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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
biocompatibility
osteoinduction and osteopromotion/osteoconduction
porosity
stability under stress
resorbability/degradability
plasticity
sterility
stable and long-term integration of implants
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
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
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.
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
Fig. 2. Morphology and microstructure of Bioss granules (SEM image, magn. X 50).
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
4.1. Hydroxyapatite
Fig. 5. Morphology and microstructure of Cerabone (bovine HA) (SEM image, magn.
X 50).
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
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
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
Fig. 8. Morphology and microstructure of glass granulate (SEM image, magn. X 50).
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
Fig. 9. Morphology and microstructure of PDLLA (Ro 203) (SEM image, magn. X 50).
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
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).
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
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
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
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.
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
References
Abramovitch-Gottlib L, Geresh S, Vago R: Biofabricated marine hydrozoan:
a bioactive crystalline material promoting ossication of mesenchymal stem
cells. Tissue Eng 12: 729e739, 2006
Abshagen K, Schrodi I, Gerber T, Vollmar B: In vivo analysis of biocompatibility and
vascularization of the synthetic bone grafting substitute NanoBone. J Biomed
Mater Res A 91: 557e566, 2009
Aebi M, Zuber K, Marchesi D: Treatment of cervical spine injuries with anterior
plating. Indications, techniques, and results. Spine (Phila Pa 1976) 16: S38eS45,
1991
Ambard AJ, Mueninghoff L: Calcium phosphate cement: review of mechanical and
biological properties. J Prosthodont 15: 321e328, 2006
Asti A, Visai L, Dorati R, Conti B, Saino E, Sbarra S, Gastaldi G, Benazzo F: Improved
cell growth by Bio-Oss/PLA scaffolds for use as a bone substitute. Technol
Health Care 16: 401e413, 2008
Barth A: Histologische Untersuchung ber Knochenimplantationen. Beitr Pathol
Anat Allg Pathol 17: 65e142, 1895
Bibbo C, Patel DV: The effect of demineralized bone matrix-calcium sulfate with
vancomycin on calcaneal fracture healing and infection rates: a prospective
study. Foot Ankle Int 27: 487e493, 2006
Bienengraber V, Gerber T, Henkel KO, Bayerlein T, Proff P, Gedrange T: The clinical
application of a new synthetic bone grafting material in oral and maxillofacial
surgery. Folia Morphol (Warsz) 65: 84e88, 2006
Birk RZ, Abramovitch-Gottlib L, Margalit I, Aviv M, Forti E, Geresh S, Vago R:
Conversion of adipogenic to osteogenic phenotype using crystalline porous
biomatrices of marine origin. Tissue Eng 12: 21e31, 2006
Biswas A, Bayer IS, Zhao H, Wang T, Watanabe F, Biris AS: Design and synthesis of
biomimetic multicomponent all-bone-minerals bionanocomposites. Biomacromolecules 11: 2545e2549, 2010
Boccaccini AR, Blaker JJ: Bioactive composite materials for tissue engineering
scaffolds. Expert Rev Med Devices 2: 303e317, 2005
Bohner M: Calcium orthophosphates in medicine: from ceramics to calcium
phosphate cements. Injury 31(Suppl. 4): 37e47, 2000
Bostrom MP, Seigerman DA: The clinical use of allografts, demineralized bone
matrices, synthetic bone graft substitutes and osteoinductive growth factors:
a survey study. Hss J 1: 9e18, 2005
Brandoff JF, Silber JS, Vaccaro AR: Contemporary alternatives to synthetic bone
grafts for spine surgery. Am J Orthop (Belle Mead NJ) 37: 410e414, 2008
Bucholz RW: Nonallograft osteoconductive bone graft substitutes. Clin Orthop Relat
Res: 44e52, 2002
Bucholz RW, Carlton A, Holmes RE: Hydroxyapatite and tricalcium phosphate bone
graft substitutes. Orthop Clin North Am 18: 323e334, 1987
Buser D, Hoffmann B, Bernard JP, Lussi A, Mettler D, Schenk RK: Evaluation of lling
materials in membrane-protected bone defects. A comparative histomorphometric study in the mandible of miniature pigs. Clin Oral Implants Res 9:
137e150, 1998
Chesnutt BM, Viano AM, Yuan Y, Yang Y, Guda T, Appleford MR, Ong JL,
Haggard WO, Bumgardner JD: Design and characterization of a novel chitosan/
nanocrystalline calcium phosphate composite scaffold for bone regeneration.
