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Bone grafting, orthopaedic biomaterials, and the clinical need of bone

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 SPECIAL ISSUE PAPER 1329

Bone grafting, orthopaedic biomaterials, and the clinical

need for bone engineering
A S Brydone, D Meek*, and S Maclaine
Southern General Hospital, Glasgow, UK

The manuscript was received on 30 March 2010 and was accepted after revision for publication on 12 August 2010.

DOI: 10.1243/09544119JEIM770

Abstract: As the population ages, the number of operations performed on bone is expected to
increase. Diseases such as arthritis, tumours, and trauma can lead to defects in the skeleton requiring
an operation to replace or restore the lost bone. Surgeons can use autografts, allografts, and/or bone
graft substitutes to restore areas of bone loss. Surgical implants are also used in addition or in isolation
to replace the diseased bone. This review considers the application of available bone grafts in different
clinical settings. It also discusses recently introduced bioactive biomaterials and highlights the clinical
difficulties and technological deficiencies that exist in our current surgical practice.

Keywords: bone graft, autograft, allograft, hydroxyapatite, osteolysis, nanotopography,

osteoconductive, osteoinductive

1 INTRODUCTION (cells which are differentiated from mesenchymal

Deficits exist in current surgical practice for the
regeneration of lost tissue such as bone, cartilage,
muscle, and tendons. Due to the ageing world popula-
tion, techniques to replace, restore, or regenerate bone
have become a major clinical need in the fields of
orthopaedic, spinal, dental, cranial, and maxillofacial
surgery. This paper aims to highlight the clinical need
for continued advances in bone engineering. It also
reviews the current options available for bone grafting,
recent developments in cell engineering, and how these
principles are being applied to surgical implants.
2 BONE BIOLOGY
There are 206 bones in the human body [1]. The
adaptation of each bone to a specific role has led to
great variation in size, shape, and composition. A
surgeon must appreciate the function of the bone
before approaching surgical reconstruction.
Bone is a complex and highly organized miner-
alized tissue. It is a composite of hydroxyapatite and
type-I collagen which contains a hierarchy of com-
ponents [2](see Fig. 1). It is produced by osteoblasts
*Corresponding author: Orthopaedic and Trauma, Southern
General Hospital, 1345 Govan Road, Glasgow G51 4TF, UK.
email: rmdmeek@doctors.org.uk
stem cells present in bone marrow). They are typically
cuboidal and flat in their morphology and are around
20 mm in diameter [3]. Osteoblasts produce a dis-
organized (or woven) matrix of type-1 collagen, which
they mineralize with hydroxyapatite crystals to form
bone [4]. Osteoclasts resorb areas of woven bone,
which allows it to be remodelled into a highly
organized framework of parallel running fibres,
orientated in alternate directions dependent on the
forces applied to the bone.
There are two types of mature bone: cancellous
and cortical. Cancellous bone forms the internal
porous framework of bones. It contains stem-cell-
rich bone marrow which is essential for the growth
of new connective tissue (e.g. muscle, cartilage,
bone, and tendons) and the production of blood
cells. Cortical bone surrounds the cancellous bone
and forms an outer shell, thus giving the bone shape
and form. In bones that are principally load bearing,
e.g. the femur, the cortical component of the bone is
markedly thickened to form a strong shaft.
3 BONE HEALING
After injury, bleeding from adjacent structures
causes a haematoma to form around the broken
bone ends [5]. Fibroblasts enter the site and lay
down granulation tissue, which is composed pre-

