Maxilo

Journal of Cranio-Maxillo-Facial Surgery xxx (2012) 1e13
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Journal of Cranio-Maxillo-Facial Surgery

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Current trends and future perspectives of bone substitute

materials e From space holders to innovative biomaterials
Andreas Kolk a, *, Jrg Handschel b, Wolf Drescher c, Daniel Rothamel d, Frank Kloss e,
Marco Blessmann f, Max Heiland f, Klaus-Dietrich Wolff a, Ralf Smeets f
a
Department of Oral and Maxillofacial Surgery, Technische Universitt Mnchen, Klinikum rechts der Isar, Ismaninger Str. 22, 81675 Munich, Germany
Department for Cranio- and Maxillofacial Surgery, Heinrich-Heine-University Dsseldorf, Dsseldorf, Germany
Department of Orthopedics, RWTH University Hospital, Aachen, Germany
d
Department for Oral and Cranio-Maxillo and Facial Plastic Surgery, University of Cologne, Cologne, Germany
e
Department for Cranio-Maxillofacial and Oral Surgery, Medical University Innsbruck, Austria
f
Department of Oral and Maxillofacial Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
Paper received 23 June 2011
Accepted 3 January 2012
An autologous bone graft is still the ideal material for the repair of craniofacial defects, but its availability
is limited and harvesting can be associated with complications. Bone replacement materials as an
alternative have a long history of success. With increasing technological advances the spectrum of
grafting materials has broadened to allografts, xenografts, and synthetic materials, providing material
specic advantages. A large number of bone-graft substitutes are available including allograft bone
preparations such as demineralized bone matrix and calcium-based materials. More and more
replacement materials consist of one or more components: an osteoconductive matrix, which supports
the ingrowth of new bone; and osteoinductive proteins, which sustain mitogenesis of undifferentiated
cells; and osteogenic cells (osteoblasts or osteoblast precursors), which are capable of forming bone in
the proper environment. All substitutes can either replace autologous bone or expand an existing
amount of autologous bone graft.
Because an understanding of the properties of each material enables individual treatment concepts
this review presents an overview of the principles of bone replacement, the types of graft materials
available, and considers future perspectives. Bone substitutes are undergoing a change from a simple
replacement material to an individually created composite biomaterial with osteoinductive properties to
enable enhanced defect bridging.
2012 European Association for Cranio-Maxillo-Facial Surgery.
Keywords:
Bone replacement materials
Bone regeneration
Gene therapy
BMP
1. Introduction
The breakthrough in the present-day development of bone
substitute materials (BSM) was initially achieved by Barth and Ollier
who carried out animal experiments in order to study different bone
replacement materials for the rst time (Barth, 1895). Historically,
autogenous bone grafts, allografts, and a variety of biomaterials
have been used for the repair of osseous defects and the augmentation of compromised bone. The ideal bone-graft substitute
is biocompatible, bioresorbable, osteoconductive, osteoinductive,
structurally similar to bone, easy to use, and cost-effective.
Approximately 2.2 million bone graft procedures are performed
* Corresponding author. Tel.: 49 89 4140 4051; fax: 49 89 4140 2934.
E-mail addresses: Kolk@mkg.med.tum.de, Andreas.Kolk@gmx.de (A. Kolk).
each year worldwide to repair bone defects in orthopaedics, neurosurgery and oral & maxillofacial surgery with a yearly estimated costs
of $2.5 billion (Van Heest and Swiontkowski, 1999). Problems related
to the availability of graft material, donor-site morbidity, immunogenicity and biomechanical integrity have limited its success. An
increasing number of bone graft materials with completely different
origins are commercially available for many applications throughout
the human body. They are variable in their composition, their
mechanism of action and, therefore, their indications.
BSM are generally considered to be a highly important alternative
to bone grafting in dental surgery, implantology and periodontology.
Donor site morbidity is diminished while simultaneously guaranteeing a nearly unlimited level of material disposition. In this way,
a large variety of osseous defects can be repaired using BSM. Due
to current developments innovative BSMs with new chemical,
1010-5182/$ e see front matter 2012 European Association for Cranio-Maxillo-Facial Surgery.
doi:10.1016/j.jcms.2012.01.002
Please cite this article in press as: Kolk A, et al., Current trends and future perspectives of bone substitute materials e From space holders to
innovative biomaterials, Journal of Cranio-Maxillo-Facial Surgery (2012), doi:10.1016/j.jcms.2012.01.002
A. Kolk et al. / Journal of Cranio-Maxillo-Facial Surgery xxx (2012) 1e13
structural and subsequent biological properties will embrace a lot of

requirements in order to imitate the characteristics of the bone
defect. Crucial for the clinical success of BSMs are their interactions
with the adjacent tissue structures and cells due to a macroporous
interconnecting structure of >100 micron diameter promoting cell
inltration, bone growth and vascularisation. In the context of large
osseous augmentations, autogenous bone is still used as the
preferred gold standard material. However, in certain clinical
settings and appropriate indications a combination of BSM with
living tissue/cells or BSM alone may be suitable.
The current functions of BSM are as follows
space maintenance for bone regeneration
pre-setting of the desired anatomical form
supporting functions for the periosteum and associated
membranes
acceleration of bone remodelling
osteoconductive structural guidance for the regeneration of
osseous tissue
carrier substance for antibiotics, growth factors or approaches
by gene therapy (Rupprecht et al., 2007; Fischer et al., 2011;
Maus et al., 2008a; Smeets et al., 2009b; Kolk et al., 2011)
scaffolds for tissue engineering approaches (Handschel et al.,
2009a; Naujoks et al., 2011)
The morbidity associated with autogenous bone graft harvest
and concerns regarding transmission of live viruses from allografts
have been the impetus for research into a variety of bone grafting
materials. Current requirements for an ideal BSM are rigorous, as
listed below:

biocompatibility
osteoinduction and osteopromotion/osteoconduction
porosity
stability under stress
resorbability/degradability
plasticity
sterility
stable and long-term integration of implants
be vascularized with an adequate diameter (>approx. 100 mm)

(Cornell, 1999; Klawitter and Weinstein, 1974). Smaller pore diameters are more advantageous in the adhesion and incorporation of
mineralized tissues, cell-to-implant contacts and in the absorption
of extracellular liquids (Chesnutt et al., 2009; Hertz and Bruce,
2007). An incomplete co-mingling of the material with adjacent
vessels can result in particles that are encased by connective tissue.
Condensation of the materials can cause a reduction or a loss of their
porosities (Maus et al., 2008b). A process that yields biomechanical
properties such as those that exist in normal bone is highly desirable
(Kao and Scott, 2007). In particular, form stability is of essential
importance with regard to larger bony defects. Resorption of the
material and replacement by normal bone is either biologically
based on the inuence of cells or by chemical-physical dissolving
processes (Misch and Dietsh, 1993), and should occur simultaneously in the ideal case. If not, the formation of connective tissue
may occur resulting in biomechanical inferior structures (Kao and
Scott, 2007). The BSM should be easy to use, should withstand
sterilization and should come in sufcient quantities. In a time of
global economic downturns, costs are an important issue in clinical
applications.
To date, no BSM is available that is equal to autogenous bone
(Horch et al., 2006; Smeets et al., 2009a; Aebi et al., 1991), and
current BSMs serve primarily as lling and frame building materials, mostly providing osteoconductivity for the bone healing
process (Horch et al., 2006; Spector, 1992; Buser et al., 1998). In
addition, every current allograft and xenograft product carries
histocompatibility antigens different from those of the host with an
increased risk of potential graft versus host reaction.
Ideally, the healing processes of the defects should result in
regenerated and vital bone without residual foreign bodies.
2. Variety of bone replacement materials

