http://www.revmaterialeplastice.ro MATERIALE PLASTICE ♦55♦No. 4 ♦2018 555Additive Manufacturing and Synthetic Polymers for Bone Reconstruction in the… [614787]

http://www.revmaterialeplastice.ro MATERIALE PLASTICE ♦55♦No. 4 ♦2018 555Additive Manufacturing and Synthetic Polymers for Bone
Reconstruction in the Maxillofacial Region
CORINA MARILENA CRISTACHE1, ALEXANDRA RALUCA GROSU2, GHEORGHE CRISTACHE3, ANDREEA CRISTIANA DIDILESCU4,
EUGENIA EFTIMIE TOTU2*
1University of Medicine and Pharmacy Carol Davila, Faculty of Midwifery and Medical Assisting (FMAM), Department of Dental
Techniques, 8 Eroilor Sanitari Blvd., 050474, Bucharest, Romania
2University Politehnica of Bucharest,Faculty of Applied Chemistry and Material Science, 1-5 Polizu Str, 11061 Bucharest, Romania
3Concordia Dent Clinic, 7D-7E Vitan-Barzesti Str., 042121, Bucharest, Romania
4University of Medicine and Pharmacy Carol Davila, Faculty of Dental Medicine, Department of Embryology, 37 Dionisie Lupu,
020021, Bucharest, Romania
The aim of the present paper is to give an up-to date on computer aided design and manufacturing (CAD/
CAM) additive techniques and synthetic polymers for bone reconstruction in the maxillofacial region. Additive
manufacturing represents a promising field for future research in bone replacement/regeneration. However,
standard guidelines for mimicking clinical environment with the different bone characteristics are strongly
required. The rapid prototyping techniques, particularly, bioprinting allows the construct of 3D living functional
tissues able to replace, in the near future, large defects caused by tumor excision, trauma, clefts or infections,
limiting the autogenous bone graft requirement.
Keywords: synthetic polymers, bone graft, maxillofacial region, biomolecules, additive manufacturing
Reconstruction of maxillofacial bone defects has always
been a challenging task for the scientists and surgeons
over the years, with the main goal to restore facial form,masticatory and phonetic functions, full esthetic and
improve quality of life [1]. When bone defect is relatively
small, regeneration by intrinsic mechanism fromsurrounding tissues may occur [2,3]. Bone is known to be
the second most commonly transplanted tissue after blood
[4].
Natural bone is a dynamic organ with outstanding
regenerative properties, its homeostasis requiring viablecells (osteoblasts, osteoclasts, and osteocytes), adequate
vascularity, stability, as well as presence of growth factors
and a matrix for growth [5].
Currently, autologous bone graft from intraoral
(tuberosity, chin, mandibular ramus) or extraoral donor
sites (iliac crest, tibia, calvaria, and many others) isconsidered as the
gold standard among all bone grafts
[4,6,7]. Nevertheless, autogenous grafting has several
limitations related to the bone volume requested (e.g. forcraniofacial defects reconstruction) and the harvesting
process.
Synthetic bone substitutes [8], mostly made of
hydroxyapatite (HA), Ca
10(PO4)6(OH)2 or β-tricalcium
phosphate ( β-TCP , Ca3(PO4)2 with rhombohedral structure)
[3], are an osteoconductive alternative to both autologousand allogenic graft options, with wide availability,
comparatively low cost and absence of risks such as donor
site morbidity and viral transmission [9], but usually lackingof osteogenic or osteoinductive activity [10–12].
Recently, with the development of tissue engineering
(TE) as previously defined ‘
an interdisciplinary field of
research that applies the principles of engineering and the
life sciences towards the development of biological
substitutes that restore, maintain, or improve tissue
function’ [13], a new era of bone substitute materials raised.
In contrast to classic biomaterials approach, it is based on
the understanding of tissue formation and regeneration,
*email: eugenia_totu@yahoo.comand aims to induce new functional tissues, rather than just
to implant biocompatible spare parts [14].
To date, two main types of bone scaffolding
manufacturing technologies are described: the first one is
usually referred to as conventional technology, including:solvent casting, solvent/particulate leaching [15], freeze-
drying, thermally induced phase separation (TIPS), gas
foaming/supercritical fluid processing, electrospinning,
powder-forming process, or sol-gel technique [16] and the
second type of technologies is referred to as RapidPrototyping (RP), which involves computer-aided design
(CAD) and manufacturing (CAM).
