.38 MPa for chitosan/alginate/hydroxyapatite the tensile strength of UHMWPE-SF/VEGF decreased slightly
ones). Gelatin-alginate hydrogel coating onto beta-tricalcium (from 1.676±0.041 GPa for the pristine UHMWPE to
phosphate scaffolds also had maximum compressive stress less 1.488±0.062 GPa). Although it is too high for using as a bone
than 0.6 MPa.72 substitute material (too strong bone substitute material can
In the study of Zheng et al silk fibroin/calcium silicate/sodium lead to relaxation of surrounded bone tissues and then lead to
alginate scaffolds with porosity ≥ 75.3 % the maximum bone disruption), this composite has a great potential for the
compressive strength (strain = 10 %) was < 5 kPa.76 The application to anterior cruciate ligament reconstruction, and
mechanical behavior of the composite materials above could be the addition of less strong component may lead to creating a
controlled by varying inorganic filler amount, however if the composite with suitable mechanical characteristics.
amount of filler is over the particular level, the compressive and Polyether ether ketone (PEEK)
tensile strength would decrease significantly. During last few years PEEK-based materials have been
Leppiniemi et al investigated alginate/nanocellulose investigated for oral and cranio-maxillofacial surgery. Han et al85
hydrogels.77 Abouzeid et al could achieve better mechanical showed that 3D-printed carbon fiber reinforced PEEK
properties in alginate based materials.78 They fabricated composites have great mechanical properties (tensile modulus
alginate/TEMPO-oxidized cellulose nanofibril hydrogel scaffolds more than 7 GPa and compressive modulus ~3.5 GPa), which
using 3D printing method and than immersed them in simulated are similar to those of cortical bone, and sufficient
body fluid for biomimetic mineralization. These hydrogel biocompatibility.
scaffolds had compressive strength in range 419~455 MPa at PEEK is bioinert, and this is a limiting factor for medical
strain 50 % and compressive modulus 1078~1233 MPa. One can application. Xu et al reported about the surface modification
suggest that 3D printed alginate/ TEMPO-oxidized cellulose method to improve biological behavior of PEEK after
nanofibril hydrogel may be very promising material for bone implantation by dexamethasone plus minocycline-loaded
substitute application. liposomes (with polydopamine coating before immersing in
2.2 Synthetic biopolymers liposome solution).86 In vitro (hMSCs, bacterial cultures seeding)
As one can see natural polymers are usually biocompatible. Also and in vivo (C57BL/6 mice) experiments showed sufficient
some addition components could enhance bioactivity of natural osteoinductive ability and cytocompatibility. To improve
polymer based composites: for example, in the study of Tong et biological behavior of PEEK other surface modification methods
al cell growth and proliferation of BMSCs seeded onto silk were used: tropoelastin-functionalized plasma immersion ion
fibroin/chitosan scaffolds were enhanced by adding of vascular implantation (the treatment provided suitable environment for
endothelial growth factor (VEGF).79 However the mechanical human osteoblast-like osteosarcoma cells spreading),87
properties of the most of natural polymer based composites are reinforcing by addition of tantalum nanoparticles (besides
unsufficient for load-bearing bone parts. Another one drawback increase in mechanical properties for the composites containing
3~5% Ta nanoparticles, Ta-OH groups can co-operate with Ca2+

and phosphate ions for stimulating apatite nucleation),88 The elastic modulus of PEEK-based materials is inView
theArticle
range of
Online
sulfonation and further incorporation with copper natural bone, thus, PEEK is expected to gain more popularity in
DOI: 10.1039/C9BM00664H
nanoparticles using magnetron sputtering (for improving future for bone tissue repairing.
antibacterial and immunomodulatory ability of PEEK and Polylactic acid (PLA) based composites
creating a porous surface, Figure 3)89, fast sulfonation Polylactic acid (PLA) is a biodegradable polymer and one of the
treatment at ambient temperature (for enhancing most studied biopolymers used last years, and is applied in food,
hydrophilicity and osteoconductivity),90 neutral atom beam packaging, medical, pharmaceutical industries. PLA and its co-
technology,91 decoration by strontium and adiponectin,92 polymer composites showed great characteristics over other
coating by titanium using plasma spraying (the Ti-PEEK samples materials in tissue engineering.80, 98 There exist two stereoforms

showed better bone ingrowth ability compared to the pure of lactic acid: D,D-lactide and L,L-lactide. Furthermore, lactide
PEEK),93 loading by mouse beta-defensin-14,94 etc. Although can be formed by combining one D- and one L-lactide molecule
creating a porous surface on the PEEK implant does not resulting in D,L-lactide.99
decrease the mechanical properties of a scaffold significantly, Kao et al improved cell adhesion and promoted ECM protein
Deng et al concerned about poor binding between PEEK and a secretion in 3D printed PLA scaffolds by coating with
surface material, so they preferred to equip a PEEK scaffold with polydopamine via direct immersion.100 Guduric et al evaluated
a delivery system containing simvastatin, PLLA and biological behavior of human BMSCs and endothelial progenitor
tobramycin.95 The scaffolds exhibited excellent antibacterial cells in the 2D- and 3D-structure of PLA membranes assembled
behavior and osteogenic ability for MC3T3-E1. layer-by-layer.101 The PLA membranes were prepared by 3D
printing and had 100 µm of thickness, 200 µm of pore diameter.
The microscope observation showed that external structure