Currently the most important biomaterials for routine clinical
use in the head and neck region are divided in ve subcategories
according to their origin (Laurencin et al., 2006).
1. BSMs of natural origin
Biocompatibility ensures the absence of toxicity, teratogenity or

carcinogenicity. The lack of antigenicity guarantees the avoidance
of pro-inammatory and immunologic reactions. All such requirements serve as a basis for effective long-term tolerance (Horch
et al., 2006), and such criteria are mainly fullled by available
synthetic materials.
In addition BSMs should support osteogenesis conductively,
stabilize the coagulum, ll up osseous defects and contribute to
mechanical resistance. In this way BSMs serve as an articial
extracellular matrix in order to support and later stabilize the new
creation of bone. This so called osteoconductive effect means that
the attachment of new osteoblasts and osteoprogenitor cells is
supported by the graft, providing an interconnected structure for
migration of new cells and formation of new vessels (Kao and Scott,
2007). Moreover, a stimulating effect on the osteogenetic cells
called osteogenicity or osteopromotive represents the ability of
a graft to induce non differentiated stem and/or osteoprogenitor
cells to differentiate into osteoblasts causing new bone formation at
locations where it is unexpected. These processes are inuenced by
cytokines such as bone morphogenetic protein (BMP) that induce
differentiation of mesenchymal stem-cells, to result in new bone
formation that parallels direct osseous interconnection.
Interconnecting porosity of a BSM is one of the most important
requirements for continuous vascular ingrowth (Eggli et al., 1988;
Hing et al., 2005). Many pores extend to the surface and can
Materials are subdivided into harvested bone grafts and graft

substitutes: autogen (from same individual) (Gerressen et al., 2009;
Kirmeier et al., 2007; Nkenke et al., 2004; Schlegel et al., 2003a;
Springer et al., 2004) allogen (from same species) (Kubler et al.,
1994), xenogen (from a different species) (Mardas et al.) and phytogenic (marine origin) with coral, chitosanic or spongious structure
(Wang et al., 2010; Birk et al., 2006; Abramovitch-Gottlib et al., 2006).
2. Synthetical (alloplastic) materials (Horch et al., 2006; Asti et al.,
2008; McAllister and Haghighat, 2007; Bucholz, 2002)
These include ceramic-based bone graft substitutes such as
calcium phosphate, calcium sulphate, and bioglass (Tadic and
Epple, 2004; Tadic et al., 2004), as well as degradable and nondegradable polymers, each alone or in combination with other
materials.
3. Composite materials (Chesnutt et al., 2009; Xu et al., 2009;
Boccaccini and Blaker, 2005)
The combination of different materials (e.g. bioactive Calcium
phosphates and polymers) on the one hand combines the osteoconductive properties of different classes of BSM; on the other hand
it serves to improve mechanical strength.
4. BSM combined with growth factors

Natural and recombinant growth factors used alone or in
combination with other materials such as transforming growth
factor-beta (TGF-beta), platelet-derived growth factor (PDGF),
broblast growth factor (FGF), and bone morphogenetic protein
(BMP) (Fischer et al., 2011).
5. BSM with living cells
These act with cells to generate new tissue alone or are seeded
onto a scaffold serving as a matrix e.g., mesenchymal stem cells
(MSCs).
3. BSMs of natural origin
In principle, biologic materials, with the exception of autogenous transplants, generally have a minimal risk of transmission of
infectious disease and antigenicity resulting in graft versus host
reaction. Worldwide either autograft or allograft tissue is used in
90% of all bone replacement procedures.
Table 1
Different osteogenic capacities depending upon the harvesting site of auto- and
allografts.
Characteristics of BSMs with natural origin
Autograft
Cancellous
Cortical
Allograft
Cancellous
Frozen
Freeze-dried
Cortical
Frozen
Freeze-dried
Xenogen
Cancellous
Cortical
Phytogen
Cancellous
Cortical
No
No
No

No
/

No

3.1. Autogenous transplants

Autogenous transplants are also called body transplants. They
represent almost the ideal bone substitute containing living cells,
a resorbable and osteconductive scaffold as well as multiple human
growth factors. Vascularized and avascular autogenous bone has
a greater osteogenic capacity than any other bone replacement
material, as revascularization attracts mesenchymal differentiation
into osteogenic, chondrogenic or other cell lines. Autogenous
bone transplants exhibit an inherent biocompatibility and are
therefore incorporated more easily without immunogenic
responses (Den Boer et al., 2003). Therefore they are still the Gold
standard.
3.2. Allogenic material
In general surgery allogenic materials (allografts) are the
preferred bone substitutes and have seen increasing use over the
past decade (Bostrom and Seigerman, 2005).
Allografts overcome the limitations associated with the
procurement of autografts for bone grafting. It may be derived from
cadaveric bone sources or from living donors harvested during hip
arthroplasty, and has both osteoinductive (they release bone
morphogenic proteins that act on bone cells) and osteoconductive
properties, but lack osteogenic properties because of the absence of
viable cells (Habibovic and de Groot, 2007). Beside limitations in
the essential bone graft characteristics (Table 1) there is an ongoing
controversial discussion about the association of allogenic material
with a risk of transmission of infectious agents such as the human
immunodeciency virus (HIV), hepatitis B and C viral infection
(HBV/HCV), malignancies, systemic disorders (autoimmune
disease), or toxins (Conrad et al., 1995; Tomford, 1995). Removal of
osteoarthritic femoral heads throughout hip arthroplasty showed
an 8% evidence of diseases not previously known (Palmer et al.,
1999). Elimination of this major concern of allogenic material
requires tissue-processing, sterilization and a deactivation process
of proteins in the extracellular matrix which contains bone growth
factors, proteins, and other bioactive substances necessary for
osteoinduction and, ultimately, successful bone healing. The goal of
preparation is designed to eliminate the hosts immunogenic
activity and therefore, in the vast majority of allografts, without
osteogenic cells (Habibovic and de Groot, 2007). Although the risk
of transmission of disease is much lower than with blood products,
Fig. 1. Morphology and microstructure of maxgraft granules (SEM image, magnication (magn.) X 100). Figs. 1e11: all SEM images (scanning electron microscopy (SEM)
were carried out with a LEO 1530 instrument on gold-sputtered samples.
it is still possible. The more aggressive the allograft processing, the