JEIM770 Proc. IMechE Vol. 224 Part H: J. Engineering in Medicine

1330 A S Brydone, D Meek, and S Maclaine
Fig. 1 Hierarchical structure of bone. Reproduced
with permission, from reference [2]
dominantly from type-III collagen. At the proximal
bone end, chondroblasts arise from the periosteum
and produce hyaline cartilage [6]. At the distal bone
end, osteoblasts arise from the periosteum and
produce woven bone (predominately type-I col-
lagen). These combine to form the fracture callus [5].
The woven bone then undergoes bone substitution
and the hyaline cartilage undergoes endochondral
ossification. These processes both produce lamellar
bone. Osteoblasts and vascular channels penetrate
the mineralized matrix and stronger trabecular bone
is laid down. Final remodelling of the bone is
completed by deposition of compact bone by osteo-
blasts in resorption pits prepared by osteoclasts [5].
Primary or direct osteonal healing occurs in
cortical bone when the gap between bone ends is
less than 2 mm and absolute stability exists [4].
Osteoclasts tunnel across the fracture site; followed
by the osteoblasts which produce new bone. [5]
There are four prerequisites for bone healing
described by the diamond concept:
(a) cells with osteogenic potential;
(b) an osteoconductive matrix;
(c) an osteoinductive stimulus;
(d) a mechanically stable environment [9].
Proc. IMechE Vol. 224 Part H: J. Engineering in Medicine
For successful union to occur the four prerequisites
must be active.
If mechanical stability is deficient a hypertrophic
non-union may occur which is characterized by
exuberant callus formation around the fracture site.
Fibrous scar tissue intervenes between the bone
ends as a result of excessive motion. Stability must
be optimized to facilitate union [10].
Atrophic non-unions lack a biological reaction and
may be due to a poor blood supply or excessive dis-
traction of bone fragments [10]. Ensuring a good vas-
cular supply is a priority in these patients before further
intervention is undertaken [10]. Any defect then needs
to be closed or filled with an appropriate osteoconduc-
tive scaffold to enable healing. If these requirements
have already been met then osteoinductive agents
should be used to provide a biological stimulus [10].
4 CLINICAL NEED FOR BONE ENGINEERING
4.1 Trauma
In the USA there are an estimated, 280 000 hip frac-
tures, 700 000 vertebral, and 250 000 wrist fractures
each year at a cost of $10 billion [11]. Delayed healing
or non-union occurs in 5 per cent of all fractures, and
20 per cent of high-impact fractures [12]. Large areas
of bone loss due to trauma may exceed the body’s
regenerative capabilities unless surgeons intervene to
bridge the skeletal defect. Management of a non-union
is a challenging and costly exercise, and provides a
target for further bone tissue engineering strategies.
The demand in the surgical market is highlighted by
the fact there are around 4000 000 operations involving
bone grafting or bone substitutes performed around
the world annually [13].
Open reduction and fixation of fractures with
dynamic compression plates and screws is a method
of achieving absolute stability in order for primary bone
healing to occur [4]. Absolute stability is preferable in
peri-articular fractures in order to maintain reduction if
early movement to reduce joint stiffness is desirable.
Unfortunately, this method can damage the cambial
layer of the periosteum – a key source of osteopro-
genitor cells necessary for bone healing [4].
Secondary bone healing requires a degree of
micromotion at the fracture site in order to stimulate
callus formation as previously described [7]. Exam-
ples of this include cast immobilization, external
fixation, intramedullary fixation, and bridging plates.
Locking plates aim to support fracture fragments
whilst permitting controlled micromotion to en-
able rapid secondary bone healing [8]. Screws with
JEIM770
 Bone grafting, orthopaedic biomaterials, and bone engineering
threaded heads lock into holes in the plate. This
prevents backing out of screws which can occur in
osteoporotic or fragmented bone. There is also less
compression of the plate onto the bone which helps
protect the periosteum.
Distraction osteogenesis is a useful technique for
eliminating a large gap between bone ends. Short-
ening-distraction involves opposing the bone ends
by shortening. The two fragments are then progres-
sively distracted to restore the correct bone length.
