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Allograft bone matrix versus synthetic bone

graft substitutes
Article in Injury August 2011
DOI: 10.1016/j.injury.2011.06.199 Source: PubMed

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Injury, Int. J. Care Injured 42 (2011) S16S21

Contents lists available at ScienceDirect

Injury
journal homepage: www.elsevier.com/locate/injury

Allograft bone matrix versus synthetic bone graft substitutes

Gerald Zimmermann a,*, Arash Moghaddam b,c
a
b

Theresienkrankenhaus Mannheim, Department of Trauma and Orthopaedic Surgery, University of Heidelberg, Germany
BG Trauma Centre, Ludwigshafen Department of Trauma and Orthopaedic Surgery, University of Heidelberg, Germany

A R T I C L E I N F O

A B S T R A C T

Keywords:
Synthetic bone substitutes
Bone morphogenetic protein
Demineralized bone matrix
Allograft

Autologous bone is used very often in the treatment of fresh fractures, delayed unions and non-unions.
Alternatives have included allografts and in recent years also demineralized bone matrix. The growing
availability of good synthetic bone grafts and their advantages in safety and avoiding donor-site
morbidity are the reasons that these products are being used more and more. There are on the market a
wide variety of substitutes with different capabilities. Nevertheless autologous bone graft is still
considered as the gold standard and will be discussed here in that context. Osteoconductive, osteogenic
and osteoinductive products will also be classied and their advantages and disadvantages described.
2011 Elsevier Ltd. All rights reserved.

Introduction
According to the diamond concept, which includes the
prerequisites for bone healing and treatment of defects, bone
substitutes are an important component. The four parts of the
diamond concept are:





osteogenic cells
scaffolds
growth factors
mechanical stability.

All of the following substances and substitutes can provide one or

more or even all of the four parts. However, in most cases we do not
yet have the ideal implant, and we may need a combination of
substrates or have to accept compromises. Moreover, good studies
are often not available (Table 1), and the market gets overloaded
with new products from a rising number of companies. This paper
aims to give a comprehensive overview of principal advantages and/
or problems of the main groups of bone substitutes.
Bone grafts
Autologous bone grafts
Autologous bone grafts are considered as the gold standard for
nearly all indications of bone space lling to load bearing

* Corresponding author. Tel.: +49 621 424 0.

E-mail addresses: g.zimmermann@theresienkrankenhaus.de (G. Zimmermann),
a.moghaddam@bgu-ludwigshafen.de (A. Moghaddam).
c
Tel.: +49 621 6810 0.
00201383/$ see front matter 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.injury.2011.06.199

replacement in the human skeleton. They offer no immunological

rejection and are thought to provide the best osteoconductive,
osteogenic and osteoinductive properties.60 Autologous tricortical
grafts can offer structural support to implanted devices and ultimately
become mechanically efcient structures as they are incorporated
into surrounding bone through creeping substitution.34 However,
they suffer from resorption, limited availability and viability.
The theoretical advantage of osteogenic, osteoconductive and
osteoinductive properties is diminished through the fact that the
cells inside the graft will not survive longer than 2 h, and the
ideal60 ultrastructure of the cancellous bone is altered through
the transplantation process, which should effectively support the
ingrowth of new blood vessels and the inltration of new
osteoblasts and osteoblast precursors.48 The principal advantage
of autologous cancellous grafts is that only the potential
osteoprogenitor cells are transferred to the recipient site.
Cancellous graft does not provide immediate structural support;
it integrates quickly, and ultimately achieves strength equivalent
to a cortical graft within 612 months.28
Autologous cortical grafts are mostly osteoconductive, but the
surviving osteoblasts do provide some osteogenic properties as
well.19,20 Non-vascularized cortical grafts provide immediate
structural support; they become weaker than vascularized cortical
grafts during the initial 6 weeks after transplantation as a result of
resorption and revascularization.19,20,62 Vascularized cortical
grafts heal rapidly at the hostgraft-interface, and their remodelling is similar to that of normal bone in a fresh fracture.
Vascularized grafts do not undergo resorption and revascularization. Therefore they28 provide superior strength during the rst 6
weeks.19 On the other hand, if a bone graft is fragmented into small
particles, even cancellous bone is killed and will no longer be
osteogenic.2,6 The main advantages of autologous cancellous graft
are their excellent success rate and low risk of disease transmis-