less intense immunologic responses will occur, but this results in
a decrease of the osteoinductive properties. For this reason fresh
allografts are clinically no longer used. Frozen allografts induce
stronger immune responses than freeze-dried allografts (Ehrler and
Vaccaro, 2000). Allogenic replacement materials are available in
many different shapes, ranging from complete bone segments
through corticocancellous or cortical grafts, cancellous chips to the
most common form, of demineralized bone matrix (DBM).
One of the latter types is offered as maxgraft (botissdental
GmbH, Berlin, Germany), an allogenic bone replacement material.
The extraction of the immunological components is performed
with specied standardised removal protocol (Fig. 1). The origin of
maxgraft granules are femoral heads of living donors (not cadaver
bone as from other manufacturers). Each donor gives consent, is
screened in an extensive examination and each donor bone is
tested for potential communicable diseases (as HIV, HBV/HCV,
Syphilis). The donor bone is treated in a multi-step chemical
cleaning process, of which each step is validated for virus and
bacteria inactivation, and ultimately gamma-sterilized. maxgraft
products are available as granules or blocks. The natural structure
of the mineralized tissue is not affected by the gentle tissue process
(Fig. 1). Other suppliers of allografts are Zimmer Dental GmbH
(Freiburg, Germany) (Puros/Tutoplast) and the German institute
Deutsches Institut fr Zell- und Gewebeersatz (DIZG). These
materials differ in terms of the manufacturing process and the type

of donor tissue (i.e. cadaver bone).
3.3. Demineralized bone matrix
DBM consists of sponge-like collagen from human, bovine
(Naujoks et al., 2011) or equine origin that has undergone decalcication and sterilization, so it can be classied as allogenic or
xenogenic material dependent on the origin. The trabecular structure of the original tissue remains, therefore maintaining its biological structure (Vaccaro et al., 2002). DBM has been shown to
have osteoconductive and osteoinductive properties (Katz et al.,
2009; McKee, 2006), but it provides no structural stability and
therefore should only be applied in a structurally stable environment. It is mainly used as a bone graft extender. DBM also
revascularises quickly and acts as suitable carrier for autologous
bone marrow. It does not evoke any appreciable local foreign body
reaction as the antigenic surface structure of the bone is destroyed
during demineralization (Tuli and Singh, 1978). More growth
factors are available after the removal of bone minerals, so the bone
inductance of DBM is higher than that associated with mineralized
allogenic transplants (Khan et al., 2005; Sandhu et al., 2001). DBM
is a derivative of allograft bone. It is prepared by pulverization of
allogenic bone to a consistent size, followed by mild acid extraction
of the mineralized phase of bone (Gamradt and Lieberman, 2003).
This process, principally developed by Urist et al in 1965, results
in a composite of non-collagenous proteins, growth factors, and
collagen (Urist and Dawson, 1981). A commercially available
product is Grafton (BioHorizons, Birmingham, USA), which is
available in putty block form, as a gel or a exible strip like material,
a mouldable paste with bone-chips and an injectable bone paste.
Fig. 2. Morphology and microstructure of Bioss granules (SEM image, magn. X 50).
3.4. Xenogenic material

Fig. 3. Morphology and microstructure of human bone (SEM image, magn. X 50).
Porous natural hydroxyapatite (HA) can be obtained from

animal bones or seaweeds. Xenogenic HA is the preferred biological
material because of its stability concerning absorption (i.e. dependent on the porosity value, crystallinity, crystal structure, etc.).
BioOss (Geistlich AG, Wolhusen, Switzerland) is one of the
most common used BSMs in all elds of dental surgery, containing
the inorganic component of bovine bone. Apart from betatricalcium phosphate (b-TCP) used in sinus oor elevation, BioOss is the only BSM which can be regarded as evidenced based
(Handschel et al., 2009b). All organic material is removed by
a stepwise annealing process (up to 300 C), followed by a chemical
treatment (NaOH) resulting in a porous HA bone chip material
(Fig. 2). The particle size of the granulate measures 0.25e2 mm.
BioOss consists of a material combination with a certain proportion of bovine bone mineral with good mechanical properties and
a pore structure similar to human bone (Fig. 3). It is osteoconductive, stable over the long-term and deproteinized. BioOss is
integrated into the bodys natural bone regeneration process. The
carbonate content in natural HA is highly variable. Calculated
weight ratios of Ca5(PO4)3OH to CaCO3 give values between 6 and
30 (Tadic and Epple, 2004). The range in natural bone samples with
ratios from 13 to 37 is also highly variable, so that even after
extensive chemical and moderate thermal treatment the similarity
with bone mineral is still present and the structure of natural bone
remains intact (Tadic and Epple, 2004).
Clinically, BioOss is used to stabilize the blood clot, promote
bone formation, regenerate peri-implant defects and act in sinusaugmentations (Handschel et al., 2009b). The augmented volume
can survive long-term via the absorptive protection (Schlegel et al.,
2003b). Another characteristic is that it results in permanent hard
tissues.
OsteoGraf N (DENTSPLY Friadent, Mannheim, Germany)

(Fernandes et al., 2011) and Cerabone (botiss dental GmbH, Berlin,
Germany) are natural bone replacement materials based on bovine
bone. The manufacturing process involves high-temperature
procedures that removes all the organic components and thus
prevents possible immunological reactions. The pure mineral
composition is very similar to human bone with regard to physical,
chemical and biological characteristics. Cerabone is characterized
by its long-term volume resistance and natural bone structure. This
product is available as granulate and block (Figs. 4 and 5).
Additional xenogenic products include Nu-Oss (Henry Schein
Dental Deutschland GmbH, Langen, Germany), Biotek (mectron
Deutschland Vertriebs GmbH, Kln Dellbrck, Germany) and
Osteobiol (American Dental Systems, Vaterstetten, Germany).
These products differ with respect to their source of origin (cow,
horse or pig bones) and their manufacturing processes (i.e. solvent
conservation or sintering). Pepgen P-15 (DENTSPLY Friadent,
Mannheim, Germany) is a bovine HA, which is coated with
a synthetically produced cell binding peptide P-15. Osteoblast
stromal cells are bound by the peptide P-15. Supporting their
differentiation and proliferation, analogous to the naturallyphysiological mechanism, only a few P-15 sequences (i.e. as part
of the collagen structure) are available in the organism. Osteoblast
stromal cells can be activated by enabling numerous binding points.
This amplied event cascade causes increased and accelerated bone
regeneration with PepGen P-15. Thus, with PepGen P-15 the
natural bodys regeneration potential is used maximally and bone
regeneration is therefore optimized. The particles have an interconnecting pore structure and a ball-shaped size of 250e420 mm.
4.1. Hydroxyapatite
Fig. 4. Morphology and microstructure of Algipore (SEM image, magn. X 100).
Fig. 5. Morphology and microstructure of Cerabone (bovine HA) (SEM image, magn.
X 50).
3.5. Phytogenic material