and struts organization had pores 165-375 µm. The results for
cellularized PLA membranes revealed better cell proliferation
and differentiation. The layer-by-layer approach may be
suitable for non-bearing bone tissues to enhance homogenous
cell proliferation into the scaffold.
The PLA/10 wt % graphene oxide composite was reported as a
material which can be applied as lightweight electromagnetic
interference shielding material.102 The tensile properties of the
composite are higher than in the previous article for TPU/PLA
matrix103: the tensile strength is 40.2 MPa and the tensile
modulus is 2454 MPa for 3D printed samples (fused deposition
modeling FDM method was used). PLA is widely known as a
biodegradable material, and Chen et al reported about good
biocompatibility of composites with graphene oxide addition,
thus the present composite103 have possibility to be applied in
tissue engineering with magnetic field as external stimuli, or as
Figure 3 3D atomic microscope images of PEEK surface after sulfonation (SPEEK)
and different Cu content (0.67 at%, 1.08 at% and 1.40 at% for Cu1, Cu2 and Cu3 the authors suggested – for bioelectronics and biosensors.
respectively). Reprinted from [83] Biomaterials, Vol 208, Liu et al, A surface-
engineered polyetheretherketone biomaterial implant with direct and PLLA/collagen/hydroxyapatite composites were investigated by
immunoregulatory antibacterial activity against methicillin-resistant
Staphylococcus aureus, Pages 8-20, Copyright (2019), with permission from Zhou et al.104 The composites containing collagen and HA had
Elsevier.
better cell viability, conductivity to cell growth, and significantly
Mei et al prepared PEEK/Ta2O5 composites with further sand higher mineralization of MC3T3-E1 cells in comparison with the
blasting treatment (to obtain a rough surface).96 The PLLA and PLLA/collagen composites, however lower tensile
compressive strength of composites containing Ta2O5 was strength (2.75 MPa instead of 3.95 MPa for PLLA and 3.41 MPa
higher compared to the pure PEEK, and it was shown that sand for PLLA/HA) and faster degradation rate (34.5 % weight loss up
blasting treatment did not decrease the compressive strength, to 80 days compared to less than 5 % for PLLA and 16.8 % for
however rough surface was beneficial for biological behavior of PLLA/HA). Containing collagen and HA composites may be used
the scaffolds (protein absorption – bovine albumin - on the for non-critical size defects in non-bearing places.
composite with 50 vol.% Ta2O5 without sand blasting 0.75 mg/g, According to Seitz et al, the most of commonly used
and 0.94 mg/g for the composite with the same Ta2O5 content, biopolymers are biodegradable and their degradation time is no
but with further sand blasting treatment). Ma and Guo used more than 1 year.105 Only some biodegradable biopolymers
popular HA as a filler for PEEK.97 The tensile strength of the such as polyglycolic acid (PGA), PLA, L-PLA, DL-PLA and
composites decreased significantly from 85 MPa for pure PEEK polycaprolactone (PCL) are required more than 12 months to
to 45 MPa for the PEEK/40 wt% HA, in contrast the elastic fully degradation from a body. For serious bone injuries
modulus increased by 468 % and reached ~10.5 GPa. especially in case of bone diseases and older age of a patient
Incorporation of HA enhanced bioactivity and osteogenesis of the long period of time is needed to fully treatment of a bone
PEEK compared to UHMWPE and pristine PEEK. fracture. Only the L-PLA tensile strength can reach 150 MPa to
make L-PLA applicable as a bone substitute material,105 and the

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data from Van de Velde and Kiekens (also, in Table 1) show the proliferation, the adding of GO acceleratedView stem cells
Article Online
same information.106 differentiation and increased increased osteocalcin production.
DOI: 10.1039/C9BM00664H
Besides application as a scaffolds, PLA based materials may be Thus, GO-doped PLGA composites may be promising as
used as a microcarriers for tissues cell-based therapy duo to biodegradable materials for bone regeneration in non-bearing
controllable degradation rate and biocompatibility of PLA. This application due to weak mechanical properties (tensile stress in
field is still to be investigated further.99 range from 2.8±0.3 MPa for 15 % PLGA to 5.7±0.7 MPa for 18 %
Poly(lactic-co-glycolic acid) (PLGA) PLGA).
PLGA is a copolymer of glycolic acid and lactic acid.98 Since PLGA Polycaprolactone
contains both PLA and PGA, its degradation rate depends on the Marei et al investigated PLA- and PCL-based nanofibrous