J Biomed Mater Res A 88: 491e502, 2009
Chow LC: Solubility of calcium phosphates. Monogr Oral Sci 18: 94e111, 2001
Claes L, Augat P, Suger G, Wilke HJ: Inuence of size and stability of the osteotomy
gap on the success of fracture healing. J Orthop Res 15: 577e584, 1997
Conrad EU, Gretch DR, Obermeyer KR, Moogk MS, Sayers M, Wilson JJ, Strong DM:
Transmission of the hepatitis-C virus by tissue transplantation. J Bone Joint Surg
Am 77: 214e224, 1995
Cook SD, Baffes GC, Wolfe MW, Sampath TK, Rueger DC: Recombinant human bone
morphogenetic protein-7 induces healing in a canine long-bone segmental
defect model. Clin Orthop Relat Res: 302e312, 1994
Cornell CN: Osteoconductive materials and their role as substitutes for autogenous
bone grafts. Orthop Clin North Am 30: 591e598, 1999
Cornell CN, Lane JM: Newest factors in fracture healing. Clin Orthop Relat Res:
297e311, 1992
Costache AD, Sheihet L, Zaveri K, Knight DD, Kohn J: Polymer-drug interactions in
tyrosine-derived triblock copolymer nanospheres: a computational modeling
approach. Mol Pharm 6: 1620e1627, 2009
Cunningham LL: The use of calcium phosphate cements in the maxillofacial region.
J Long Term Eff Med Implants 15: 609e615, 2005
Daculsi G, Legeros RZ, Heughebaert M, Barbieux I: Formation of carbonate-apatite
crystals after implantation of calcium phosphate ceramics. Calcif Tissue Int
46: 20e27, 1990
Dai KR, Xu XL, Tang TT, Zhu ZA, Yu CF, Lou JR, Zhang XL: Repairing of goat tibial bone
defects with BMP-2 gene-modied tissue-engineered bone. Calcif Tissue Int 77:
55e61, 2005
Damien E, Revell PA: Coralline hydroxyapatite bone graft substitute: A review of
experimental studies and biomedical applications. J Appl Biomater Biomech 2:
65e73, 2004
11
De Koker S, De Cock LJ, Rivera Gil P, Parak WJ, Auzely Velty R, Vervaet C, Remon JP,
Grooten J, De Geest BG: Polymeric multilayer capsules delivering biotherapeutics. Adv Drug Deliv Rev, 2011a
De Koker S, Lambrecht BN, Willart MA, Van Kooyk Y, Grooten J, Vervaet C, Remon JP,
De Geest BG: Designing polymeric particles for antigen delivery. Chem Soc Rev
40: 320e339, 2011b
Den Boer FC, Wippermann BW, Blokhuis TJ, Patka P, Bakker FC, Haarman HJ:
Healing of segmental bone defects with granular porous hydroxyapatite
augmented with recombinant human osteogenic protein-1 or autologous bone
marrow. J Orthop Res 21: 521e528, 2003
Eggli PS, Muller W, Schenk RK: Porous hydroxyapatite and tricalcium phosphate
cylinders with two different pore size ranges implanted in the cancellous bone
of rabbits. A comparative histomorphometric and histologic study of bony
ingrowth and implant substitution. Clin Orthop Relat Res: 127e138, 1988
Ehrler DM, Vaccaro AR: The use of allograft bone in lumbar spine surgery. Clin
Orthop Relat Res: 38e45, 2000
Elhasid R, Ben Arush MW, Katz T, Gan Y, Shechter Y, Sami I, Postovsky S, Reisner Y,
Rowe JM: Successful haploidentical bone marrow transplantation in Fanconi