The conventional technology has several drawbacks,
mainly concerning the lack of reproducibility of pore
structure (size, geometry, spatial distribution) and the
persistence of solvent and porogens residues leading tohost tissue inflammatory response.
The CAD/CAM technology, extendedly used nowadays
in dental practice [17,18], is envisaged as an opportunityto overcome the challenges in biomimetic bone substitutes
fabrication for the maxillofacial region.
The natural bone matrix is composed of biological
ceramics (70% in weight), the inorganic part formed mainly
by hydroxyapatite and of biological polymers (30% in
weight), the organic matter, which is primarily collagentype I and ground substance [16]. For bone substitute,
several naturally derived biopolymers have been used, such
as collagen, demineralized ectodermal-degeneratedproteins (i.e. gelatine), and chitosan with good results due
to excellent biocompatibility, biodegradability and cell-
binding properties but with major drawbacks mainlyconsisting in immunogenicity, rapid degradation, and poor
mechanical properties [19]. To overcome this drawbacks,
attention has been paid to biocompatible andbiodegradable synthetic polymers with a considerable
number of advantages such as controllable degradation
rate, predictable and reproducible mechanical properties,sterilization ability, and ease of fabrication with tailorable
shapes and sizes, as required for the bone defect need to
be replaced [20].

http://www.revmaterialeplastice.ro MATERIALE PLASTICE ♦55♦No. 4 ♦2018 556The aim of the present paper was to give an up-to date
on CAD/CAM additive techniques and synthetic polymer
materials for ideal bone reconstruction in the maxillofacialregion.
Experimental part
An extensive review of the recent literature focusing on
the mechanisms of bone repair, mechanical characteristics
of maxillofacial bone, characteristics of an ideal bonesubstitute, bone graft design, additive manufacturing
technologies and synthetic polymers have been performed.
The following databases: Pubmed, Summon database -ProQuest, Embase, Cochrane have been assessed for
articles in English language, from 2000 to date. A manual
search in Dental Materials, Journal of Dentistry, Journal ofCranio-Maxillofacial Surgery, Revista de Chimie, Journal of
Materials, Revista de Materiale Plastice and Acta
Biomaterialia, has been also performed.
Results and discussions
Bone repair: Requirements for an ideal bone substitute
Bone repair has been classified into three distinct
phases: inflammatory, proliferative, and remodeling [21].
The result of the inflammatory phase is the primitive callusformation followed by its organization during the
proliferative phase. The resulted immature woven bone is
then converted into lamellar bone by replacement of themineralized callus with mature mineralized bone and
remodeling of the area of bone, back to its original shape
and size [5] (fig. 1).
A bone engineering construct relies on a combination of
living cells, biologically active molecules and a structural
scaffold in order to promote the repair and regeneration oftissues [22].
The scaffold component plays an important role, being
expected to support cell colonization, migration, growth
and differentiation, so that it guides the development of
the required tissue and, in the meantime, provides sufficientinitial mechanical strength and stiffness to substitute for
the mechanical function of the diseased or damaged bone
to be replaced [22]. It acts as a temporary matrix for cellproliferation and extracellular matrix deposition, with
consequent bone ingrowths until the new bony tissue is
totally restored/regenerated [14,23,24].
Bone scaffolds are typically made of porous degradable
materials providing the mechanical support during repair
and regeneration of damaged or diseased bone and servingas a reservoir of progenitor cells, water, nutrients, cytokines,
and growth factors [25].
The following properties for bone substitutes are
required, depending on the etiology of bone loss, as well as
volume, structure, size and localization of the structure to
be replaced:Biocompatibility , described as the ability to support
normal cellular activity including molecular signaling
systems without any local or systematic toxic effects tothe host tissue [26], is an essential requirement of any
bone scaffold. Scaffolds are also used to deliver
biomolecules facilitating new bone formation.
Osteoconductivity is the process of osteogenic cells
migration to the surface of the scaffold into the fibrin cloth,
established right after the material implantation [27].Microscopically, scaffolds should have similar structure to
cancellous bone [28]. An ideal bone scaffold must facilitate
bone cells to adhere, proliferate and form extracellularmatrix (ECM) on its surface and pores.