Alternatively, the length of the bone can be main-
tained using a bone transport technique. An osteot-
omy is performed to create a mobile segment which
can be transported from one side of the bone gap to
the other, creating callus as it is distracted.
Distraction osteogenesis can be undertaken at a
maximum rate of 1 mm every day [14] (too quickly
can result in fibrous tissue formation). Once the
desired length of bone has been achieved, a static
consolidation phase is required (two to four times the
length of the distraction phase)[14]. During treat-
ment, the bone can be supported using an external
fixator (e.g. Illizarov) or an adjustable intramedullary
nail [15]. Both methods are associated with long
periods of treatment and pain. The rate of infection,
however, is reduced by using an intramedullary
device [15].
4.2 Spinal surgery
Back pain is a crippling condition for individuals and
society alike. Data from 1998 estimated that the
direct cost of back pain to the UK is £1632 000 000,
and the indirect cost £10 668 000 [16]. The Health
and Safety Executive reported back pain as the
second most common cause for sick leave, with
4707 000 working days lost in 2005–6 [17].
Surgical intervention can be effective for disabling
back pain due to degenerative disease [18]. A total of
500 000 autologous bone graft operations are per-
formed per year in the USA. Fifty percent are for
spinal fusions [19]. Non-union rates in these
procedures are reported to range from 5 to 35 per
cent. Spinal surgery is a large market with scope for
improvement in bone graft technology.
Table 1 Prevalence of lower limb arthroplasty by country
Scotland [20] Australia [21]
(Apr. 07– (Jul. 06–
Mar. 08) Jun. 07)
Primary hip + knee replacements 12 472 49 937
Revision hip + knee replacements 1 296 6 740
Crude hip revision rate (%) 12.17 14.97
Crude knee revision rate (%) 6.40 9.52
JEIM770
1331
4.3 Joint replacement surgery
If the articulation between two bones is extensively
diseased or has been injured beyond repair, a joint
replacement procedure is necessary. Joint replace-
ment operations relieve pain and disability, and
permit a continued active working life by replacing a
natural joint with an insensate prosthetic implant.
Table 1 shows the number of hip and knee replace-
ments performed throughout the world [20–27].
Hip arthroplasty techniques were refined and
popularised by Sir John Charnley. He used polished
stainless steel femoral prostheses with bone cement
(polymethylmethacrylate, PMMA) and polyethylene
as a bearing surface [28]. If the operation is per-
formed correctly, and infection can be avoided, joint
replacements can provide many years of service
before loosening occurs. A study of 2000 primary
cemented Charnley femoral components at the
Mayo Clinic demonstrated 25-year revision rates of
18 per cent for patients , 40 years old, in compar-
ison to none for those over 80 years of age [29].
Multiple theories exist for the biomechanical basis
of implant loosening. Harris et al. [30] described
cases of aseptic loosening involving linear and focal
areas of osteolysis. Particulate wear debris (e.g.
PMMA, ceramic, metal, or polyethylene) have been
considered instrumental in this process. These
particles can initiate a biological and immunological
response, involving macrophages and IL-1, IL-6, IL-
10, and TNFa activation. This results in the forma-
tion of chronic inflammatory cells which produce
metalloproteinases and stimulate osteoclast-medi-
ated resorption of bone and fibrous capsule forma-
tion around the implant [31]. The inflammatory fluid
generated causes an increase in the hydrostatic
pressure within the joint. This pressure affects cell
behaviour and leads to further osteolysis and
mechanical loosening of the implant [32].
The UKs population is ageing. The percentage of
the population aged over 65 was 16 per cent in 2008
[33]. This increase represents 15 000 000 people. By
2033, 23 per cent of the population will be aged 65 or
over [33]. Presently, around 10 per cent of primary
joint replacements undergo revision surgery [20, 26].
Norway [22] USA [23] Sweden [24, England [26] Canada [27]
(Jan. 07– (Jan. 06– 25] (Jan. 07– (Apr. 07– (Apr. 05–
Dec. 07) Dec. 06) Dec. 07) Mar. 08) Mar. 06)
10 199 773 000 24 485 130 907 28 512
1 342 77 000 1 845 9 134 2 494
13.57 14.13 8.01 8.46 11.74
7.76 6.71 5.61 4.69 5.39
Proc. IMechE Vol. 224 Part H: J. Engineering in Medicine
1332 A S Brydone, D Meek, and S Maclaine