anemia. Bone Marrow Transplant 26: 1221e1223, 2000
Ewers R: Maxilla sinus grafting with marine algae derived bone forming material:
a clinical report of long-term results. J Oral Maxillofac Surg 63: 1712e1723,
2005
Fernandes PG, Novaes Jr AB, De Queiroz AC, De Souza SL, Taba Jr M, Palioto DB,
Mf Grisi: Ridge preservation with acellular dermal matrix and anorganic bone
matrix cell-binding peptide P-15 after tooth extraction in humans. J Periodontol
82: 72e79, 2011
Fischer J, Kolk A, Wolfart S, Pautke C, Warnke PH, Plank C, Smeets R: Future of local
bone regeneration e Protein versus gene therapy. J Craniomaxillofac Surg 39:
54e64, 2011
Fleming Jr JE, Cornell CN, Muschler GF: Bone cells and matrices in orthopedic tissue
engineering. Orthop Clin North Am 31: 357e374, 2000
Fujikawa K, Sugawara A, Murai S, Nishiyama M, Takagi S, Chow LC: Histopathological reaction of calcium phosphate cement in periodontal bone defect. Dent
Mater J 14: 45e57, 1995
Fulmer MT, Ison IC, Hankermayer CR, Constantz BR, Ross J: Measurements of the
solubilities and dissolution rates of several hydroxyapatites. Biomaterials 23:
751e755, 2002
Gamradt SC, Lieberman Jr : Bone graft for revision hip arthroplasty: biology and
future applications. Clin Orthop Relat Res: 183e194, 2003
Gerressen M, Hermanns-Sachweh B, Riediger D, Hilgers RD, Spiekermann H,
Ghassemi A: Purely cancellous vs. corticocancellous bone in sinus oor
augmentation with autogenous iliac crest: a prospective clinical trial. Clin Oral
Implants Res 20: 109e115, 2009
Gross U, Brandes J, Strunz V, Bab I, Sela J: The ultrastructure of the interface
between a glass ceramic and bone. J Biomed Mater Res 15: 291e305, 1981
Habibovic P, de Groot K: Osteoinductive biomaterialseproperties and relevance in
bone repair. J Tissue Eng Regen Med 1: 25e32, 2007
Handschel J, Berr K, Depprich R, Naujoks C, Kubler NR, Meyer U, Ommerborn M,
Lammers L: Compatibility of embryonic stem cells with biomaterials. J Biomater
Appl 23: 549e560, 2009a
Handschel J, Naujoks C, Langenbach F, Berr K, Depprich RA, Ommerborn MA,
Kubler NR, Brinkmann M, Kogler G, Meyer U: Comparison of ectopic bone
formation of embryonic stem cells and cord blood stem cells in vivo. Tissue Eng
Part A 16: 2475e2483, 2010
Handschel J, Simonowska M, Naujoks C, Depprich RA, Ommerborn MA, Meyer U,
Kubler NR: A histomorphometric meta-analysis of sinus elevation with various
grafting materials. Head Face Med 5: 12, 2009b
Handschel J, Wiesmann HP, Stratmann U, Kleinheinz J, Meyer U, Joos U: TCP is
hardly resorbed and not osteoconductive in a non-loading calvarial model.
Biomaterials 23: 1689e1695, 2002
Heidemann W, Jeschkeit S, Rufeux K, Fischer JH, Wagner M, Kruger G,
Wintermantel E, Gerlach KL: Degradation of poly(D, L)lactide implants with or
without addition of calciumphosphates in vivo. Biomaterials 22: 2371e2381,
2001
Hertz A, Bruce IJ: Inorganic materials for bone repair or replacement applications.