Osteoinductivity is
the process of simulating the osteogenic differentiation
pathway [29] upon recruiting stem and osteoprogenitorcells to a bone healing site.
Bioresorbability is the ability of an ideal scaffold to
degrade with time in vivo , preferably at a controlled
resorption rate, creating space for the new bone tissue
ingrowths [26]. The degradation behavior of the scaffolds
should vary based on site specific characteristics. Ideally,by the time the injury site is totally regenerated, the scaffold
should be totally degraded [13,20,30].
Angiogenesis in bone scaffolds: In vivo conditions,
supply of oxygen and nutrients is essential for the survival
of growing cells and tissues within scaffolds [31]. The
inflammatory wound healing response inducesspontaneous vascularization after scaffold implantation;
however, it takes weeks to form a complex network of
blood vessels. Osteoconductive or osteoinductive bonescaffolds do not induce vascularization. Moreover, improper
and insufficient vascularization leads to oxygen and
nutrient deficiency, which may result in non-uniform celldifferentiation and cell death [32]. Specific biomolecules,
such as vascular endothelial growth factor (VEGF) can be
used to induce a complex network of blood vessels
throughout a scaffold [33–36].
The mechanical properties of the implanted graft should
ideally match, in vivo , those of living surrounding bone, so
that an early mobilization/functionalization of the injured
site can be made possible [24,37,38].
There are two types of bone structures, classified
according to their porosity, structure and metabolic activity:
cortical bone , which is dense solid material (>3 mm),
organized osteons (10-500 µm), lamellae (3-20 µm) and
collagen mineral composite (60-600 nm) [39,40] and
cancellous bone, which is highly porous, consisting of solid
material (>3 mm), trabeculae (75-200 µm), lamellae (1-
20 µm) and collagen-mineral composite (60-600 nm)
forming an interconnected network of trabeculae, usuallyfilled with marrow [40,41]. Mechanical properties of bone
vary widely from cancellous to cortical bone. Modulus of
elasticity (Young’s modulus), described as the ratio
Fig.. 1. Bone repair phases [3,5,21]

http://www.revmaterialeplastice.ro MATERIALE PLASTICE ♦55♦No. 4 ♦2018 557between the stress applied and the resulting deformation
in the material [42] of cortical bone is between 15 and 20
GPa, while that of cancellous bone is between 0.1 and 2GPa. Compressive strength varies between 100 and 200
MPa for cortical bone, and between 2 and 20 MPa for
cancellous bone [30].
Architecture: Scaffolds must possess a fully
interconnected geometry involving both micro- and macro-
porosities [43], with large surface, allowing cells migrationand neo-vascularization of the construct from the
surrounding tissue [44].
For bone tissue engineering purposes, most of the
researchers agreed with pore size within the 200–900 µm
range [45–47]. Holy and co-workers [48] believed that bone
reconstruction will only be achieved by having a 3Dtemporary matrix with a large macro-porous inter-
connected structure, with pore size ranging from 1200–
2000 µm. This later approach has evident advantages dueto its high surface to volume ratios that will facilitate cell,
tissue and blood vessels in-growth, but being detrimental
in mechanical resistance. Murphy and co-workers [49]
found pore size in the range of 200 to 350 µm to be optimal
for bone tissue proliferation, allowing successful diffusion
of essential nutrients and oxygen for cell survival andremoval of metabolic waste resulting from the activity of
the cells that had meanwhile grown into the scaffold.
Karageorgiou and Kaplan [50] agreed with pore sizesgreater than 300 µm being required for adequate vascular
ingrowth. However, if the pores employed are too small,
pore occlusion by the cells will occur. According to Di Luca
and coworkers [51], heterogeneous distribution of pore
size enhances osteogenic potential. Nevertheless, it should
always be a balance between mechanical needs and poredimension of the particular tissue that is going to be
replaced [25].
Scaffold structure should mimic the complex bone
architecture needed to be replaced, therefore, a non-
homogeneous design requires to be reproduced [52].Materials used as scaffolds for bone tissue regeneration
need to promote the cells’ adhesion [53], involved in
stimulating signals that regulate cell differentiation, cellcycle, cell migration, and cell survival [54]. The affinity of
cells to the implanted substrate is an important aspect to
be considered in biomaterial design and development.