This is likely to increase as the population ages and
younger patients request joint replacements.
Revision joint replacement surgery is a technically
more challenging undertaking which should only be
performed by specialist orthopaedic surgeons. Os-
teolysis around implants results in a loss of bone,
which needs to be replaced to regain a stable joint.
Options involve the use of metal components or the
restoration of bone using bone grafting techniques.
In a Norwegian study, 26 per cent of 4762 revision
hip joint replacements failed within 10 years [34].
4.4 Bone tumour surgery
Resection of tumours from long bones often leaves
large skeletal defects. Limb reconstruction and
salvage procedures for bone tumour surgery utilize
combinations of massive bone allografting and bone
transportation operations [35].
5 BONE GRAFTING
Bone grafting is performed to restore bone that has
been lost due to trauma or disease. Orthopaedic
surgeons and bone tissue engineers must consider
the function of the bone that requires replacement.
There are a number of options currently available to
orthopaedic surgeons. They differ in their strength
and osteoconductive, osteoinductive, and osteogenic
potential (see Table 2 that has been modified from a
table by Khan et al. [36]).
The choice of graft or bone graft substitute
depends upon the following factors:
(a) the intended clinical application;
(b) defect size and total bone mass required;
(c) biomechanical properties;
(d) chemical composition;
(e) availability;
(f) desired bioactivity (osteoconductive/osteoin-
ductive/osteogenic);
(g) desired resorption rate;
(h) handling characteristics;
(i) associated side effects;
(j) cost;
(k) ethical issues.
5.1 Autografts
Autografts are transplants of tissue from one site to
another within an individual. Autogenic bone is
usually considered the ideal bone graft as it incorpo-
rates osteogenic cells and an osteoconductive mineral
matrix. Autograft bone may be available locally in
operations that require the removal of bone as part of
the surgical procedure. For example, the femoral
head excised during a total hip replacement can be
retained and cut into pieces or milled into chips and
used to fill any bone defects encountered.
Bone can also be harvested from sites distant to the
primary area of concern. These procedures can be
associated with donor site problems such as pain,
bleeding, and infection [37–39]. This method provides
a limited mass of bone and is therefore not a suitable
source when large or multiple defects are present. It is
usually harvested from the iliac crest (but the proximal
tibia distal radius, and calcaneus can also be used as
donor sites for cancellous bone).
In selected surgical scenarios when the structural
integrity of bone is compromized, cortical autografts
can be used for bone reconstruction. Fibular autografts
have been used to replace defects in the forearm, face,
and long bones [35]. The bone segment, which
contains both cancellous and cortical bone, can also
be harvested with its blood supply intact. The vascular
pedicle is anastomosed onto blood vessels at the
recipient site to reduce the risk of subsequent necrosis
of the fibular autograft.
Vascularized fibular grafts can be used to bridge
intercalary defects in long bones. Up to around

Table 2 Bone graft activity by type

Bone graft Structural strength Osteo-conduction Osteo-induction Osteogenic
Autograft
Cancellous + ++ + ++
Cortical ++ + +/2 +
Allograft
Cancellous + ++ + 2
Demineralized bone matrix 2 ++ +++ 2
Cortical ++ +/2 +/2 2
Bone graft substitutes
Hydroxyapatite/tricalcium phosphate/ 2 + 2 2
biphasic calcium phosphates
Bioactive composites + + 2 2
Growth factors 2 2 + 2