ratio of monomers, and can vary from months to years. The samples (fabricated by electrospinning technology) to enhance
degradation rate also depends on molecular weight, shape, interaction between stem cells and scaffolds.112 To evaluate the
structure, and porosity.80 feasibility of applying these scaffolds for bone tissue repairing,
The pure PDLGA samples obtained by compression molding the adhesion and proliferation of two types of stem cells
showed high value of elastic modulus about 1.2 GPa and (BMSCs and adipose tissue stem cells, ASCs) were investigated.
suddenly dropped after reaching yield point during tensile BMSCs and ASCs attached and retained their cytoskeleton to
strength, so PDLGA scaffolds are brittle.107 When PDLGA was both the PCL and PLA fibers, but in case of ASCs cultured on the
mixed with L-lactide-co-ε-caprolactone, the samples showed PLA nanofibers low cell viability was observed. The authors
more plastic behavior, however elastic modulus and yield consider further optimization by varying electrospinning
strength values were significantly lower 7.1~650 MPa of elastic parameters and using of additional treatment methods.
modulus and 5.6~28 MPa of yield strength for composites with In the work of Le et al porous HA/PCL composites were obtained
20~80 % of L-lactide-co-ε-caprolactone component. by microsphere based selective laser sintering.113 The scaffolds
In the study of Wu et al the PLGA/graphene nanoplates have controlled microstructure, porosity, excellent
composites were investigated.108 The results of seeding rat histocompatibility and enhanced proliferation and
BMSCs on the films revealed accelerated differentiation, differentiation of MSCs in vitro. This work proved that the
enhanced adhesion and better guiding bone regeneration micropores created by microspheres about 100 µm provide
properties. appropriate surface for cell adhesion, spread and cell
Namini et al used PLGA to create composites with HA using both ingrowth.113 PCL/HA composites promoted the angiogenesis in
electrospinning and freeze-drying methods.109 The seeding of comparison to the pure PCL scaffolds, but in was shown that
human endometrial stem cell (hEnSC)-derived osteoblast-like compressive modulus decreased from 3.1 MPa for the PCL
cells onto the PLGA/HA samples revealed that the results for the scaffold to 1.6 MPa for the composite contained 20%
freeze-dried composites were better than for the electrospun hydroxyapatite (HA). And the compressive strength is much
ones. The freeze-dried samples were more porous, and cell lower than the one of cortical or cancellous bone.
viability was higher compared to the samples made by There was an attempt to reinforce PCL by addition of silica
electrospinning. The good adhesion and proliferation of the nanoparticles and to create a cytocompatible composite
cells make the PLGA/HA composites made by freeze-drying membrane as a physical barrier preventing fibroblasts from
method a candidate for applying in bone regeneration. moving to the wound and preserving a space for new bone
Park et al proposed a composite material contains poly(D,L- tissues.114 The PCL/Si-NPs membranes were cytocompatible
lactic-co-glycolic acid) PDLGA and magnesium hydroxide and had improved biofunctional properties. Addition of 25-50
(MH).110 The porous scaffolds PDLGA/MH were obtained by wt% of silica nanoparticles to PCL (100 wt%) matrix increased
freeze-drying method using ice particles as porogen. The the tensile strength and tensile modulus of composites (2.9 and
diameter of MH particles was 80~200 nm, the scaffold 9.5 MPa respectively for pure electrospun PCL, 5.8 and 13.5
micropores were in range of 30~70 µm. The composite scaffolds MPa for 50:100 Si-NP:PCL ratio composites), further addition
showed enhanced chondrogenesis markers, reduced (up to 75 wt %) is not beneficial for mechanical properties of a
calcification and the release of inflammatory cytokines in PCL/Si-NPs composite materials.
comparison to the PLGA scaffolds. The containing MH scaffolds Hendrikson et al showed that the more is PCL molecular weight,
supported healing of osteochondral defects in rats. The authors the better are mechanical properties of a scaffold.115 The
suggested potential application of PDLGA/MH composites for stiffness measured during unconfined compression test was
cartilage and other soft tissue regeneration. 204.2 MPa for high PCL (Mw=65000) and 147.5 MPa for low PCL
Luo et al fabricated PLGA nanofiber scaffold doped by (Mw=14000).
grapheme oxide (GO) using electrospinning method.111 The The composite of poly(L-lactide-co-ε-caprolactone) prepared by
porous structure and fibers diameter were similar to the compressive molding method showed small elastic modulus
structure of natural extracellular matrices. Doping by GO only of 3.2 MPa, however the strain at rupture was 937 % and
facilitates cell attachment and proliferation, but decreases the stress at rupture was 19 MPa.107
mechanical parameters such as the breaking strength and Goncalves et al proposed to use carbon nanotubes (CNT) as a
Young’s modulus. The authors allow that GO cannot bear the responding component to external stimuli for accelerating the
part force, and it leads to the breaking strength decrease. healing process.116 It was expected that electrical stimulation
Nanofibrous mats111 showed excellent hemocompatibility, cell after material implantation would induce osteointegration.

Between PCL/HA/CNT composites with 0~10 wt% of CNT the In this subchapter there collected other less popular materials
View Article Online
samples with 0.75 wt% CNT showed the best mechanical supposed to be applied in bone tissue repair.
DOI: 10.1039/C9BM00664H
behavior, but these samples were not electrically conductive. Poly(3-hydroxybutyrate-co-4-hydroxybutyrate) co-polymer
The best combination of electrical conductivity and mechanical (P34HB)/poly(ethylene glycol) (PEG) nanofiber membranes
properties was shown by the samples with 2 wt% of CNT. The were prepared by electrospinning technology by Wang et al.117
compressive yield strength was about 4 MPa, elastic modulus The mechanical and biological properties increased compared
44 MPa, what is in the range for trabecular bone. However, to pure P34HB (weak mechanical properties of P34HB also were
CNTs could not be used as a reinforcing agent for composites: introduced by Yang and Cai)118, however this composite is not
CNTs may enhance electrical conductivity, but mechanical suitable for load-bearing application.