The most common phytogenic BSM is Algipore (DENTSPLY
Friadent, Mannheim, Germany), which is a bone-analogue calcium
phosphate that was originally obtained from lime scaffolds of
marine algae in 1985 (Ewers, 2005). Subsequently several alternative products with different physicochemical properties have
come on the market (Damien and Revell, 2004). The materials are
designed for the reconstruction and contouring of at least a triplewall alveolar osseous bone defect. The selection of different pore
diameters (Fig. 4) (e.g. 0.3e0.5 mm; 0.5e1.0 mm and 1.0e2.0 mm)
is related to the size of the bony defect. Coral derived materials have
good elastic properties very similar to human bone (Nomura et al.,
2005). Depending on the cellulose activity, the integration of
Algipore should be completed after 15 months.
4. Synthetic (alloplastic) materials
ceramics: biological glasses, TCP, HA and glass ionomer
cements
metal: titanium
polymers: polymethylmethacrylate, polylactides/polyglycolides
and copolymers
cements: calcium phosphate (CP) cements
The inorganic basic bone substance contributes to approximately two thirds of the dry substances of osseous tissues. It is
represented by CP (85e90%), calcium carbonate (8e10%), magnesium phosphate (1.5%) and calcium uoride (0.5%). In osseous
tissues, minerals exist as apatite crystals. These CP connections
build hexagonal crystals, according to the principle of space grids.
HA is very abundant, and, these acicular crystals exist both within
and outside the collagen brils. Hardness and resistance of bone are
set by the connections between HA and collagen bres. HA is
a hydroxylated CP salt with a high degree of hardness, which
comprises the main component of inorganic substance in bones
and teeth, where it is partly substituted by uorapatite. It is only
soluble in a strongly acidic environment. Osteoblasts form HA from
phosphate and calcium ions. They are built into naturally occurring
human bones, which are composed of approximately 70% mineral
matrices. HA ceramics are chemically nearly identical to natural HA.
A favourable component ratio of calcium phosphate-ceramics
(Ca/P 1.67) leads to an osteotropic interface mechanism, which
means HA is a bioactive material that sets free calcium and phosphate ions in the organism. The result is a micro-morphological
anchorage of endosseous implants. It is no longer a denable
ceramic-bone-compound and is called compound bone genesis
(Osborn and Newesely, 1980). Generally, it does not matter whether
HA ceramics are of natural or synthetic origin. Nanosized HA
particles are associated with a minor level of cytotoxicity in vitro
with good cell attachments and cell growth of human osteoblasts
(Huang et al., 2004). According to Koster et al. the tissue compatibility of calcium phosphate ceramics depends on the mineralogical
and chemical composition of the material (Koster et al., 1976). In
addition, there is a difference between precipitated and sintered HA
ceramics The latter demonstrate no or only very sluggish biodegradation (Lu et al., 2002; Tadic et al., 2002; Fulmer et al., 2002). If
the crystallite size of the HA ceramics is very small (like in bone)
and/or if there is carbonate incorporated, the biodegradation is
strongly enhanced due to a higher solubility.
Ceramics with CaO: P2O5 ratios ranging from 2:1 to 4:1 have
proven to have the best biocompatibility, while the optimal ratio is
3:1. This represents tri-calcium-phosphate-ceramics. Klein et al. also
showed a good biocompatibility with all calcium-phosphateceramics with a CaO: P-ratio of 10:6 or 3:2 (Klein et al., 1983). In
their study normally structured bone, was deposited directly on the
ceramics without a separating connective tissue layer, and were later
replaced by lamellar bones. An inammatory reaction did not occur.
4.2. Ceramics
Calcium phosphate ceramics are synthetic scaffold substances.
They have been used since the early 1970s in dentistry and since
the 1980s in orthopaedics (Brandoff et al., 2008; McAndrew et al.,
1988; Horch et al., 2006; Bohner, 2000). This bone replacement
material consists of HA or alpha- respective beta-TCP ceramic
(a-, b-TCP). They are similar in composition to the inorganic apatite
(Vaccaro et al., 2002; Schnurer et al., 2003).
a-TCP and the corresponding b-TCP differ from each other in
biological properties. Currently the b-TCP is preferred in dental
surgery.
In general both TCP and HA have good biocompatibility, with
osteoconductive properties without immunogenic or toxic side
effects (Kao and Scott, 2007; Vaccaro et al., 2002, Schnurer et al.,
2003). Synthetic ceramics possess no osteogenic or osteoinductive properties, and demonstrate minimal immediate structural
support. When attached to healthy bone, osteoid is produced
directly onto the surfaces of the ceramic in the absence of a soft
tissue interface. Consequently, the osteoid mineralises and the

resulting new bone undergoes remodelling. Both TCP-ceramic and
HA are highly biocompatible. They differ, however, in the biologic
response created at the host site: porous TCP is removed from the
implant site as bone grows into the scaffold; HA is more permanent.
The surface layers of TCP enhance bonding with adjacent host bone.
This stimulates osteoclastic resorption and osteoblastic new
bone formation within the resorbed implant (Horch et al., 2006;
Mittelmeier et al., 1998). Although HA sintered ceramics are
widely used, its bioresorbability is so low that HA remains in the
body for a long time after implantation (Kamitakahara et al., 2008).
HA has been established as an excellent carrier of osteoinductive
growth factors and osteogenic cell populations, which greatly add
to their utility as bioactive delivery vehicles in the future (Noshi
et al., 2000). TCP show better degradation characteristics during
bone regeneration when compared to HA (Lu et al., 2002). In nonloaded critical size defects the degradation is also very slow
(Handschel et al., 2002). The degradation of the materials follows
a hydrolytic process; the intratrabecular integrated ceramic
remnants underlie a dynamic remodelling process and will be
completely substituted by natural bone (Daculsi et al., 1990; Horch
et al., 2006). In contrast to autogenous grafts, calcium phosphate
ceramics show no bone genes or bone inductive properties
(Schnurer et al., 2003; Vaccaro et al., 2002).
When manufacturing synthetic ceramics, powdery substances
are used with a high pressure sintering process, subjected to
temperatures ranging from 1000 to 1500 C (Schnurer et al., 2003;
Vaccaro et al., 2002). The biologically tolerable calcium/phosphorus
ratio of the resulting ceramics is between 1.5 (TCP) and 1.67 (HA)
(Schnurer et al., 2003).
In contrast to ceramics from biological materials, the synthetic
ceramics created via sintering show a poor interconnecting pore
system. To create a rough surface, a special manufacturing process
must be utilized (Schnurer et al., 2003).
Certain minor differences in the chemical composition and
crystalline structure of the various tri-calcium-phosphates can
have a big inuence on their physical properties in vivo. Ceramics
show greater mechanical resistance due to higher density and
crystallization and thus they are more slowly degraded (Vaccaro
et al., 2002). Biomechanical resistance and x-ray density are also
inuenced by the range of the porosity of the ceramics (Kao and
Scott, 2007).
The porosity of ceramics plays a crucial role in bone integration
(Kao and Scott, 2007; Schnurer et al., 2003). Pores ranging in size
from 150 to 500 mm are optimal for interfacial engineering activities, penetration of bones and implant absorption (Hertz and Bruce,
2007) (Fig. 6). Fleming et al. report that TCP with a porosity of
Fig. 6. Morphology and microstructure of HA (SEM image, magn. X 50).
35e50% and a pore diameter of 100e300 mm is commonly used