By including mesenchymal stem cells (MSCs) ,
biomolecules, or adding functional nanoparticles, the
characteristics of the bone scaffold could significantly be
improved.
Cells : MSCs, first isolated in bone marrow [55] but also
in blood, adipose tissue, trabecular bone, muscle anddermis [56] are multipotent cells, easy to isolate, relatively
abundant and able to differentiate along chondrogenic,
osteogenic, myogenic, and other mesenchymal pathwaysunder appropriate inductions [22-24].
Nowadays, it is generally accepted that MSCs exhibit
tissue specific functional biodiversity, which is mediatedby a direct
cell-to-cell communication associated with
the activity of adhesion molecules, cytokines, growth
factors and cell signaling pathways.
Biomolecules: Molecular control over bone regeneration
follows very closely the developmental osteogenesis [57]
and fracture healing. Biomolecules with potentialtherapeutic activities in promoting bone regeneration are
proteins / growth factors with biological action and temporal
expression during the healing cascade. Molecularpromoters for bone regeneration are divided in three main
categories [58]: the transforming growth factor beta (TGF-β) superfamily, pro-inflammatory cytokines, and
angiogenic factors.
The TGF-β superfamily consists of a large number of
growth and differentiation factors, the most important
members, in terms of bone regeneration, are likely the bone
morphogenetic proteins (BMPs), osteoinductive bythemselves (especially BMP-2,-6,-7, and -9) [59] making
them attractive therapeutically for tissue engineering
products. TGF- β, release by the platelets after initial blood
clot formation, plays a role in the production of extracellular
proteins for callus formation [60], also initiating the
production of BMPs in osteoprogenitor cells while inhibitingosteoclast activation [61].
In the initiation of the repair phase of bone regeneration,
macrophages secrete pro-inflammatory cytokines:interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis
factor alpha (TNF- α), with maxim expression in the first
24 h of bone healing [61,62].
In the early stages of bone healing, platelets entrapped
within the local hematoma release Platelet-derived growth
factor (PDGF), and up-regulates VEGF, responsible ofgenerating new blood vessels in the tissue. Despite of their
important role in bone healing and new bone formation,
angiogenic factors alone are not osteoinductive [62].
Many
natural hormones (Melatonin), biodegradable
polymers (Hyaluronic acid) or other bio-factors including
β-glycerol phosphate, dexamethasone, alendronate,
polydopamine, have been used [63] to facilitate bone
regeneration in particular cases.
Melatonin (N-acetyl-5-methoxytryptamine) -figure 2, a
natural hormone secreted mainly by the pineal gland during
the night, is an important mediator in bone formation and
mineralization by promoting osteoblast differentiation andactivity [64] through MEK/ERK1/2, runt-related transcription
factor 2 (RUNX-2), osteocalcin [65], BMP-2 [66], BMP-4
[64], and Wnt [64] signal transduction pathways and by
regulating the balance of bone remodeling through
osteoclast activity suppression via increase inosteoprotegerin (OPG) and actions on receptor activator
of NF-kB ligand (RANKL) [67].
Melatonin is also known for its antioxidant properties
[68], reducing oxidative damage by directly scavenging
free radicals and thereby protects cells from pro-
inflammatory cytokines [69] and exhibits anti-angiogenic
effects on endothelial cells [70,71].
Recently, in an in vitro study, He and coworkers [72]
found that melatonin bound to decellularized ECM improves
the differentiation of human bone marrow (BM) MSCs intoosteoblasts and suppress the levels of matrix
metalloproteinase genes (MMPs), with role in bone
resorption, thereby preventing degradation of the calcifiedmatrix.
Hyaluronic acid (Hyaluronan, HyA) -Figure 3, a linear
anionic nonsulfated glycosaminiglycan composed by therepetition of a disaccharide unit of an N-acetyl-glucosamine
and a β-glucuronic acid, with negative charge, viscoelastic
properties and high hidratation ratio, plays an importantrole in the control of tissue hydration [73,74], stimulating
bone wound healing.