behavior would get worse. The mechanical properties of Wu et al investigated pearl powder/poly-amino acid (P/PAA)
PCL/HA/2~10 wt% CNT were worse than ones of PCL/HA composites for load-bearing bone repair.119
samples.
Other materials for bone tissue engineering
Table 1 Mechanical properties of natural bone and some polymer materials for bone substitutes (not filled cells mean no data)
Compressive Elastic Strain at

Compressive Tensile strength, Flexural Ultimate
Material modulus, *MPa, modulus, Porosity, % breaking, Reference
strength, MPa MPa strength, MPa strain, %
**GPa *MPa, **GPa %
100~150a, 10~20a, a -120, b -

Cortical bone 50~151 135~193 5~10
100~230b 16~20c ** 121, c - 122
0.1~5a, a -120, b -
Cancellous bone 2~12a,b 1~5 10~20 50~90
4.6~15b ** 122
Bacterial cellulose +
0.27±0.03** 57.7±1.8 No 21.6±2.6 36
collagen + apatite
12~24
Silk (forced reeling) 12,4~17,9** 360~700 No 59,60
3D printed alginate/
TEMPO-oxidized 419~455 (at Yes (3D
1078~1233* 78
cellulose nanofibril strain 50 %) scaffolds)
hydrogel
PEEK (polyether ether
ketone) based 2.79~3.51** 137.11~138.63 3.79~7.37** 95.21~101.41 No 85
materials
PLA (PLA, L-PLA, DL-

0.35~4.14** 15,5~150 No 106
PLA)
Carbon fiber reinforced

256 210 No 123
PLA (3D printing)
PLGA (18 % solution for

electrospinning)/graph 76.3~182.7* 2.8~6.4 No 66.9~133.6 111
eme oxide
PCL/HA (selective laser
1.6~1.8* 0.7~1.3 65~70 113
sintering)
PCL/HA (3d printing) 15.43±1.28 80.16±3.18 * 26±8 124
Pearl powder/poly-
133~161 34~42 36~50 No 119
amino acid composites
Polyamide 12/ZrO2/β- 929.88~1286.

30.63~36.60 49.87~61.75 No 125
TCP 80*
Polyamide/HA 14.3~28.1 10.6~24.3 40~70 126

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DOI: 10.1039/C9BM00664H
ARTICLE
Table 2 Methods of polymer scaffold fabrication

Method Advantages Disadvantages References
Solvent casting/particle - porous structures can be produced; - porosity leads to significant loss of mechanical 127-133
leaching - simplicity, no requirement of any properties;
special equipment - possible difficulty with leaching out particles;
- a residue of organic solvents may have toxic
effect
Thermally induced phase - ability to control pore size and - it is not easy to achieve pore sizes more than 134-138
separation structure 200 µm;
- it is difficult to adjust micro- and
macrostructure of a sample
Melt molding (injection - structures of varying shapes and sizes - nonporous layers on the surface, it is difficult 139-146
molding, compression can be produced to leach out particles and porogen compounds;
molding) - does not require organic solvents - requires high operating temperatures
Electrospinning - the ease to control over the physical - small pore size; 138, 147-151
morphology - small thickness of nanofibers
Hydrogels - no requirement of any special - low mechanical properties, not for load- 152-156
equipment; bearing applications;
- does not require solvent; - gel shrinkage because of the loss of water
- porosity is easily controlled
Gas foaming - does not require organic solvents - it is difficult to control pore size and 133, 157-160
interconnectivity;
- low mechanical properties, not for load-
bearing applications
Emulsion freeze drying - ability to control pore sizes and - emulsions may be unstable, require additional 138, 161, 162
interconnectivity; surfactants;
- requires less solvent; - low mechanical properties, not for load-
- no need of time-consumming bearing applications
processes (drying or porogen leaching)
Rapid prototyping (3D - ability to create low-volume or one-of- - requirements to a filament; 138, 152, 163,164,165
printing, selective laser a-kind parts based on patient-specific - inability to manufacture multicomponent
sintering, stereolithography needs; structures;
(SL), fused deposition - geometrical freedom (complex shaped - surface roughness cannot be controlled
modeling (FDM), PolyJet) functional implants)
The samples with 0~50 wt% of pearl powder exhibited 100~161 Hydroxyapatite/poly xylitol sebacic adibate/vitamin K
MPa of compressive strength, 27~42 MPa of tensile strength, composites were investigated by Dai et al to apply in bone
and mineralization ability was enhanced due to interaction repair.167 The weight loss after 28 days in PBS at 37°C was about
between Ca2+ from pearl and PO43-from SBF, what is a trigger 28 %, what is critical for repairing of defects in load-bearing
for apatite nuclei formation. The degradation experiments bones. This type of material is supposed to stimulate bone
showed only 1.46~3.64 % of weight loss after 28 days in PBS, formation in non-critical defects.
thus, P/PAA composites may be used for repair of critical bone Last years polyamide composites were discussed as a potential
defects. bone substitute material. Nano-hydroxyapatite/polyamide 66
Mills et al doped into poly(methyl methacrylate) (PMMA) (especially doped by peptide D-RADA16-RGD),168 ZrO2/β-
several types of antibiotics (gentamicin sulfate, tobramycin, and TCP/polyamide 12,125 porous polyamide/HA composites
nitrofurantoin).166 The result showed that antibiotic-doped prepared by selective laser sintering126 exhibited sufficient
PMMA could prevent osteomyelitis because of an ability to bioactivity and cytocompatibility, however mechanical behavior
inhibit bacterial activity by providing antibiotics release. of composites still needs to be improved (see Table 1).