G. Zimmermann, A. Moghaddam / Injury, Int. J. Care Injured 42 (2011) S16S21

Table 1
Evidence of application of bone substitutes.
Bone graft substitute
Osteoinductive
Allograft bone
Demineralized bone matrix
Puried human bone morphogenetic protein
(BMP) (not commercially available)
OP-1 device
INFUSE
Osteoconductive
CaPO4
CaSO4
Allograft
Hydroxyapatite
Osteogenic and osteopromotive
Selective cellular retention
Bone-marrow aspirate injection/implantation
Platelet-rich plasma and blood concentrates

Grade of
recommendation
I
C
C
A
A
B
B
C
A
I
B
I

A, good evidence (level-I studies with consistent ndings) for or against

recommending intervention; B, fair evidence (level-II or -III studies with consistent
ndings) for or against recommending intervention; C, poor-quality evidence
(level-IV or -V studies with consistent ndings) for or against recommending
intervention; I, there is insufcient or conicting evidence not allowing a
recommendation for or against intervention.
From De Long.18

sion. However, disadvantages, as cited above, include potential

morbidity at the donor site, availability in limited quantities, and
risk of wound infection, increased blood loss and prolonged
anaesthetic time.23,55
The time interval between harvesting and transplantation of
the graft is also an important factor.7 Autogenous bone grafts
retain their viability for 2 h when kept in normal saline.45
Coupland concluded that the graft remained unchanged in shape
and acted as a passive scaffold for new bone growth to ll the
defect even after autoclaving.14 In another study9 freeze-drying of
autogenous bone did not alter the normal repair process associated
with fresh autografts.
Little is really known about the quality of autologous bone graft
in elderly patients. It seems clear that all properties of the
autologous bone should be altered. The scaffold is of lower
strength, as every surgeon can feel during harvesting, and
sometimes after opening of the iliac crest nothing substantial
can be seen. It is known that the number of mesenchymal stem
cells is less than in young men, and it is assumed that there is a
lower concentration of growth factor.
The clinical efcacy of autologous bone graft is not clear. There is
only one prospective randomized study which showed an efcacy of
about 80%, albeit in a very select group of patients. Despite the high
number of applications of the golden standard autologous bone
graft, we have few or no good evidence-based papers.
Allogenic bone grafts
Allografts are implanted up to 300,000 times worldwide, which is
25 times more than kidney transplantations and 100 times more
than heart transplantations. The limitations associated with the
harvesting of autograft for bone grafting can be overcome by the use
of allografts. Different sources of bone can be used. There is bone
from living donors, in which rejections of over 50% have been
recorded. Another source is the multiorgan donor, and in this case the
bone is quarantined until seroconversion and is safer with regard to
disease transmission, unlike post-mortem-donors where there is a
higher risk of transmitting diseases because of the lack of monitoring.
Allograft bone obtained from donor bone from cadavers has
both variable osteoinductive (releasing bone morphogenic proteins that act on bone cells) and osteoconductive properties, but

S17

lack osteogenic properties because of the absence of viable cells.35

However, harvesting and conservation of allogenic grafts are
additional limiting factors.22,38,47 The major advantages of allograft
bone harvested from cadavers are its ready availability in various
shapes and sizes, avoidance of the need to sacrice host structures,
and no problems of donor-site morbidity. Still, there is some
controversy regarding association of allograft bone with the
transmission of infectious agents, a major concern which is virtually
eliminated through tissue processing and sterilization. The processing itself also has inuence on the graft. Unprocessed and frozen
material can be ordered from several bone banks and consists of all
growth factors and a normal ultrastructure. Processed allografts are
defatted and the bone marrow is removed. Frozen allografts are
mechanically stable whereas freeze-dried bone is mechanically less
resistant, but can be stored at room temperature. Irradiation of bone
is not virucidal for the human immunodeciency virus (HIV), but the
bone is also mechanically less resistant.
Allogenic bone is available in many forms: demineralized bone
matrix (DBM), morselized and cancellous chips, corticocancellous
and cortical grafts, and osteochondral and whole-bone segments.
There are some denitions which are used. Structural allografts are
mechanically stable, as is the massive allograft which offers full
circumference (at least 5 cm). On the other hand there are
cancellous-bone-like non-structural allografts used as paste,
morsellized fragments and chips.
As with autologous bone grafts, allografts are replaced over
time by creeping substitution.
Despite all the advantages offered by allografts, it should be
kept in mind that there are documented cases of HIV and hepatitis
C virus (HCV) infections, the possibility of bacterial contamination,
and also possible infections by unknown viruses.
Demineralized bone matrix (DBM)
DBM has osteoconductive and osteoinductive potential, but has
no osteogenic capacity because of its processing. It does not evoke
any appreciable local foreign-body immunogenic reaction, as the
antigenic surface structure of the bone is destroyed during
demineralization.64 The biological activity of DBM is presumably
attributable to proteins and various growth factors present in the
extracellular matrix and made available to the host environment
by the demineralization process. Prepared by acid extraction of
allografts, it retains collagen and other proteins as well as bone
morphogenetic proteins (BMPs) The osteoinductive capacity of
DBM can be affected by storage, processing, and sterilization
methods and can vary from donor to donor, but the BMP
concentration is less than that found in normal human bone.
The amount of BMPs in DBM is highly variable, unlike the constant
low levels of growth factors; between and even within batches of
commercially available DBM products there are big differences
(intervariability and intravariability) in BMPs.4,65
DBM can also augment and expand autologous cancellous bone
graft when the supply of autogenous bone is limited or the defect is
very large. But does it stimulate bone healing in an environment
that really requires additional bone-healing stimulation? Or is it
merely providing a good osteoconductive scaffold?
DBM has several potential disadvantages. Because it is an
allergenic material, there is the potential to transmit HIV. No
efcacy testing is required from the FDA (since it is not a drug, nor a
medical device, but processed human tissue). Transmission of
diseases has not yet been reported but is theoretically possible.
Growth-factor-based bone graft substitutes
BMP-7 (Osigraft) and BMP-2 (InductOs) have been shown in a
prospective randomized human trial as a cytokine which can