Nanomedicine (Lond) 2: 899e918, 2007
Hing KA, Annaz B, Saeed S, Revell PA, Buckland T: Microporosity enhances bioactivity of synthetic bone graft substitutes. J Mater Sci Mater Med 16: 467e475,
2005
Hollinger JO, Brekke J, Gruskin E: Lee D Role of bone substitutes. Clin Orthop Relat
Res: 55e65, 1996
Hollister SJ, Lin CY, Saito E, Schek RD, Taboas JM, Williams JM, Partee B, Flanagan CL,
Diggs A, Wilke EN, Van Lenthe GH, Muller R, Wirtz T, Das S, Feinberg SE,
Krebsbach PH: Engineering craniofacial scaffolds. Orthod Craniofac Res 8:
162e173, 2005
Horch HH, Sader R, Pautke C, Neff A, Deppe H, Kolk A: Synthetic, pure-phase betatricalcium phosphate ceramic granules (Cerasorb) for bone regeneration in the
reconstructive surgery of the jaws. Int J Oral Maxillofac Surg 35: 708e713, 2006
Hoshino M, Egi T, Terai H, Namikawa T, Takaoka K: Repair of long intercalated rib
defects using porous beta-tricalcium phosphate cylinders containing recombinant human bone morphogenetic protein-2 in dogs. Biomaterials 27:
4934e4940, 2006
Huang J, Best SM, Boneld W, Brooks RA, Rushton N, Jayasinghe SN, Edirisinghe MJ:
In vitro assessment of the biological response to nano-sized hydroxyapatite.
J Mater Sci Mater Med 15: 441e445, 2004
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12
Joy A, Cohen DM, Luk A, Anim-Danso E, Chen C, Kohn J: Control of surface chemistry, substrate stiffness, and cell function in a novel terpolymer methacrylate
library. Langmuir 27: 1891e1899, 2011
Kahle M, Wiesmann HP, Berr K, Depprich RA, Kubler NR, Naujoks C, Cohnen M,
Ommerborn MA, Meyer U, Handschel J: Embryonic stem cells induce ectopic
bone formation in rats. Biomed Mater Eng 20: 371e380, 2010
Kaito T, Myoui A, Takaoka K, Saito N, Nishikawa M, Tamai N, Ohgushi H, Yoshikawa H:
Potentiation of the activity of bone morphogenetic protein-2 in bone regeneration by a PLA-PEG/hydroxyapatite composite. Biomaterials 26: 73e79, 2005
Kamitakahara M, Ohtsuki C, Miyazaki T: Review paper: behavior of ceramic
biomaterials derived from tricalcium phosphate in physiological condition.
J Biomater Appl 23: 197e212, 2008
Kao ST, Scott DD: A review of bone substitutes. Oral Maxillofac Surg Clin North Am
19: 513e521, 2007 vi
Katz JM, Nataraj C, Jaw R, Deigl E, Bursac P: Demineralized bone matrix as an
osteoinductive biomaterial and in vitro predictors of its biological potential.
J Biomed Mater Res B Appl Biomater 89: 127e134, 2009
Khan SN, Cammisa Jr FP, Sandhu HS, Diwan AD, Girardi FP, Lane JM: The biology of
bone grafting. J Am Acad Orthop Surg 13: 77e86, 2005
Kirker-Head: Ca Potential applications and delivery strategies for bone morphogenetic proteins. Adv Drug Deliv Rev 43: 65e92, 2000
Kirmeier R, Payer M, Lorenzoni M, Wegscheider WA, Seibert FJ, Jakse N: Harvesting of cancellous bone from the proximal tibia under local anesthesia:
donor site morbidity and patient experience. J Oral Maxillofac Surg 65:
2235e2241, 2007
Klawitter JJ, Weinstein AM: The status of porous materials to obtain direct skeletal
attachment by tissue ingrowth. Acta Orthop Belg 40: 755e765, 1974
Klein CP, Driessen AA, De Groot K, Van Den Hooff A: Biodegradation behavior of
various calcium phosphate materials in bone tissue. J Biomed Mater Res 17:
769e784, 1983
Kolk A, Haczek C, Koch C, Vogt S, Kullmer M, Pautke C, Deppe H, Plank CA: strategy
to establish a gene-activated matrix on titanium using gene vectors protected in
a polylactide coating. Biomaterials 32: 6850e6859, 2011
Koster K, Karbe E, Kramer H, Heide H, Konig R: Experimental bone replacement
with resorbable calcium phosphate ceramic (authors transl). Langenbecks Arch
Chir 341: 77e86, 1976
Kubler N, Reuther J, Kirchner T, Priessnitz B, Michel C, Eckstein T, Ordung R,
Zerdoner D, Meier C: Osteoinductive, morphologic and biomechanical properties and clinical use of autolysed, antigen extracted, allogenic bone. Fortschr
Kiefer Gesichtschir 39: 28e31, 1994
Lane JM, Tomin E, Bostrom MP: Biosynthetic bone grafting. Clin Orthop Relat Res:
S107eS117, 1999
Laurencin C, Khan Y, El-Amin SF: Bone graft substitutes. Expert Rev Med Devices 3:
49e57, 2006
Lu J, Descamps M, Dejou J, Koubi G, Hardouin P, Lemaitre J, Proust JP: The
biodegradation mechanism of calcium phosphate biomaterials in bone.