Proc. IMechE Vol. 224 Part H: J. Engineering in Medicine JEIM770

 Bone grafting, orthopaedic biomaterials, and bone engineering
30 cm of fibula can be sacrificed; but the procedure
is technically demanding and complications are
common [35]. Due to the inherent weakness of the
fibula, stress fractures are frequently observed in the
first year [40–42]. The live osteogenic cells contained
in this autograft allow the bone to remodel with time
in response to the forces applied [43]. Ribs and iliac
crest can also be harvested as free vascularized
osteocutaneous flaps [44].
5.2 Allografts
Allograft bone can either be collected from cadavers or
living donors. In Scotland, femoral heads removed from
living osteoarthritic donors during hip replacement
operations is the source of most allogenic bone [45].
To prevent the host-versus-graft immune re-
sponse, allografts are processed to remove the live
cellular component of bone. This allows tissue
transplantation without prior HLA tissue typing or
ABO blood grouping [46, 47]. The end product is a
bone graft that contains the osteoconductive mineral
basis for bone healing, but lacks the osteogenic
properties of autograft.
Allogenic bone has the inherent risk of disease
transmission (e.g. CJD) and immune reactions [48,
49]. Donors are screened for serological markers
(including HIV, Hepatitis B & C, and VDRL), bacter-
iology swabs are taken during the harvest procedure,
and a comprehensive patient history is gathered (see
Table 3). If negative, the bone is deep frozen for 6
months, before re-testing. Approximately 18 per cent
of donated femoral heads are found to have bacterial
or fungal contamination following quarantine [50].
Contaminated samples are further processed to
inactivate microbes prior to use [51, 52].
The porous structure of cancellous bone makes it
unsuitable as a replacement biomaterial for compact
load-bearing bone. A stable load-bearing construct
Table 3 Contraindications to skeletal allo-
graft harvest [45]
Exclusion criteria for bone graft donation
Age , 18 years old
History of drug abuse
Chronic or high-dose steroid use
History of vCJD infection
Previous history of malignancy
Inflammatory arthritis
Dementia or chronic neurological disease
Recent live vaccine immunization
Positive Hepatitis B or C serology
Positive HIV serology or risk factors for HIV infection
Positive VDRL serology
History of growth hormone treatment
JEIM770
1333
can, however, be formed by impaction and pressur-
ization of morcellized cancellous bone into an
enclosed space (e.g. the femoral shaft) [53, 54]
Allogenic bone is also available in the form of mas-
sive allografts, demineralized bone matrix, processed
bone chips, or cortical struts. Massive bone allografts
have been used in isolation for the reconstruction of
limbs following bone resection for tumours. Compli-
cations, however, are commonly encountered. There
was a 19 per cent incidence of fracture, 14 per cent
rate of non-union, and 10 per cent chance of infection
in one study [55]. The method of healing, through
creeping substitution of bone, can take an average of
6.5 months at the metaphyseal level and 16 months
for the diaphysis [56].
Demineralized bone matrix (DBM) is produced from
cadaveric bone processed in acid to remove the mineral
components. This leaves a trabecular structure which
preserves its osteoconductivity, whilst the collagen and
bone morphogenic proteins permit osteoinductivity. It
is available in many different preparations e.g. cancel-
lous chips, gel, putty, or cement.
Some commercially available DBM products (Osteo-
filTM allograft bone paste (Medtronics Sofamor Danek,
Memphis, Tennessee) and GraftonTM putty (Osteotech
Inc., Eatontown, New Jersey) are more effective at
producing ectopic bone in a rat model of posterolateral
spinal fusion than autograft [57]. Natural products
however are subject to individual batch variability. For
example, a comparison of ten production lots of a DBM
product revealed that the concentrations of BMP-2
varied between 22 and 110 pg/mg and those for BMP-7
between 44 and 125 pg/mg [58]. There are also sug-
gestions that donor age affects osteoinductivity, but
this point is controversial [59, 60].
Cortical strut grafts can transfer higher loads
compared to a cancellous allograft, and add me-
chanical integrity to the surgical reconstruction.
Although they lack osteogenic cells, they can provide
a biological framework which contains the mineral
constituents of bone. The majority of the strut graft
will slowly be resorbed. This gradual resorption
facilitates an increased loading of the newly formed
native bone over time, bone remodels and strength-
ens in response to the increased load. This process is
described by Wolff’s law. Ten year survivorship for
hip prostheses constructed with large cortical allo-
grafts is around 69 per cent [61].
6 BONE GRAFT SUBSTITUTES
Bone graft substitutes aim to provide reconstruc-
tive surgeons with off-the-shelf alternatives narural
Proc. IMechE Vol. 224 Part H: J. Engineering in Medicine
1334 A S Brydone, D Meek, and S Maclaine