Zhang et al prepared porous scaffolds from polyetherimide View Article Online

(PEI).169 Although the compressive modulus of the porous DOI: 10.1039/C9BM00664H
2.3 Manufacturing methods for bone substitute materials.
scaffolds was lower than the pure PEI (78.95 and 1376.61 MPa, Materials for rapid prototyping technology
respectively), the modulus of the porous PEI was in the range of
natural cancellous bone. For the purposes of this chapter, the popular technologies for
Poly(acrylonitrile butadiene styrene) (ABS)165 and its composite making polymer scaffolds are introduced in the Table 2.174
with silver nanoparticles170 showed great mechanical properties As one can see, all fabrication methods have their limiting
(elastic modulus more than 1.6 GPa, tensile strength more than factors. Nowadays polymer based composites fabricated by
44 MPa) and sufficient cytotoxity and Hs680.Tr (human tracheal rapid prototyping (RP) methods are gaining in popularity.163
Using 3D printers increases the speed of production and lowers

fibroblast) and Saos-2 (human osteosarcoma) cell viability.
Several poly(glycerol-sebacate) (PGS) based materials were one-of-a-kind product cost,175 because there is no need to
reported recently. PGS-co-PEG polymer with PEG content adjust manufacturing equipment to create a new implant, it
20~40 % had weak tensile stress (168~801 KPa), Young’s only needs to adjust STL-file on a computer program. Also, only
modulus (183~668 KPa), and very fast degradation (20~50 % RP method allows to create scaffolds with any kind of pore size
weight loss after 21 days in Tris-HCl solution), that can lead to and configuration. The difficulty of scaffold configuration is
rapid loss of mechanical support in a wound side.171 Addition of defined only by application requirements and the drawing 3D-
β-TCP into PGS also didn’t increase mechanical properties models skill of an operator.
significantly (0.21 MPa of tensile strength and 1.95 MPa of There exists no technology without drawbacks, and RP
Young’s modulus).172 Biocompatible PGS/PCL blend was technology has several of them (Table 3).
reported by Salehi et al and was proposed for cornea tissue As one can see, RP methods (especially, FDM technology) have
engineering.173 One can suggest that PGS-based biopolymers great promise for bone substitute application because of RP’s
are more suitable for soft tissue repair than for bone repairing. ability to mimic complex structure of a natural bone. Han et al
To sum up the 2.1-2.2 chapters, some significant data were used a 3D printer for carbon fiber reinforced PEEK (CFR-PEEK)
collected to the Table 1. As one can see, most of the natural and composites, and the authors claim that RP technology is more
synthetic biopolymers cannot reach the range of mechanical appropriate method for matching CFR-PEEK composites to
strength of natural bones. mimic human bones and avoid stress-shielding.85
Addition of reinforcing component and supplementary Murphy et al investigated PCL/13-93B3 (bioactive borate glass)
treatment may lead to enhancing of mechanical and biological composites.176 The scaffolds were fabricated by 3D-printing
performance of a material. However, it is important to find a method and pores of 100 to 300 µm were obtained, what is
balance between degradation rate, porosity, and mechanical beneficial for bone growth.177 The scaffolds showed a
properties. controllable release of 13-93B3 glass over a period of 2 weeks
In further chapters other groups of synthetic polymers will be into minimum essential medium alpha modified (α-MEM):
discussed, but shortly before it manufacturing methods of about 70 % of the 13-93B3 borate glass reacted in 14 days. It
polymer materials should be reviewed. makes that scaffold material beneficial in drug delivery
application.
Table 3 Advantages and disadvantages of RP technology
Technology Advantages Disadvantages

3D-printing Complex scaffolds The liquid binder can lead to toxicity of a scaffold;
Loose powder;
Requires cleaning after printing;
The nozzle size limits the scaffold resolution 179
FDM Large variation of Problems occurring during printing process (a failed print or a print
Comfort for a patient applicable polymers looks not like in a STL-file180,181);
(individually shaped Requirements to a filament (diameter, ductility)
SL implants); The limited types of photopolymerizable materials are available179;
Speed178; Newly printed parts have to be washed, cured, and dried, because
Pore size control; they are sticky and messy182;
No need in solvents (excl. SL The SL equipment is more expensive than the FDM one; process
method), no toxic reagents; costs are quite expensive183
SLS Complex geometries Minimization in use of The laser beam diameter is a limiting factor in the scaffold
excessive polymer resolution179;
powder The powdery surface induces difficulties in terms of sterilization and
cell culture184
PolyJet Layer resolution, printing The limited types of photopolymerizable materials are available
precision165