HyA is a highly attractive natural biomaterial also due to
its participation in cell behavior and cell signaling, widely
distributed throughout connective, epithelial, and neuralFig. 2. Melatonin
structure

http://www.revmaterialeplastice.ro MATERIALE PLASTICE ♦55♦No. 4 ♦2018 558tissues. According to Selvin and coworkers, low-molecular-
weight HyA (LMW-HyA) enhances angiogenesis andincreases collagen production by endothelial cells as
compared to high-molecular-weight HyA with inhibitor
effect on angiogenesis [75].
Recently, the results of several studies performed on
animal models reveled promising results with the addition
of HyA [74,76], being incorporated in hydroxyapatite/beta-tricalcium phosphate (HA- βTCP) [76], or biphasic calcium
phosphate (BCP) ceramic [74,77].
Alendronate, part of bisphosphonate family, was
previously used [76], in a rat model, released through
Polycaprolactone (PCL)-coated 3D printed porous TCP
scaffold, for its potential inhibition of bone resorption.
Ma and coworkers fabricated a bi-functional scaffold
from 3D-printed bioceramic covered with a uniformly self-
assembled nanostructured Ca-P/polydopamine surfacewith proved tumor cell death induction in vitro and
remarkable capability for both cancer therapy
(osteosarcoma cells and breast cancer cells) and boneregeneration, in vivo, on mice model [78].
Functionalized Nanoparticles, including functionalized
ferroferric magnetic nanoparticles, may be suitable for
numerous potential uses such as improvement of tissue
regeneration, enhancing implants osseointegration, and the
prevention of infections [78]. Three main directions wereenvisaged for the usage of nanoparticles in bone
regeneration/remodeling: cell labeling, to assess the
regenerative therapy; controlled, sustained drug delivery,according to requirements, of adequate tuned
nanoparticles; and more advanced, for a longer therapeutic
effect, gene delivery [79].
CAD/CAM for bone grafting in the maxillofacial region
Bone graft design : Radiological images, such as those
derived from X-ray cone beam computed tomography
(CBCT) – for maxillofacial region, medical computedtomography (MDCT) or magnetic resonance (MR)
scanners, provide excellent sources for 3D anatomical data
acquisition [80-82] for graft design and scaffold tissueengineering [81,83-86].
Additive manufacturing requires the conversion of CBCT
files, commonly saved as DICOM (Digital Imaging andCommunication in Medicine) files into STL (standard
tessellation language). The DICOM to STL conversion
involves a segmentation of voxels into different tissuestypes according to the gray scale, performed, most
commonly to date, by manual or default thresholding [87].
DICOM to STL conversion is often a potential source oferror [88]. However, despite of the large existing number
of automatic tissue identification algorithms, for the
complex anatomical maxillofacial region and/or thepresence of artefacts (metallic crowns, bridges), manual
segmentation or a combination of automated and manual
segmentation are often required for increasing accuracy[88,89].
In order to improve accuracy, future research should
focus on developing new medical image segmentationsoftware that is suitable for different CT imaging modalities
[87].
Rapid Prototyping (RP) technology and polymeric
materials for bone substitutes : To adequate replace a
biological structure, with appropriate shape and tissue
forming characteristics, the rapid prototyped bonereplacement can be obtained either by printing acellular
scaffold that can be eventually populated with cells or
biomolecules prior to implantation, or directly printing a
living cellular construct, namely bioprinting [90]. In the first
approach, scaffolds, from either natural or synthetic
materials, provide the appropriated biomechanicalenvironment to allow cells to produce their own
extracellular matrix. In the second approach, specific
additive manufacturing techniques are used to print cells
immobilized within polymeric hydrogels producing cell-
laden three-3D constructs [91].
RP techniques (additive manufacturing or solid free form
fabrication) for a cellular scaffold, recently introduced with
the aim of overcoming the limitations of standardtechnologies, are additive fabrication processes that
manufacture the final 3D object, based on a CAD design
file, by deposition layer-by-layer, with the use of liquid-,solid-, and powder-based materials [92]. The general steps
of the RP technique are presented in figure 4. Among the
Fig. 4. Steps in Rapid prototyping.