bone. The concept of engineering bone tissue is a 6.2 Ion-substituted bioceramics

current focus of orthopaedic research. Products are
The mineral in bone is an impure form of HA. The
currently being modelled to reflect the structure and
‘phase purity’ of a bioceramic refers to the relative
chemical composition of natural bone, using synthe-
mass percentages of different crystalline phases
sized materials. Some biomaterials are loaded with
within the material [75]. There is increasing interest
growth factors such as the bone morphogenic
in developing biomaterials with carefully selected
proteins to induce bone healing.
impurities to improve bioactivity. By substituting
As previously discussed (Table 3), there are many
ions such as silicate, carbonate, magnesium, fluor-
factors to consider when designing and manufactur-
ide, and strontium an increased variety of biomater-
ing a bone graft substitute. In addition, all these pro-
ials compositions has emerged [76–78].
perties are interlinked. For example, a change in the
Silicate-substituted calcium phosphate (Si-CaP) is
composition or structure of a biomaterial will lead to
a bioceramic in which phosphate ions (PO432) have
alterations in the biomechanical and physical proper-
been substituted with silicate ions (SiO442) at a level
ties. Moreover, small alterations may illicit a very
of 0.8 wt% [78]. Using a sheep model of instrumen-
different cellular response once implanted. Investigat-
ted posterolateral lumbar spine fusion Si-CaP was
ing one factor in isolation can therefore be misrepre-
compared with iliac crest autograft using biomecha-
sentative of the overall behaviour of the biomaterial.
nical, radiographic (computed tomography), and his-
Bone substitutes are available as chips and gran-
tological analysis [79]. It demonstrated results equiva-
ules of different sizes, putty, and injectable paste.
lent to autograft, but also caused more rapid bone
The handling characteristics of different substitutes
formation and maturation.
are of great importance to the orthopaedic surgeon.
This property encompasses the preparation method
of the bone substitute pre-implantation, its consis-
6.3 Calcium sulphate
tency, the delivery system, and its curing behaviour
(if cement). Additional surgical containment is some- Calcium sulphate (CaSO4) in the form of Plaster of
times required to prevent the bone substitute from Paris was first used to fill bone defects caused by
migrating into surrounding tissues. tuberculosis [80]. It is resorbed within 6 weeks – which
is faster than both HA and TCP [81]. Calcium sulphate
pellets (OSTEOSETTM, Wright Medical Technologies,
6.1 Calcium phosphate Arlington, TN) have been used as autograft extender
for instrumented short segment posterolateral spinal
Hydroxyapatite (Ca5(PO4)3OH or Ca10(PO4)6OH2) is a
fusions for degenerative disease [82]. In a study of 35
naturally occurring mineral form of calcium phos-
patients receiving two-level pedicle screw fixation, 82.9
phate that comprises up to 70% of the dry weight of
per cent fused when calcium sulphate and local
bone. The synthetic form of hydroxyapatite (HA) is
autograft was used compared to 85.7 per cent when
osteoconductive and has a crystalline structure
only iliac crest autograft was implanted [82].
similar to the HA in bone. Synthesized HA is slower
to resorb than the endogenous form and may stay at
the site of implantation for many years [62, 63].
6.4 Bioactive composites
Tricalcium phosphate (Ca3(PO4)2 [64]) is a bio-
ceramic that is resorbed faster than synthetic HA, HAPEXTM was an early bioactive composite of poly-
but is not as strong [63, 65]. It exists in alpha and ethylene (PE) matrix reinforced with HA, used as a
beta crystal forms. b-Tricalcium phosphate (TCP) medical implant for repairing fractures of the orbital
has been successfully used in posterolateral spinal floor and in middle ear implants [83]. Human osteo-
fusions [66, 67], dental procedures [68], and as a blasts cultured with 40 per cent HA/PE exhibit increased
component of bio-resorbable screws [69]. proliferation rate and differentiation, and form more
Biphasic calcium phosphates are blends of differ- focal contacts [84].
ent bioceramics. They aim to balance biomechanical The next generation of orthopaedic biomaterials
properties with resorption rates to develop the ideal are likely to involve composites which are tailored to
bone substitute [62–64]. For example, Stryker Corpo- meet a particular demand. Biodegradable polymers
ration have produced BoneSaveTM which is a mix- such as polylactic acid, polyglycolic acid, polycapro-
ture of 20% wt. HA and 80% wt. b-TCP. HA/b-TCP lactone, and co-polymers such as polylactic—poly-
has been used clinically in spinal [70–72], dental glycolic acid and L- and DL-lactide are currently
[73], and hip procedures [74]. being investigated. While the natural tissue regener-