G. Zimmermann, A. Moghaddam / Injury, Int. J. Care Injured 42 (2011) S16S21

S18

induce bone formation in tibial non-unions at the same rate

autologous bone graft,24 and can induce and accelerate bone
healing in fresh tibia fractures.33 BMPs are members of the
transforming growth factor-b (TGFb) superfamily and are
characterized by immense osteoinductive potential. They induce
a sequential cascade of events for chondro-osteogenesis during
bone formation and ultimately fracture healing, including chemotaxis, proliferation of mesenchymal and osteoprogenitor cells, and
their differentiation into a chondrogenic or osteogenic lineage.29,31,59
Several clinically relevant studies can now be found via
Medline. Overall, 30 clinical trials have been conducted, mostly
relevant for spinal surgery. Autograft and allograft, the standard
approaches for lumbar fusion procedures, have important disadvantages. Bone graft substitutes such as recombinant human
BMPs (rhBMP-2 and rhBMP-7) have emerged as viable alternatives.
The authors conducted a systematic review to compare the efcacy
and safety of osteoinductive bone graft substitutes using autografts and allografts in lumbar fusion.
In an overview from Agarwal et al.,1 17 of 732 potential studies
were found to be relevant for BMPs and spinal surgery, with nine
examining rhBMP-2, three examining rhBMP-7. They found that
recombinant human BMP-2 signicantly decreased radiographic
non-union when compared with autologous iliac crest bone graft
(AIBG) in a meta-analysis (relative risk 0.27, 95% CI 0.160.46), and
also reduced operating time and surgical blood loss. The limited
data on DBM and autologous growth factor showed no signicant
improvement in radiographic outcomes.
For long bones only a few trials are available. Three of them are
described below.
In England, an overview of clinical BMP-7 application in all long
hollow bones has recently been published. In 60.5% of 653
documented cases, application was indicated for pseudoarthrosis.
In 74% an autologous bone graft was performed additionally, in
23% BMP-7 had been implanted without own-bone transplantation. All cases that healed radiologically and clinically without
requiring further treatment were considered successes. The
success rate was 82%. Details concerning localization of the
fracture, number of previous therapies, other diseases of the
patients, or duration of the healing process are not reported.
For BMP-7, one prospective, randomized and partly blind
clinical study exists, describing 122 patients that had been treated
over a period of 7 years in seven different trauma centres in the
USA. The criterion for inclusion in the study was a tibia
pseudoarthrosis at least 9 months old. The planned surgical
techniques had to be intramedullar nailing and autologous bone
grafting. The control group received also intramedullar nailing;
however, BMP-7 instead of autologous bone was implanted. Nine
months after treatment, the success was evaluated according to
the clinical criteria of full weight-bearing and radiological fusion.