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DOI: 10.1039/C9BM00664H
ARTICLE
But quick degradation rate of a scaffold material is not proliferation, no cytotoxic effects were observed. The Young’s
preferable for bone substitute materials for elderly and people modulus was specified 3.2±0.4 GPa for PLA bulk sample created

with bone diseases due to their bone renewing speed is low, by FDM, and that is the lowest for cortical bone (3.3~20 GPa)
and the quick biodegradation of borate bioglass can lead to and within the range for trabecular bone (0.76~10 GPa), as it
decreased mechanical properties of the scaffold, so the scaffold was reported by Mow and Huiskes.189 The authors claimed that
after 2 weeks cannot support a weight of an adult patient. PLA is an attractive material for reconstructive surgery and very
In the work of Wu et al185 polyhydroxyalkanoate/wood flour appropriate for maxillofacial applications. The FDM method did
(PHA/WF) and maleic anhydride (MA) grafted (PHA-g-MA)/WF not alter biocompatibility of PLA, and one of the advantages of
composites were investigated. PHA-g-MA/WF samples showed FDM is the possibility to make individually shaped scaffolds,
better mechanical behavior, water resistance, antibacterial what could decrease psychological strain of a patient.
activity, and higher quality of 3D printed strips than ones of the Polyurethanes
PHA/WF samples. The tensile strength at failure could reach ≈
Parisi et al190, Xu et al35 and Chung et al174 claim that although

26 MPa for PHA-g-MA/40 wt % WF, and the antibacterial polyurethanes (PU) require complicated and expensive
properties were improved with the addition of 20 wt % WF. manufacturing process, the application of PU in biomedical field
The same authors185 also investigated PHA-g-MA/TPF (a is dramatically growing due to their toughness, biocompatibility
coupling agent-treated palm fibre) composites.186 The and hemocompatibility. The authors also suggest the promising
composites are nontoxic and have good water resistance. application of PU as a material for long-term implants and as a
Although the tensile strength at break could reach ≈ 23 MPa for scaffold for different types of tissues.191
the composite with 20 wt % of TPF, the rapid weight loss and In the study of Guo et al the reactive polyurethane (PUR)
high degradation rate were observed. The biodegradation rate scaffolds were fabricated using t-FDM (new template-fused
increased with addition of PF or TPF, the composite with 40 wt % deposition modeling) process.192 The pore size of PUR scaffolds
of TPF degraded quickly over the first 30 days. The application was adjusted by changing the diameter of sacrifice fibers, which
of both materials as bone substitutes is limited by their were removed by dissolving after pouring of PUR into the
degradation speed and too high water resistance, however the templates and curing. The results of measuring of substrate
PHA based composites can be potentionally used as modulus (the method of Oliver and Pharr193 was used) showed
environment friendly biomaterials. that the modulus of t-FDM manufactured PUR scaffolds
In the article of Filgueira et al biocomposites containing PLA and (10~900 MPa) covers the one for trabecular bone (93~365 MPa)
wood pulp fibers were investigated.187 The thermomechanical and cortical bone (871~11500 MPa).194
pulp (TMP) was modified by laccase-assisted grafting of octyl Tsai et al made a complete adult tracheal construct by using
gallate (OG) and lauryl gallate (LG) to get strong biomaterials FDM technique.195 As a material the authors chose the mixture
with low water absorption rate. The strength of the most of TPU: a polyester (polycaprolactone) polyol based and a
composites was lower compared to the pure PLA, which could polyether polyol based. The mechanical properties of the
be caused by a porous structure, insufficient homogeneity, poor trachea sample were sufficient, and the authors suggested that
fibers-matrix interaction and fiber dispersion in the PLA matrix 3D printing technology is a very promising technology for tissue
(that can lead to fiber agglomeration and initiate the failure and engineering, especially for TPU materials due to low price and
crack propagation). Only one filament sample with 90 % PLA easiness of processing.
and 10 % OG-modified TMP showed the tensile strength about
58 MPa, and the samples with 10 and 20 % TMP (OG-modified)
showed higher values of maximum force in comparison with the
PLA filament. The tensile strength of 3D-printed dog bones was
lower than the one made of PLA prepared by traditional
methods. Although the PLA/TMP composites have some
difficulties with mechanical properties, the authors suggest that
the uses of OG-treated wood pulp fibers for antibacterial
devices could be extended.
The biological effect of FDM printed PLA on osteoblasts in vitro
Figure 4 The TPU/PLA/GO scaffold after FDM printing. Reprinted with permission
was investigated by Wurm et al.188 The results of seeding human from Chen, Q., et al., 3D Printing Biocompatible Polyurethane/Poly(lactic
acid)/Graphene Oxide Nanocomposites: Anisotropic Properties. ACS Applied
fetal osteoblasts (hFOB 1.19) revealed high viability, Materials & Interfaces, 2017. 9(4): p. 4015-4023 [103]. Copyright (2017) American
Chemical Society [103].
homogenous covering of sample surface and good cell

Chen et al fabricated TPU/PLA/GO composites (Figure 4).103 invasiveness. Deployable implants are fullyViewporous to
Article Online
Graphene oxide significantly improved mechanical properties of allow new bone ingrowth (Figure 5). 206,10.1039/C9BM00664H
DOI: 207
TPU/PLA (7:3) matrix: the compressive modulus reached about