(Fleming et al., 2000). Moreover, the pore size seems to affect the
biocompatibility of ceramics (e.g. b-TCP). Higher porosity and lower
density of the ceramic provides a greater surface area for vascularisation and bony ingrowth. A higher pore size is correlated with
an increased compatibility in vitro (Naujoks et al., 2011). In addition
minimum pore sizes and volumes can complete spread of the
ceramic with new bone occurring. In smaller pore sizes bone
growth is only possible on the outer surface of the ceramic
(Schnurer et al., 2003). Depending on the surface size to which the
biological environment is exposed larger pores can accelerate the
absorption and the cellular adhesion, as well as the settling of the
osteoid. After incorporation of the latter, ceramics slowly gain
mechanical strength similar to cancellous bone (Ransford et al.,
1998). One of the modern synthetically materials is Maxresorb
(botiss dental GmbH, Berlin, Germany) which is a 100% synthetic
bone replacement material. The synthesis-based composition,
which is composed of 60% slowly absorbing HA and 40% b-TCP
results in two different mineral activity stages. Maxresorb
supports new bone formation by replacing the same defect volume,
which results in newly formed bone and mechanical stability. The
bone conductivity of Maxresorb is obtained through an optimized
matrix design of interconnecting pores with up to 80% porosity and
pore sizes of 200e800 mm and is available in granulates, blocks or
in cylindrical shape. Ostim (Heraeus Kulzer, Hanau, Germany) is
a fully synthetic, nano-crystalline and phase-pure HA incorporated
in an H2O carrier. The chemical composition and crystalline structure of its calcium phosphate component are identical to that of
natural bones. In contrast to other materials it is un-sintered, which
leads to a large specic surface. Because of the small particle size it
is optimally resorbable. Ostim is osteoconductive, so the new
formation of bone is accelerated. It adapts the role of a framework
for new bones. In the course of the healing process, Ostim
is phagocytosed, completely invaded by bone and replaced by
autologous bone.
4.3. a-TCP (Biobase)
Pure-phase a-TCP consists of long term bioresorbable and
porous bone substitute granules, which have an absorption time of
up to 24 months. Principally a-TCP is spontaneously soluble in the
body but some a-TCP spontaneously converts into HA, so that it is
radiologically detectable at the implantation site for many years
(Wiltfang et al., 2002). This is the big difference to phase-pure.
4.4. b-TCP (Cerasorb M, Vitoss) [Ca3(PO4)2]
b-TCP (>99%) is completely absorbed within a few months at the

implantation site via the simultaneous formation of new bone
(restitutio ad integrum) and has good biological compatibility and
bone conductivity (Horch et al., 2006, Wiltfang et al., 2002).
Unfortunately, it can lead to inammatory reactions and volume
loss due to rapid breakdown.
Bone-conductive b-TCP has a continuous microporosity (e.g.
micro pore size b 5 mm) and a homogeneous ceramic sintered
structure (Fig. 7). The body is immediately tied to the blood
circulation of the embedding tissue via the invasion of blood vessels
after the implantation and thus b-TCP might be an optimal matrix
for the formation of new bone. In addition, the structure of the
material dependent absorption kinetics of the phase pure b-TCP is
ideally coupled to the dynamics of osseous substitution, without
leading to unphysiological or disturbing inuences on the cellular
processes in bone regeneration. This process of growth ends with
the total metabolism of the implant material and the nearly total
restoration of the compromised bone region.
4.6. Polymer-based bone graft substitutes
Fig. 7. Morphology and microstructure of TCP (SEM image, magn. X 50).
Fig. 8. Morphology and microstructure of glass granulate (SEM image, magn. X 50).
Cerasorb M is a fully synthetic manufactured granule

comprised of b-TCP. Cerasorb M is completely resorbable and has
an interconnecting micro pore structure. It is absorbed by the body
within a few months and therefore faster than HA ceramics
(Lu et al., 2002, Walsh et al., 2008) and is available in four grain
sizes: 50e150 mm, 150e500 mm, 500e1000 mm and 1000e2000 mm
(RIEMSER Arzneimittel AG, Greifswald e Insel Riems, Germany).
The polymers used today can be subdivided into natural polymers and synthetic polymers which can be further separated into
degradable and non degradable types. They are hydrolytically
divided into their building blocks and metabolized. A result of the
low stiffness of polymers is greater strain on bone (Biswas et al.,
2010). In surgical practice polymers are therefore mainly used in
the orthopaedic eld for fracture xation via bolts and pins (e.g.
SmartPins, SmartScrew, SmartTack) (self-reinforced PLLA) by
Bionx Implants, Orthosorb Pin by J & J Orthopedics, Polypin (PLLAco-DLLA) by Zimmer Dental GmbH (Freiburg, Germany) (Middleton
and Tipton, 2000). In addition they are used to manufacture
surgical sutures and networks. Polymers used as bone replacement
materials include polyglycolid (PGA), Poly-L-lactid and Poly-D-lactid
and copolymers. The resorbtion speed of the copolymers depends
on their composition, as resorbtion of polyglycolide is faster than of
polylactide. To improve mechanical resistance and organic integration as well as reasons of x-ray opacity, polymers are combined
with CP (Schnurer et al., 2003). Degradable polymers such as polylactic acid and polylactic-co-glycolic acid have also been used in
periodontal treatment as stand-alone devices and combined with
hyaluronic acid for guided tissue regeneration (Park et al., 2009).
The suitability of the biologically absorbable polymers as bone
replacement material is being tested. A lot of preclinical in vivo
studies (e.g. in animal models) are being conducted with differing
success: in most cases, no complications have been found, though
inammatory reactions were sometimes observed.
A further domain of polymers is the eld of spatiotemporal
control of different drug delivery processes (De Koker et al., 2011a,
De Koker et al., 2011b, Costache et al., 2009). Polymer libraries do
exist for individual requirements concerning degradation time and
characteristics, encapsulation capacity and stability (Place et al.,
2009b). (Fig. 9) New classes of biomaterials on based on polymers
have been developed (Joy et al., 2011). Improved understanding of
the interaction between material properties and the cellular
behaviour and the methodology to incorporate biologically relevant properties into biomaterials is hereby a basic requirement
(Place et al., 2009a).
4.7. Calcium phosphate cements
These cements are two or three-component systems, which
consist of one or two powder components and an aqueous solution.
After combination they create a mouldable paste, which can be
4.5. Bio glasses (bioactive glasses)