Proc. IMechE Vol. 224 Part H: J. Engineering in Medicine JEIM770

 Bone grafting, orthopaedic biomaterials, and bone engineering
ates in vivo, these polymers degrade by hydrolysis
into non-toxic, natural metabolites which are even-
tually eliminated from the body in the form of
carbon dioxide and water [85]. There have been
some concerns expressed that the small polymeric
particles produced by degradation of these type of
polymers may stimulate an inflammatory reaction,
although this remains an area of debate and
investigation [85].
To simulate physiological characteristics (stiffness,
bending, compressive, and tensile strengths) for
load-bearing circumstances, it may be mechanically
favourable to use polymers in these composites [86].
For example, a novel biodegradable nanocomposite
porous scaffold comprising a b-TCP matrix and HA
nanofibres has been developed for load-bearing
bone tissue engineering [87]. Furthermore, these
biomaterials will be designed to stimulate cells in
specific ways at the molecular level.
6.5 Osteoinductive growth factors
Incorporation of growth factors into implants can
confer osteoinductivity to a biomaterial [88, 89]. Two
osteoinductive growth factors of the TGF-beta super-
family, rhBMP-7 (OP-1 ImplantH/OP-1PuttyH, Stryker-
Biotec, Hopkington, MA, USA) and rhBMP-2 (INFU-
SEH/InductOsH, Wyeth, UK), have received approval
for restricted clinical use [90–92]. These products
provide a supraphysiological doses (10–1000 fold
higher than the concentration of native BMPs) of
growth factors over a finite period (60–240 min) [93,
94]. Osteoinductive growth factors are more expen-
sive than many other bioactive bone biomaterials
(BMP-2 is £3,200 and BMP-7 is £2,450 for 100 mg) and
are also subject to a limited shelf life [94, 95].
When rhOP-1 (BMP-7) and a type-I collagen
carrier was used in intramedullary nailing for tibial
non-unions it provided results comparable to bone
autograft, without the donor site morbidity [92]. The
use of OP-1/BMP-7 has been investigated in poster-
olateral spinal fusions. It produced fusion rates of 55
per cent compared with 40 per cent for iliac crest
autograft during the study period [96]. Now rhBMP-
2 is being increasingly used as an adjunct to facilitate
fusion in spinal surgery [97–99].
Incorrect placement of the carrier can induce
undesired ectopic bone formation in surrounding
tissues such as adjacent muscles, nerves, and blood
vessels. Also, antibody formation and immunologi-
cal reactions have been observed in some patients
following administration of BMPs. Such side-effects
can result in critical complications particularly in
JEIM770
1335
cervical spine surgery when the margin for error is
minimal [100, 101]. Recently, a Food and Drug
Administration (FDA) advisory committee voted six
to one against allowing the expanded use of OP-1
putty [102]. The FDA approved the use of OP-1 in
2004 under the Humanitarian Device Exemption pro-
gramme for its use in up to 4000 patients a year. To
date concerns regarding bone morphogens produ-
cing mitotic or neoplastic changes have remained
unfounded.
The high costs involved in using systemic or topical
agents, such as BMPs, precludes their routine applica-
tion. The identification of patients at high risk of