145 MPa for the composite with 5 wt% of GO, and the tensile
modulus reached 80 MPa for the composite with 0.5 wt% of GO.
The effect of printing orientation to mechanical properties also
was shown (the differences can be explained by formation of
large/small voids between layers). The results of seeding by
NIH3T3 mouse embryonic fibroblast cells revealed good cell

viability, and small amount of graphene oxide was preferable
for cell proliferation. Although the mechanical properties of the Figure 5 Deployable bone implant: A – retracted implant; B – implanted inside the
body; C – deployed inside the body. Reproduced from [206] with permission from
composites were increased by addition of graphene oxide, they the Royal Society of Chemistry, copyright 2018.
are not enough for applying as bone substitutes, and the

fabricated specimens did not meet the requirements to Of late, many studies based on biomaterials having shape
controlled porosity of a material, however TPU/PLA/GO memory properties were published.
composites can be used as a material for bioengineering due to Tian et al proposed the new method of manufacturing tough
their great biocompatibility. carbon fiber reinforced PLA composites.123 It contains
Polyurethane themselves have limited bio-, cyto- and additional manufacturing stages such as recycling and
hemocompatibility, so it is needed to enhance their remanufacturing to enhance the bonding and permeation
performance for inner-body applications using addition of other between fiber and matrix, and achieve excellent interfacial
components and various fabrication technics.196 Taking this into properties. The mechanical properties of that composite
account, Chung et al offered several ways to provide material are outstanding, and it is very promising for the
antibacterial behavior to PUs, including modifying of PU surface, applications where a degradable “green” material is needed,
using antimicrobial agents or a copolymer with specific but for using this material as a bone substitute the possibility of
properties, etc.174 Some examples of enhancing making this material porous needs to be considered.
cytocompatibility and antibacterial activity of PU scaffolds were In the work of Arnebold and Hartwig an epoxy based SMP
shown in chapter 2.3. composite was presented.208 A poly(ω-pentadecalactone)
(PPDL) and poly(ɛ-caprolactone) (PCL) were polymerized. The
2.4 Shape memory polymers for bone implants epoxy/PPDL sample exhibited fast shape fixity, sufficient shape
memory cycle stability, enhanced strength and toughness (due
The fatal drawback of biopolymers as a material for bone
to heterogeneous morphology as a result of segregation and
implants is their mechanical properties. Soft polymers cannot
crystallization) in comparison with the epoxy/PCL samples.
be used as a material for load-bearing bone scaffold. Hence, it
Recently, some authors reported about biocompatible
is necessary to create a polymer with high mechanical
hydrogels with shape memory effect. Gupta et al fabricated
properties for bone substitutes. Some attempts for creating a
strong polymer composite material have been done recently,
including very promising experiments in the field of polymers
with shape memory effect (SMP).197,198
SMP is a so called smart material that has the ability to regain
its permanent shape from a deformed state under an external
stimulus, such as heat, electric/magnetic field, light, solvent
exposure, water immersion etc. In contrast to traditional
polymer materials and alloys with shape memory effect, SMPs
have significant benefits:
1. In comparison to Ni-Ti shape memory alloy, stainless steel
and Co-Cr-based alloys that is frequently applied for bio-
implants, there is no metal ion release from implants for
SMP.199, 200 The release of Ni, Cr etc. ions can cause allergic
reactions and cytotoxicity,201, 202 and associated with a risk
for diseases including cancer203;
2. Several external stimuli types: heat, light, magnetic field,
solvent exposure etc. what can trigger relaxation;
3. Self-healing effect204 under load that can prolong service
life of an implant205;
4. The most important benefit is the possibility to create Figure 6 Silk fibroin 3D-printed scaffolds: a) cube shape 3D scaffold; b) meniscus
implant before freeze-drying; c) cube shape scaffold after freeze-drying; d)
deploying structures that can minimize surgical meniscus implant after freeze-drying treatment. Reproduced from [210] with
permission from Wiley, copyright 2017.

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anion-controlled shape-memory hydrogel using Nvjp-1 and appropriate mechanical strength (tensile stress inArticle
View range of
Online
(histidine-rich jaw protein taken from marine sandworms 37.3~48.3 MPa), this PCL-AT copolymer DOI:degraded faster than it
10.1039/C9BM00664H
Nereis virens).209 It was found that exchanging anions could needs to be suitable for bone recover: the samples lost 10~50 %
modulate the interaction of Zn with the Nvjp-1 protein, increase of their weight within 36 hours. The PCL-AT copolymer is more
stiffness and adjust viscoelastic properties. Silk fibroin bioinks suitable for soft tissue engineering.
also demonstrated memory-shape feature.210 Kawaguchi et al used chitosan fiber (biomass nanofibers, BiNFi-
The enzymatically cross-linked silk hydrogels had 59.1 % s) to improve antibacterial properties of polyether-based
porosity, and the compressive stress at strain 50 % was about thermo-plastic polyurethane (TPU).216 The composite with 5 wt%
0.25 MPa, this value is very similar with the amount for human BiNFi-s had elastic modulus increased by 40 % compared with