Bioactive glasses (bioglasses) such as Biogran (BIOMET 3i; Palm
Beach Gardens, USA) are amorphous materials, based on acid
oxides (e.g. phosphorus pentoxide), silica (also alumina oxide) and
the alkalines (e.g. calcium oxide, magnesium oxide and zinc oxide).
Calcium uoride is also one of the bio glasses. During production,
the ground substances are mixed and melted for several hours at
approximately 1500 C. The resulting product is a threedimensional phosphorus oxide siliconeoxide network, on which
metal ions of basic oxide accumulate (Fig. 8). By HA-crystals
a mechanically strong bond between bioactive glass and bone
forms eventually similar to that of bone (Gross et al., 1981).
Bioglasses possess an interconnective pore system and are
available both in compact and porous forms (Schnurer et al., 2003).
The bioactivity of the surface enables the growth of osseous tissue
(Hollinger et al., 1996; Elhasid et al., 2000).
Fig. 9. Morphology and microstructure of PDLLA (Ro 203) (SEM image, magn. X 50).
applied directly or by using a syringe. Hardening happens in situ by

precipitation of the calcium phosphate connection (Claes et al.,
1997, Chow, 2001). The best-known representatives of the group
are Norian CRS/SRS (Synthes GmbH, Solothurn, Switzerland) and
BoneSource (Stryker GmbH & Co. KG, Duisburg Germany). The
powder components of these products consist of dicalcium
phosphate-anhydrate (DCPA) and tetra-calcium phosphate (TTCP).
For mixing, a sodium monophosphate solution is used. Norian CRS
consists of a-TCP, mono-calcium phosphate monohydrate, CaCO3
and liquid Na3PO4. Norian CRS hardens in situ to carbonated
apatite (Dhallite) as the nal product, which ultimately represents
a large part of the mineral phase of bone in its composition and
crystalline structure. Norian, as a paste, is processed and hardens
isothermally in a warm, damp environment in approximately 6e8
minutes and reaches its nal resistance after 12e24 hours, which
then has a compression resistance of 30e50 MPa. This is signicantly higher (two to six times) than the compression resistance of
autologous spongiosa. BoneSource consists of the powdery
components tetracalcium phosphate and dicalcium phosphate
dihydrate mixed with sodium monophosphate as solvent. The
curing phase runs isothermally after approx. 6e7 minutes and the
emerging cured nal product is pure HA [Ca10(PO4)6OH2], which
reaches a hardness corresponding to that of Norian after four to
six hours. BoneSource is dimensionally stable and is very similar
to Norian concerning remodelling to bone in the body via osteoclastic resorption. BoneSource has a long term positive experience
in use, as shown in many clinical and experimental studies
(Cunningham, 2005, Ambard and Mueninghoff, 2006), but this
material has limited indications for use in the eld of oral and
maxillofacial surgery and disintegrates, unlike Norian, in an
aqueous environment.
Practical experience shows that the turnover of raw materials
did not occur fully and the precipitates consisted of a mixture of the
source substances and newly formed precipitation products
The mechanical properties and dismantling behaviour of CP
cements depend on the composition of raw materials and their
processing (Fujikawa et al., 1995). As bone-mineral resorption
occurs within an osteoclast-mediated acidic microenvironment,
the material should have characteristics that render the apatite
soluble at an acidic pH. Carbonated apatite of low crystalline order
has been shown to have the greatest solubility at an acidic pH.
A key factor for mechanical stability is the porosity of the
cement. High porosity correlates with lower mechanical properties
although it encourages the degradation of the material and osseous
reconstruction (Takagi et al., 2001). As calcium phosphate cements
have a very low or even zero load-carrying capacity, areas of highpressure load always need a stabilizing osteosynthesis (Schnurer
et al., 2003).
CP cements are used for the lling of osseous defects and the
reconstruction of fractures, where integration and absorption is
promoted through a well supported vascularized implant bed
osteoconductive matrix for ingrowth of new bone; osteoinductive

proteins, which sustain mitogenesis of undifferentiated cells; and
osteogenic cells (osteoblasts or osteoblast precursors), which are
capable of forming bone in the proper environment.
Cornell and Lane developed a composite using a combination of
collagen, bone marrow and ceramics, which can overcome 90% of
these shortfallings (Cornell and Lane, 1992). Initial clinical results
suggest that this construct represents a highly effective bone
replacement material (Bucholz, 2002, Bucholz et al., 1987). The
most osteoinductive grafts may be composites of DMB bone matrix
and autologous bone marrow or human DMB with calcium
sulphate (CaSO4). The latter has been successfully applied in displaced intraarticular calcaneal fractures (Bibbo and Patel, 2006).
Currently, composite materials are being examined as an alternative to autogenic grafts in fresh human fracture sites to avoid any
harvesting discomfort (Vaccaro et al., 2002). A relatively new
composite is NanoBone (ARTOSS GmbH, Rostock, Germany)
(Fig. 10) which, in contrast to conventional HA ceramics, is
produced in a sol-gel process at temperatures of up to 700 C.
Consequently, all the nanocrystalline HA is unsintered. NanoBone
consists of 76% w/w nanocrystalline HA and 24% w/w silicon
dioxide (SiO2). The silicon dioxide supports adhesion of autologous
proteins to the surface, which promotes collagen and skeletal
development referred as remodelling. The silicon dioxide is an
important structural material for both collagen and bone. The solid
content is only approximately 20 vol.% due to the high porosity (e.g.
r cones structure) and its loosely-packed granules. Despite the
high porosity NanoBone has a relatively high mechanical breaking
resistance of approximately 40 MPa. This purely synthetic material
immediately assimilates into the body proteins and into the nano
pores, while being reduced by osteoclasts. After ve weeks,
formation of new trabecular bone has been observed in animal
experiments. After eight months the material was almost
completely dismantled by multinucleated giant cells as well as
demonstrating the early stages of woven bone in between the
material by osteoclasts (Abshagen et al., 2009, Bienengraber et al.,
2006).
Fortoss Vital (Biocomposites Ltd., Keele, England) is a
resorbable, fully-synthetic and osteoconductive bone replacement
5. Composite materials
In ideal cases composite biosynthetic materials have osteoconductive osteogenic and osteoinductive activities (Den Boer
et al., 2003, Smeets et al., 2009a). Because of the countless
combinations of inorganic and organic components no subdivision
of the composites is possible in practice (Schnurer et al., 2003).
Although new composites have become widely available, the
search for a suitable composite that can supplant autogenic bone
grafts continues (Vaccaro et al., 2002, Smeets et al., 2009a). Often
these materials consist of one or more components: an
Fig. 10. Morphology and microstructure of nano bone (SEM image, magn. X 50).
material consisting of porous calcium phosphate and calcium

sulphate. The biphasic composite has a viscous mouldable consistency. The fast absorption of calcium sulphates (which leads to
macro porosities) attracts cells and interstitial uid; this further
leads to the extraction of calcium phosphate particles, which is
converted by the osteoblasts (Smeets et al., 2009a).
easy-graft (Degradable solutions, Schlieren, Switzerland) is
a bioresorbable and fully synthetic osseous defect ller. It consists
of two components: On the one hand, granules (syringe-injectable)
and, on the other hand, a BioLinker. After mixing the material,
easy-graft is in a paste form and can be directly injected into the
injured tissues. When in contact with the body uids, the material
hardens within minutes and creates a stable but porously moulded
body. easy-graft is both biocompatible and osteoregenerative
(Fig. 11). For phase pure b-TCP and PLGA, inammatory reactions
were observed with appropriate dosages. The purity of the phase of
TCP allows a complete dismantling of the implant material in the
body (Heidemann et al., 2001). After introduction into the freshened osseous defect, the pore volume is lled with blood, which
provides supportive factors for the healing process. Tissue and bone
can grow into the augmentation material. Parallel to ossication,
Fig. 11. Morphology and microstructure of easy graft crystal (SEM image, magn.
X 400).
Table 2
Classication and general characteristics of bone replacement materials.
Bone graft substitutes
Properties
Grafts
Osteoconduction
Calcium sulphate
CP cements
Ceramics
Collagen
Synthetic polymers
Osteoinduction
DBM
Bone growth factors/cytokines e.g. BMPs
Genetic therapy
Osteogenesis
Combined
Bone marrow aspirate (BMA)