In the autologous bone grafting group the success rate was 84%
compared with 75% for BMP-7 application. However, this
difference did not reach statistical signicance (P = 0.218). In a
subgroup of patients, namely those with nicotine abuse, BMP-7
showed a markedly higher success rate compared to autologous
bone. Also, the frequency of infections was lower when implanting
BMP-7. Because these were not the criteria the study was designed
for, the results cannot be interpreted as signicant.24
In our prospective controlled study, we showed a signicantly
higher healing rate by using BMP-7 compared to autologous bone
grafting alone in the treatment of non-unions of the tibia shaft
(P = 0.025). We compared tibia shaft non-unions treated with
autologous bone graft with multiple failed cases of tibia shaft
non-unions treated with BMP-7. Despite these encouraging
results, it cannot be denitively concluded that BMP-7 treatment
is superior to autologous bone grafting, because of the low number
of patients in the BMP group. However, the BMP group had worse
prerequisites and more previous revisions. Thus, the BMP group
demonstrated at least the same efcacy, and a higher efcacy in
multiple failed cases may be postulated based upon the results of
this study.
An overview of clinical trials and their results is shown in Table
2.
Nowadays BMPs are regarded as effective and safe products to
enhance bone healing, and will gain more and more importance in
the treatment of bone defects.
Ceramic-based bone graft substitutes
Hydroxyapatite (HA) and b-tricalcium phosphate (b-TCP) are
the most frequently used synthetic bone grafts amongst different
ceramic-based graft materials. Calcium-phosphate-based ceramics
such as bioactive glass have been used quite substantially for some
time, having been used as synthetic scaffolds in dentistry since the
early 1970s and in orthopaedics since the 1980s.8,36 They are made
from inorganic, non-metallic materials with a crystalline structure,
usually processed at a high temperature.
Most ceramics are hard and porous yet brittle. The osteoconductive CaP biomaterials allow attachment, proliferation, migration, and phenotypic expression of bone cells leading to formation
of new bone in direct apposition to the CaP biomaterial. The
resorption is determined by several features host and material,
osteoclasts and foreign body giant cells and should preferably go
slowly. The commercially sold forms are granular, cement, paste
(injectable), pre-shaped wedges and shapes.
Some advantages of these synthetic bone substitutes are:
 they are osteoconductive
 they have a long shelf life
 there is no risk of disease/virus transfer

Table 2
Overview of non-prospective randomized studies on bone morphogenetic protein 7 (BMP-7).32,44,49,57,58,6870
Author

Year

Study design

Kujala et al.
Giannoudis et al. UK
Dimitriou et al.
Ronga et al. Bios study
group Italy
Zimmermann et al.
Zimmermann et al.

2004
2005
2005
2006

Retrospective,
Retrospective,
Retrospective,
Retrospective,

Indication

Patients

BMP

Union rate%

Non-union various sites

Non-union, osteotomies etc. various sites
Non-union various sites
Non-union various sites

5
653
26
105

7
7
7
7

100
82
92
89

2006
2007

Retrospective, observational, non-randomized

Prospective, matched pairs, controlled trial

Non-union various sites

Non-union tibia shaft

23
108

7
7

2007

Prospective, controlled trial

Pilon fractures

40

2007
2008
2010

Retrospective, observational, non-randomized

Retrospective, observational, non-randomized
Retrospective, observational, non-randomized

Non-union pelvic girdle

Non-union various sites
Non-union various sites

9
172
102

7
7
7

92
89 Signicantly
higher
Signicantly
faster
89
79
93

Ristiniemi et al.
Giannoudis et al.
German chapter
Moghaddam et al.