[92,93,95]. Digital Imaging and
Communications in Medicine (DICOM),
Stereolithography File Format (STL),
Additive Manufacturing File Format
(AMF)Fig. 3. Hyaluronic
acid structure

http://www.revmaterialeplastice.ro MATERIALE PLASTICE ♦55♦No. 4 ♦2018 559RP techniques, Stereolithography (SLA), Fused Deposition
Modeling (FDM), Selective Laser Sintering (SLS) and Inkjetprinting are mostly used in the last years for synthetic
polymers bone scaffold manufacturing [92,93].
SLA is based on the use of a UV laser that is vector
scanned over the top of a bath of a photo-polymerizable
liquid material. As polymerization is initiated, the laser
beam creates a first solid layer, just below the surface ofthe bath. This laser polymerization process is repeated to
generate subsequent layers by tracing the laser beam along
the design boundaries and filling in the 2D cross-section ofthe model, layer-by-layer. Once the model is complete,
the platform is raised out of the bath and the excess resin
is drained.
The materials suitable for SLA need to be photo
crosslinked by ultraviolet or visible light according to a
sliced CAD model.
FDM is the process by which a thermoplastic material is
melted in a heated head [94] and extruded through a small
orifice onto a stage layer. The deposited material fuses tothe previous laid layer and generates a scaffold a layer-by-
layer fashion [96].
SLS uses a CO2 or Nd:YAG laser beam to sinter selected
regions of material powders onto a powder bed surface,
forming a material layer. Once a first layer is solidified, the
powder bed is lowered by one-layer thickness. The nextlayer of the material is laid down on the top of the bed by a
roller. The process is repeated until the scaffold is completed
[16,96].
Inkjet printing
(3D printing or Binder-Jet) A liquid binder
is sprayed onto the layer of the powder bed; this merges
particles together to form a solid layer. The powder bed isthen lowered so that a new powder layer is spread over
the surface of the previous layer by the roller. This process
is repeated until the designed object is obtained [16,97].
3D bioprinting -technique is a fabrication technology
used to precisely dispense cell-laden biomaterials for the
construction of complex 3D functional living tissues [98],controlling cell proliferation, attachment, and migration
within 3D structures [99]. Among the described RP
methods, solely Inkjet printing enables fabrication ofheterogeneous tissue constructs composed of deposited
cells, growth factors, ECM molecules, pharmaceutical and
biological agents, such as peptides, proteins (e.g.fibrinogen, collagen), polysaccharides (e.g. hyaluronic acid,
alginate), or other biomaterials of interest [100,101], with
no photo polymerization, no high temperatures, noextrusion, or laser-sintering requiring. To date, the most
used bioprinting technologies are jetting-, extrusion-and
laser- based printing [98,102] with hydrogel as basematerial.
In the
jetting-based (ink-jet / droplet-based) technique ,
picolitre bio-ink droplets (smaller than 30 ìm in diameter)are layered onto a substrate [103]. The
extrusion-based
bioprinting systems dispense continuous filaments of a
material consisting of cells mixed with hydrogel through amicronozzle, using piston or pneumatic pressure tofabricate two dimensional (2D) or 3D structure. After
printing 2D patterns, hydrogels are physically or chemicallysolidified and 3D structures are fabricated by stacking 3D
patterns layer by layer. The
laser-based bioprinting [ 104]
uses the energy of pulsed laser focused on the absorbinggold layer of the ribbon and this generates a high-pressure
bubble, which propels cell-containing materials towards
the collector substrate [98].
Synthetic polymers as bone grafting materials
Poly (methyl methacr ylate) (PMMA)- belonging to
methacrylate esters large family and obtained from methylmethacrylate – Figure 5.a., offers similar strength as
compared to native bone tissue, a remarkable plasticity,
long-term durability, is easily manufactured, inexpensive,and produces no visible radiographical artifacts -Figure 5.b.
However, the residual monomers from polymerization
can cause damage to human cells [123], and pore sizemay influence osteoconductivity and vascularization of the
implanted graft, therefore, processing technology is of a
great importance. Additive manufacturing allows controlpore dimensions and reduces monomer leaching, therefore
improving material’s characteristics and biocompatibility
[105-108]. In a systematic review and meta-analysisanalyzing complications with the use of PMMA for
cranioplasty, no difference was observed between the
complication rates of PMMA and autologous bone orbetween PMMA and titanium mesh [123].