Composite grafts
easy-graft is slowly absorbed, thus locally releasing both calcium

and phosphate. According to the manufacturer, the material will be
completely replaced by bone within 9e15 months.
In addition easy-graft CRYSTAL is available which uses an
applicable syringe. It is also 100% synthetic, but now contains
additional HA components (60% HA/40% b-TCP), which are intended to improve the resorption properties. Unfortunately, there are
still no controlled clinical studies of any easy-graft material so it is
not yet possible to give any scientic statements about its effectiveness (Table 2).
6. BSM combined with growth factors
Among the bone growth factors tested in heterotopic and
orthotopic locations, bone morphogenic proteins (BMPs), either in
native (BMP) or recombinant forms (rhBMPs), appear to be the
most effective and therefore the most promising (Schmidmaier
et al., 2007; Cook et al., 1994; Fischer et al., 2011). BMPs enable
skeletal tissue formation during embryogenesis, growth, and
healing, as well as throughout adulthood (Reddi, 1992; Ripamonti
and Reddi, 1994; Kirker-Head, 2000; Fischer et al., 2011).
BMPs are low-molecular-weight glycoproteins that have
a pleomorphic function ranging from extracellular and skeletal
organogenesis to bone generation and regeneration (Fischer et al.,
2011). Bone induced by BMP in post-foetal life recapitulates the
process of embryonic and endochondral ossication. BMPs are
important regulators in osteogenic differentiation during fracture
repair. Clinically, native human BMP has been used successfully for
the treatment of established non unions and spinal fusions.
Generally the clinical application of native bone growth factors
without any carrier is mainly limited by their short half-life and the
problem of delivery (Fischer et al., 2011; Smeets et al., 2009b).
Carriers have an important role in maintaining the BMP concentration at the target site for sufcient time to promote chemotaxis,
migration of bone-forming cells to the target site as well as the
proliferation and differentiation of these cells (Seeherman et al.,
2002; Dai et al., 2005; Smeets et al., 2009b).
Under certain circumstances matrices can also act as a scaffold to
allow cell recruitment, attachment, proliferation, and differentiation (Fischer et al., 2011). Excellent carrier/scaffold delivery systems
for rhBMP-2 are calcium hydroxyapatite ceramics, a synthetic
biodegradable polymer/interconnected-porous composite, strongly
promoting the clinical effects of rhBMP-2 in new bone (Kaito et al.,
2005). Clinical approval has been given to Osigraft (Stryker GmbH
& Co. KG, Duisburg Germany) which contains the recombinant
osteogenic human Protein-7 (rhBMP-7), also known as eptotermin
alfa, which works osteoinductively. It belongs to the transforming
growth factor super family (TGF-b), inducing growth and differentiation of stem cells into different specic tissue cells. Human
rhBMP-2 is a very promising composite, with beta-TCP having
osteogenicity and efciency even for repairing large bone defects
(Hoshino et al., 2006). The synthetic biodegradable polymer/
interconnected-porous calcium HA ceramics composite (IP-CHA)
is an excellent combination carrier/scaffold delivery system for
recombinant bone morphogenetic protein-2 (rhBMP-2), that
strongly promotes the clinical effects of rhBMP-2 in bone tissue
regeneration. The osteoinductive effectiveness depends on the
activation of the bodys cascade of bone formation. Type I collagen
supports this material as it offers a good framework for boneforming cells. Osigraft is a Humanitarian Use Device with FDA
approval for autograft substitute in long bone non-unions. Until
recently, Osigraft had no clinical authorization for dental surgery.
PMA approved rhBMP-2 (INFUSE Bone Graft, Medtronic, USA,
rhBMP-2 combined with collagen eece) has limited FDA approval
as an autograft replacement material for the certain indications
10
spinal fusion, open tibia fracture treatment and sinus grafting. There
is no general worldwide approval for dental surgery.
7. BSM with living cells
Composite biosynthetic transplants consist of a carrier as an
osteoconductive scaffold combined with osteogenic cells and/or
growth factors (Lane et al., 1999; Vaccaro et al., 2002). A combined
graft contains osteogenic cells and cytokines along with a BSM as
a synthetic osteoconductive matrix. Composite materials being
tested in preclinical and clinical trials may exhibit functionality
comparable to autografts and allografts. Composite synthetic grafts
offer an alternative that can potentially unite the three essential
bone-forming properties in more controlled and effective
combinations without the disadvantages found with autografts
(Handschel et al., 2010). The osteoconductive matrix becomes
a delivery system for bioactive agents, requiring less chemotaxis
and less migration of osteoblast progenitor cells to the graft site.
The direct infusion of progenitor cells should lead to more rapid
and consistent bone recovery (Kahle et al., 2010). When an osteoconductive scaffold is seeded with bone marrow aspirate or BMP,
for example, the composite graft may become both osteogenic and
osteoinductive, providing a competitive alternative to autografting
(Handschel et al., 2010). One of this promising alternatives is an
allograft cellular bone matrix containing native MSCs (Osteocel
Plus, NuVasive, Inc. USA), which have recently become available.
This BSM intends to mimic the biologic performance of autograft
without the morbidity associated with the autograft harvest.
Because the material contains living stem cells which provide
osteogenic potential, it is different from other orthobiologic products such as DBM and allograft cancellous bone because the cell
content consists of mesenchymal stem cells from an adult human
donor and not from an embryonic source.
Another option with high osteogenic potential comparable with
autografts is given by an adult human stem cell bone graft
(AlloStem, AlloSource, Denver, Colorado, USA). As adipose tissue is
a rich source of different stem cells, and some laboratory studies
have shown that it is the human bodys best primary source of
many stem cells, it is recovered from adult human adipose tissue
and is processed and cryopreserved by the manufacturer into
a stem cell bone graft (Tang et al., 2011).
8. Final evaluation of the indications for BSM
BSM can create adequate bone formation for clinical use,
depending on the indication. BSM can be used successfully in sinus
oor elevation as well as in augmentation of three-dimensional
defects up to a certain volume. Larger defect situations require
more permeable BSMs, with a minimum interconnecting pore
channel diameter of 250e300 mm for better neovascularization and
osteoconduction. In absolute vertical or horizontal alveolar ridge
augmentation procedures under compromised bone layer conditions a BSM should either not be used or at best combined with
the bodys own bone as a natural composite graft. Contraindications for BSM, due to a high failure risk, are immunodeciency
disorders, interleukin-1-polymorphism, severe periodontitis, bad
oral hygiene and i.v. biphosphonate treatment.
Human allogenic materials with good biocompatibility are