observational,
observational,
observational,
observational,

non-randomized
non-randomized
non-randomized
non-randomized

G. Zimmermann, A. Moghaddam / Injury, Int. J. Care Injured 42 (2011) S16S21

 they are available in every shape, porosity, and composition

 there is an unlimited supply.
Some disadvantages are:
 the handling of some synthetics is not optimal
 synthetics do not have cortical stability
 they are never osteoinductive or osteogenic by themselves.
The CaP ceramics have to be intact long enough for bone
ingrowth to occur and to maintain stability. Porosity is an
important factor that inuences the speed of degradability.
High-porosity materials have a high speed of degradability, and
low-porosity materials have a lower degradability. The ideal pore
size for a bioceramic should be similar to that of spongious bone. It
has been demonstrated that microporosity (pore size <10 mm)
allows body uid circulation whereas macroporosity (pore size
>50 mm) provides a scaffold (pore size 100200 mm and porosity
6065%) for bone-cell colonization.17,16 A pore size of 565 mm in
diameter is reported as the ideal macropore size for bone ingrowth
compared to a smaller size (300 mm).26
Calcium hydroxyapatite (HAp)
The Ca/P ratio ranges from below to above 1.67 (the
stoichiometric value of pure HA) and depends on the species,
age, and type of bone. Unlike TCP, HA is not easily dissolved/
resorbed by osteoclasts.
Hydroxyapatite is a biocompatible ceramic produced through a
high-temperature reaction and is a highly crystalline form of
calcium phosphate. The nominal composition of this mixture is
Ca10(PO4)6(OH)2. The most unique property of this material is its
chemical similarity to the mineralized phase of bone; this
similarity accounts for its osteoconductive potential and excellent
biocompatibility.21,30 Calcium hydroxyapatite/tricalcium phosphate (60/40) provides a structure or scaffold which can have a
close interface with adjacent bone and has a limited application in
the treatment of load-bearing segmental bone defects that did not
fail at early stages of implantation.5 Hydroxyapatite has been
established to be an excellent carrier of osteoinductive growth
factors and osteogenic cell populations, which greatly adds to their
future utility as bioactive delivery vehicles.52
Plasma spray HA coating has been used on metallic femoral
stem and cup as a means of xation in order to avoid complications
related to the use of poly(methylmethacrylate) (PMMA).50
Hydroxyapatite-coated pins enhance pin xation regardless of
bone type and loading conditions, and reduces the rate of infection
and loosening during external xation.51,54
Tricalcium phosphate (TCP)
In vitro dissolution of CaP materials depends on composition,
particle size, porosity, surface area and crystallinity. TCP is more
quickly resorbable and less mechanically stable compared to HA.
But like HA, TCP is bioabsorbable and biocompatible. The chemical
composition and crystallinity of the material are similar to those of
the mineral phase of bone. The nominal composition of TCP is
Ca3(PO4)2. It exists in either a-36 or b-crystalline forms.
TCP implants have been used for two decades as synthetic bone
space llers in orthopaedic and dental applications.36 The small
particle size and interconnected sponge-like microporosity are
believed to improve osteoconductive properties and promote timely
resorption concomitant with the process of remodelling.30,37 Zhang
et al.67 reported bone formation with bone-marrow stromal cells
(BMSCs) and b-TCP as bone substitute implanted in rat dorsal

S19

muscles. Cutright et al.15 found 95% absorption of TCP ceramic

implants in rat tibias 48 days postoperatively with extensive bone
growth and marrow reformation. Cameron et al.11 observed both the
toxicity and the bone ingrowth potential of TCP in a canine model
and reported no untoward tissue or systemic reaction when TCP was
implanted in cancellous bone; it was rapidly inltrated with bone
and slowly resorbed.
Calcium phosphate cement (CPC)
Today CPC is attracting more and more interest. Compared to
the older generation of these products, new developments have
improved wet eld properties, and newer products are much more
resistant to shear forces. Therefore after setting, they can also be
drilled for insertion of screws. Calcium phosphate ceramics
introduced more than three decades ago are considered as
bioactive bone substitutes. The paste or injectable calcium
phosphate cement offers the advantage of being freely mouldable
and adaptable to bone defects.
The combination of high biocompatibility, easy-to-shape characteristic, and the capacity for self-setting under ambient conditions
makes CPC an asset in the repair of hard-tissue defects,12,39 and
research and development on CPC have attracted much attention in
recent years.10,12,41,66 Based on its ow behaviour before setting of
the slurry, CPC has been used as a root sealer/ller in dentistry13 and
as an injectable biomaterial3,27,53,56,61 for bone replacement,
especially in percutaneous vertebroplasty42,43,46 and kyphoplasty.39,40,63 Pore size and inherent strength play a major role in
the ultimate usefulness of CPC. CPCs are reabsorbed by osteoclasts
with new bone formed by osteoblasts. Recent studies suggest that
CPCs can facilitate osteogenesis25. Clinical studies in which these
cements are used in tibia plateau fractures showed safe application
and an equal to better clinical outcome of these patients compared to
the use of autologous bone graft 71,72. The clinical use of CPCs has also
been reported in other metaphyseal defects 72.
Conclusions
Autologous bone graft would be still the best choice for a lot of
applications where bone grafting is needed. But there are
disadvantages the relatively high donor morbidity and the limited
amount which can be harvested which will eventually lead to a
very restricted use of it. Allografts dont have these limitations, but in
the form of demineralised bone matrix they have very variable
osteoinductive properties and can possibly transmit diseases.
Therefore in future synthetic bone grafts will be more and more
of interest, especially if there are further developments in stability
and handling which is currently still suboptimal.
Future biosynthetic bone implants may obviate the need for
autologous bone grafts. There is increasing interest in combining
an osteoinductive protein in an osteoconductive carrier medium to
facilitate timed-release delivery and/or to provide a material
scaffold for bone formation. But even today the combination of
different materials in the treatment of signicant bone loss or a
recalcitrant non-union might be more successful and promising
than the use of autologous bone alone.
Conict of interest
There is no conict of interest.
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