meniscus (Figure 6). Cation-triggered the plain TPU. The composites with 2 and 5 wt% of BiNFi-s
polyacrylamide/carbometyl cellulose (PAM/CMC) hydrogels exhibited shape recovery with clinically significant changes in
were synthesized by Li et al.211 After immersing in FeCl3 the temperature, the yield strength had not significant changes. X-
PAM/CMC-Fe3+ hydrogel exhibited shape fixity ratio of 95 %, Ray diffraction results showed that TPU samples were
tensile strength at break 1.23 MPa. Chitosan/grapheme oxide semicrystalline, and TPU/BiNFi-s composites had amorphous
(CS/GO) hydrogels showed pH-driven shape memory effect.212 structure. There is a risk of weakening hydrogen bonds between
The CS/5 wt% GO had the best mechanical properties amongst N-H and C=O groups because of water absorbing in thermo-
prepared hydrogels, that are similar to natural costal cartilage. responsive SMP (especially, with amorphous structure), what
It was shown that mechanical behavior of hydrogels can be leads to a decrease of glass transition temperature.
conrolled by adjusting the crosslinking parameters, however Tan et al improved the hydrophilicity and biological properties
the mechanical strength of hydrogels is still not sufficient for (antibacterial activity, cytocompability, and preventing
load-bearing application such as bone substitutes. infection ability) of shape memory PU by addition of chitosan,
In view of the work of Ban et al,213 it could be expected that gelatin and further soaking in AgNO3.217 The SMPU-based
polyurethane based materials could be one of the most composite had porous structure, tensile stress of about 3.5 MPa
promising materials in bone tissue engineering. In this work (at 30 % strain), satisfactory biological behavior. The authors
polyethylene glycol-based shape memory polyurethane (SMPU) suggested this material for smart wound treatment, not for
was incorporated by 4-octyldecyloxybenzoic acid (OOBA) and a bone material due to poor mechanical properties for bone
liquid-crystalline SMPU (LC-SMPU) was obtained. The LC-SMPU substitute application, however this study showed that
composites had triple-shape memory properties, self-healing biological behavior of PU-based materials can be controlled by
ability, also the storage modulus was above 200 MPa at indoor addition of antibacterial agent.
temperature and above 100 MPa at inner-body temperature Shape memory polymers were widely investigated over the last
(37 °C). There was no information about biocompatibility of LC- years. There are some problems still, such as degradation rate,
SMPU composites, however it has to be considered that mechanical strength, cytocompatibility and antibacterial
polyurethane based materials could achieve high mechanical response of a material. However, SMPs belong to the unique
properties through addition of potential crystallization centers type of smart programmable materials, and self-healing effect
in polyurethane. and the possibility to decrease surgical invasiveness by creating
The 3D-printed porous scaffolds made from an aromatic shape deployable structures should be taken into account. SMPs are
memory polyurethane DiAPLEX MM3520 showed both very promising materials for biological application, including
cytocompatibility and good recovery of the permanent applying as a bone substitute material with controllable
shape.214 properties.
One of the most comprehensive studies during last 4 years is a
work of Deng et al about an electroactive biodegradable shape
memory copolymer.215 The copolymer of PCL and amino capped 3. Conclusions
aniline trimer combined together by In the field of bone substitute materials recent studies focus on
hexamethylenediisocianate using a facile synthesis showed bioactive and/or biodegradable materials, including bioactive
great elasticity (elongation at break 646~1331 %), adjustable ceramics, polymers and biodegradable metals.
recovery temperature about human inner-body temperature, Both synthetic and natural polymer materials and their
decent shape memory properties (fixity ratio 61.1~77.8 %, organic/organic and organic/non-organic composites have
recovery ratio 100 %), significantly improved the biological demonstrated being promising for bone tissue engineering.218
behavior of C2C12 cells in comparison to the neat PCL. PCL with Biopolymers proved their biocompatibility during experiments
molecular weight of 3000 was used for mechanical with mice, rabbits, dogs or even people: PLA219, PLGA220,
measurements due to its recovery temperature is most suitable poly(methyl methacrylate)221, chitosan222,
to the human body. The mechanical and cell seeding results poly(hydroxybutyrate), PCL, proteins (silk, collagen)223,
showed, that decreasing aniline trimer leads to: better poly(ethylene glycol) diacrylate (PEGDA) hydrogel224, etc. The
proliferation, increased degradation rate, increasing Young’s brief review of research directions in biopolymers during last
modulus (due to various crystallization ability), increasing of few years was presented.
elongation at break (due to mobility and slip between Biopolymers exhibit a relatively high toughness and plasticity,
macromolecular chain). Despite the great shape memory effect and their behavior may be controlled by molecular design and

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Biopolymers for bone substitutes: A review

Biomaterials Science Accepted Manuscript

Nowadays bone grafting is the most frequent used method of

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Biomaterials Science Accepted Manuscript

was used to incorporate Ap into BC-COL matrix), and osteogenic

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after surgery. However, the results of mechanical properties

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The microscope observation showed that external structure

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Biomaterials Science Accepted Manuscript

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Biomaterials Science Accepted Manuscript

Compressive Elastic Strain at

100~150a, 10~20a, a -120, b -

PLA (PLA, L-PLA, DL-

Carbon fiber reinforced

PLGA (18 % solution for

PCL/HA (3d printing) 15.43±1.28 80.16±3.18 * 26±8 124

Polyamide 12/ZrO2/β- 929.88~1286.

Polyamide/HA 14.3~28.1 10.6~24.3 40~70 126

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Table 2 Methods of polymer scaffold fabrication

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Zhang et al prepared porous scaffolds from polyetherimide View Article Online

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Table 3 Advantages and disadvantages of RP technology

Technology Advantages Disadvantages

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Biomaterials Science Accepted Manuscript

Parisi et al190, Xu et al35 and Chung et al174 claim that although

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TPU/PLA (7:3) matrix: the compressive modulus reached about

Biomaterials Science Accepted Manuscript

are not enough for applying as bone substitutes, and the

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Biomaterials Science Accepted Manuscript

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manufacturing technologies. In spite of good combination of 6. Bone grafting, WikiPedia, https://en.wikipedia.org/wiki/Bone_grafting,