Polyetheretherketone (PEEK), Figure 6, is a chemically
inert polymer, with structural stability at temperaturegreater than 300 degrees Celsius, allowing steam graft
sterilization, with elastic properties similar to cortical bone,
radiolucency and suitable for additive manufacturing (FDMtechnology).
When comparing PEEK grafts to autogenous bone and
titanium mesh, Punchak and co-workers [123] found nostatistically significant differences between the bone
replacement for cranioplasty.
The synthetic biodegradable polymers with high
biocompatibility most commonly used for bone tissue
engineering are poly(glycolic acid) – PGA, poly(lactic acid)
– PLA, poly(e-caprolactone) – PCL, poly(lactide-co-glycolicacid) – PLGA. They can be produced under controlled
conditions and thus exhibit predictable and reproducible
mechanical and physical properties such as tensilestrength, elastic modulus, and degradation rate, by using
various molecular weights, structure, composition, and
copolymers and can be easily processed, being also suitablefor all additive manufacturing technologies (SLA, FDM,
SLS, Binder-Jet).
Among elastomeric polymers poly(glycerol sebacate)
(PGS) is extensively studied for use as scaffolding
biomaterial in bone tissue regeneration due to its high
biocompatibility [109]. It is synthesized through thepolycondensation (esterification) reaction of tri-functional
glycerol, HOCH
2CH(OH)CH2OH, and difunctional sebacic
acid (HOOC)(CH2)8(COOH) – figure 7.
The mechanical characteristics – Young’s modulus of
PGS is in the range of 0.056–1.2 MPa, and its elongation at
Fig. 6. PEEK structure
Fig. 5. a. Poly (methyl methacrylate) synthesis;
b. Micro-CT image of 3D printed PMMA

http://www.revmaterialeplastice.ro MATERIALE PLASTICE ♦55♦No. 4 ♦2018 560break ranges from 41 to 448 %, depending on the synthesis
conditions – and the rapid degradation, limits the application
as bone substitute. To overcome these limitations, PGS
was doped with Bioglass® filler, obtaining lower resorptionrate and improved mechanical resistance [16].
Hydrogels, composed of a great variety of synthetic and
natural polymers are three-dimensional, hydrophilic,polymeric networks able to retain large amounts of water,
or biological fluids, without disintegrating. Their high
content in water makes them similar to the living tissue.The suitability for bioprinting and the development of
fundamentally new hydrogels, such as those formed by
graphene oxide, could open up novel and more promisingavenues towards the successful clinical use of composite
hydrogels for bone regeneration.
Conclusions
Two main directions are envisaged for bone
regeneration:
Developing scaffolds with mechanical strength, required
to withstand the physiological loads seen in vivo, providing
microenvironment to induce the desired cellular responseand doping the scaffold with biomolecules able to
stimulate migration and adhesion of autogenic blood MSCs.
Developing a bio-matrix including living cells,
biomolecules, to replace the entire bone defect.
Despite of the great number of polymeric materials and
various additive manufacturing techniques proposed in thereviewed studies, only a few have, to date, successful
clinical applications, namely PMMA and PEEK. However,
an ideal bone replacement have not been yet proposeddue to the complex construction and characteristics of
the bone living tissues.
Additive manufacturing technology represents a
promising field for future research in bone grafting for
maxillofacial region, but standard guidelines for mimicking
clinical environment with the different bone characteristicsare strongly required.
Due to advanced technologies and materials, complex
individual shapes can be reproduced nowadays with thedesired porosity and geometry.
The rapid prototyping techniques, particularly, bioprinting
allows the construct of
3D living functional tissues able to
replace, in the near future, large defect caused by tumor
excision, trauma, clefts or infection, limiting the autogenous
bone graft requirement.
Acknowledgement: This work was supported by a grant of the
Romanian National Authority for Scientific Research and Innovation,
CCCDI -UEFISCDI, project number 30/2016 (ERA-NET-MANUNET II)
PRIDENTPRO within PNCDI III and partially supported by a grant of
the Romanian National Authority for Scientific Research and
Innovation, CCCDI – UEFISCDI, project number 39/2018 COFUND-
MANUNET III-HAMELDENT, within PNCDI III. Authors kindly
acknowledge the valuable help provided by George Vlasceanu and
Stefan Voicu for running micro-CT analysis on 3D printed poly
(methylmethacrylate).
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Manuscript received: 15.08.2018