J Biomed Mater Res 63: 408e412, 2002
Mardas N, Chadha V, Donos N: Alveolar ridge preservation with guided bone
regeneration and a synthetic bone substitute or a bovine-derived xenograft:
a randomized, controlled clinical trial. Clin Oral Implants Res 21(7): 688e698,
2010
Maus U, Andereya S, Gravius S, Ohnsorge JA, Niedhart C, Siebert CH: BMP-2
incorporated in a tricalcium phosphate bone substitute enhances bone
remodeling in sheep. J Biomater Appl 22: 559e576, 2008a
Maus U, Andereya S, Ohnsorge JA, Gravius S, Siebert CH, Niedhart CA: bFGF/TCPcomposite inhibits bone formation in a sheep model. J Biomed Mater Res B Appl
Biomater 85: 87e92, 2008b
McAllister BS, Haghighat K: Bone augmentation techniques. J Periodontol 78:
377e396, 2007
McAndrew MP, Gorman PW, Lange TA: Tricalcium phosphate as a bone graft
substitute in trauma: preliminary report. J Orthop Trauma 2: 333e339, 1988
McKee MD: Management of segmental bony defects: the role of osteoconductive
orthobiologics. J Am Acad Orthop Surg 14: S163eS167, 2006
Middleton JC, Tipton AJ: Synthetic biodegradable polymers as orthopedic devices.
Biomaterials 21: 2335e2346, 2000
Misch CE, Dietsh F: Bone-grafting materials in implant dentistry. Implant Dent 2:
158e167, 1993
Mittelmeier H, Mittelmeier W, Gleitz M: Pyrost, a spongious, mineral bone
substitute. Experimental bases and 13-year clinical experience in over 1000
cases. Orthopade 27: 126e135, 1998
Naujoks C, Langenbach F, Berr K, Depprich R, Kubler N, Meyer U, Handschel J,
Kogler G: Biocompatibility of osteogenic predifferentiated human cord blood
stem cells with biomaterials and the inuence of the biomaterial on the process
of differentiation. J Biomater Appl 25: 497e512, 2011
Nkenke E, Weisbach V, Winckler E, Kessler P, Schultze-Mosgau S, Wiltfang J,
Neukam FW: Morbidity of harvesting of bone grafts from the iliac crest for
preprosthetic augmentation procedures: a prospective study. Int J Oral Maxillofac Surg 33: 157e163, 2004
Nomura T, Katz JL, Powers MP, Saito C: Evaluation of the micromechanical elastic
properties of potential bone-grafting materials. J Biomed Mater Res B Appl
Biomater 73: 29e34, 2005
Noshi T, Yoshikawa T, Ikeuchi M, Dohi Y, Ohgushi H, Horiuchi K, Sugimura M,
Ichijima K, Yonemasu K: Enhancement of the in vivo osteogenic potential of
marrow/hydroxyapatite composites by bovine bone morphogenetic protein.
J Biomed Mater Res 52: 621e630, 2000
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
13
Warnke PH, Wiltfang J, Springer I, Acil Y, Bolte H, Kosmahl M, Russo PA, Sherry E,
Lutzen U, Wolfart S, Terheyden H: Man as living bioreactor: fate of an exogenously prepared customized tissue-engineered mandible. Biomaterials 27:
3163e3167, 2006
Wiltfang J, Merten HA, Schlegel KA, Schultze-Mosgau S, Kloss FR, Rupprecht S,
Kessler P: Degradation characteristics of alpha and beta tri-calcium-phosphate
(TCP) in minipigs. J Biomed Mater Res 63: 115e121, 2002
Xu HH, Weir MD, Sun L: Calcium and phosphate ion releasing composite: effect of
pH on release and mechanical properties. Dent Mater 25: 535e542, 2009
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