accompanied by a small risk of HIV- or HCV- infection and prion
transmission. The available osteoconductive materials of HA and
TCP origin have comparably good biocompatibilities but also have
different mechanical stabilities and lack osteoinductivity.
Because of this cell-based approaches have increasingly become
a focus of interest. Currently four different cell-based tissue-engineering approaches have been described, which involve the
implantation of: (I) unfractionated fresh bone marrow; (II) puried,
culture-expanded MSCs; (III) differentiated osteoblasts and (IV)
cells that have been modied genetically to express rhBMP. To
optimize and modulate bone formation, it is critical to understand
the expression patterns of the key bone specic growth factors
involved in the processes of maturation and mineralization. The
addition of osteoinductive agents to osteoconductive materials will
mimic the osteogenic ability of autogenous bone without the
morbidity associated with harvest surgery. In the future BSM will
convert from a simple lling substance to an innovative biomaterial
in the sense of a scaffold, which will play an important role in bone
tissue engineering applications. These scaffolds serve as temporary
space llers within anatomic deformities, while providing initial
mechanical support necessary for early bone regeneration to occur
(Hollister et al., 2005, Rezwan et al., 2006).
Future biosynthetic bone replacement materials may obviate
the need for autologous bone harvesting. Combining osteoinductive proteins with an osteoconductive carrier medium to facilitate
timed-release delivery and/or to provide a material scaffold for
bone formation is gaining increasing interest. The modication of
bone replacement materials by adding bioactive surfaces accelerates osseous integration and extends the range of suitability.
Inuencing chemical and mechanical properties by different
manufacturing techniques offers the ability to adjust specic
materials to the application site by changing the rate of bioresorption, mechanical strength, and porosity. In addition the
topographical nature of the biomaterial surface has a direct inuence on cellular adhesion and proliferation (Roohani-Esfahani et al.,
2010). Highly effective osteoinductive growth factors (e.g. from the
BMP-family) can lead to rapid regeneration of bony defects, but
because of the associated insufcient vascularisation, the shortterm induced bone quality does not always guarantee long-term
success for the defective region. Clinical studies involving
doseeresponse ratios are pending, which should elucidate the
necessary cytokine concentrations. Possible future solutions are
vaccinations of BSM with biological ligands such as combinations of
osteogenic and vessel-forming growth factors. Other approaches
involve the use of plasmids and the DNA of the desired cytokines
(Fischer et al., 2011, Kolk et al., 2011). To eliminate all safety
concerns for integration into genomes of cells with potential
mutagenesis, siRNA (small interfering RNA) may be used instead of
DNA in the future. Tissue engineering of bones, using osteogenic
differentiated MSCs in conjunction with microsurgical grafts, is an
additional future eld of interest (Warnke et al., 2009; Warnke
et al., 2006; Fischer et al., 2011). However, the successful in-vitro
processes of bone differentiation and maturation still lacks meaningful fundamental research work particularly as it pertains to the
inuence of pleiotropic cytokines, specic transcription factors and
osteoprogenitor cells (Kolk et al., 2011).
Acknowledgement
9. Summary and future outlook

For different bone augmentation (e.g. the creation of a sufcient
peri-implant bone bedding for successful long-term implantation),
(I) autologous bone alone, (II) autologous bone in combination with
BSM and (III) and BSM alone are all established materials.
The authors thank the following companies for providing samples

of the respective imaging materials: ARTOSS GmbH, Rostock,
Germany; Botiss Dental GmbH, Berlin, Germany; Degradable Solutions, Schlieren, Switzerland; DENTSPLY Friadent, Mannheim, Germany; Geistlich AG, Wolhusen, Switzerland; RIEMSER Arzneimittel
AG, Greifswald - Insel Riems, Germany; Synthes GmbH, Solothurn,

Switzerland; Zimmer Dental GmbH, Freiburg, Germany.
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Journal of Cranio-Maxillo-Facial Surgery xxx (2012) 1e13

Contents lists available at SciVerse ScienceDirect

Journal of Cranio-Maxillo-Facial Surgery

Current trends and future perspectives of bone substitute

A. Kolk et al. / Journal of Cranio-Maxillo-Facial Surgery xxx (2012) 1e13

structural and subsequent biological properties will embrace a lot of

be vascularized with an adequate diameter (>approx. 100 mm)

2. Variety of bone replacement materials

Biocompatibility ensures the absence of toxicity, teratogenity or

Materials are subdivided into harvested bone grafts and graft

A. Kolk et al. / Journal of Cranio-Maxillo-Facial Surgery xxx (2012) 1e13

4. BSM combined with growth factors

3.1. Autogenous transplants

it is still possible. The more aggressive the allograft processing, the

A. Kolk et al. / Journal of Cranio-Maxillo-Facial Surgery xxx (2012) 1e13

materials differ in terms of the manufacturing process and the type

3.4. Xenogenic material

Porous natural hydroxyapatite (HA) can be obtained from

OsteoGraf N (DENTSPLY Friadent, Mannheim, Germany)

A. Kolk et al. / Journal of Cranio-Maxillo-Facial Surgery xxx (2012) 1e13

Fig. 4. Morphology and microstructure of Algipore (SEM image, magn. X 100).

3.5. Phytogenic material

A. Kolk et al. / Journal of Cranio-Maxillo-Facial Surgery xxx (2012) 1e13

tissue interface. Consequently, the osteoid mineralises and the

Fig. 6. Morphology and microstructure of HA (SEM image, magn. X 50).

35e50% and a pore diameter of 100e300 mm is commonly used

b-TCP (>99%) is completely absorbed within a few months at the

A. Kolk et al. / Journal of Cranio-Maxillo-Facial Surgery xxx (2012) 1e13

4.6. Polymer-based bone graft substitutes

Fig. 7. Morphology and microstructure of TCP (SEM image, magn. X 50).

Cerasorb M is a fully synthetic manufactured granule

4.5. Bio glasses (bioactive glasses)

A. Kolk et al. / Journal of Cranio-Maxillo-Facial Surgery xxx (2012) 1e13

applied directly or by using a syringe. Hardening happens in situ by

osteoconductive matrix for ingrowth of new bone; osteoinductive

A. Kolk et al. / Journal of Cranio-Maxillo-Facial Surgery xxx (2012) 1e13

material consisting of porous calcium phosphate and calcium

Bone marrow aspirate (BMA)

easy-graft is slowly absorbed, thus locally releasing both calcium

A. Kolk et al. / Journal of Cranio-Maxillo-Facial Surgery xxx (2012) 1e13

Human allogenic materials with good biocompatibility are

9. Summary and future outlook

The authors thank the following companies for providing samples

A. Kolk et al. / Journal of Cranio-Maxillo-Facial Surgery xxx (2012) 1e13

AG, Greifswald - Insel Riems, Germany; Synthes GmbH, Solothurn,

A. Kolk et al. / Journal of Cranio-Maxillo-Facial Surgery xxx (2012) 1e13

Osborn JF, Newesely H: The material science of calcium phosphate ceramics.

A. Kolk et al. / Journal of Cranio-Maxillo-Facial Surgery xxx (2012) 1e13

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