delayed or non-union may enable clinicians to identify
subgroups of patients in whom this expense is
justified, in order to prevent the morbidity and cost
associated with delayed or non-unions.
7 BONE GRAFT ARCHITECTURE
When designing a biomaterial to substitute bone the
architecture of natural bone must be appreciated.
The framework of bone gives it strength, but still
allows cells, nutrients, and metabolic by-products to
traverse the structure. The skeletal architecture is
variable as it is adapted to meet the body’s phy-
siological demands. Broadly speaking, there are two
types of bone: cancellous bone is porous and weak
whereas cortical bone is compact and strong. The
important architectural characteristics of a bioma-
terial are the surface features (i.e. the topography
and roughness) and the porosity of the internal
framework.
The majority of synthetic bone graft substitutes
aim to replicate the highly porous architecture of
cancellous bone (50–90 per cent) [103]. This is
because mesenchymal stem cells respond to parti-
cular pore dimensions. For example, in canines: pore
diameters of 15–50 mm stimulate fibrovascular
growth, 50–150 mm induce osteoid formation, and
150–500 mm leads to mineralized bone [104].
The elaborate interconnected pore spaces found
in coral skeletons resembles the architecture of
cancellous bone. Coral skeletons, sea urchin spines,
and invertebrate microskeletons are currently used
for cranial, maxillofacial, spinal, and dental surgery
[105–108].The coralline calcium carbonate is readily
resorbed by osteoclasts, permitting the formation
of new bone [109]. Similarly, calcite (magnesium
containing calcium carbonate) derived from sea
urchin shells and spines has a porous structure and
is chemically and physically compatible with the HA
of bone [110]. Intricate porous structures can also be
Proc. IMechE Vol. 224 Part H: J. Engineering in Medicine
1336 A S Brydone, D Meek, and S Maclaine
generated in synthetic biomaterials using the many
fabrication methods available to create scaffolds
tailored to tissue regeneration [111].
8 MATERIAL SURFACES
The surface finish of biomaterials is being exten-
sively investigated to determine the ideal environ-
ment for bone formation at the interface between an
implant and the host tissues.
There is an appreciation that mechanical inter-
locking is essential to ensure good performance of
implants. The relevance of increased bone-to-im-
plant contact has been demonstrated by measure-
ment of the torque required to remove implants
exhibiting different degrees of micron-scale rough-
ness [112]. It is conceivable to imagine that topo-
graphical enhancement may aid stabilization of
fibrin clot and fragile extracellular matrix scaffolds
to enable osteoprogenitor cells to become associated
with the implant by contact guidance [113, 114].
It would be beneficial if biomaterials could induce
osseointegration through osteoblastic adherence, cell
proliferation, and differentiation along the osteoblast
lineage. Mesenchymal stem cells (MSCs) are able
differentiate into fat, fibrous connective tissue, bone,
and cartilage. To facilitate osseointegration to im-
plants, bone formation must be encouraged, and fat
or connective tissue production reduced (this would
cause unwanted fibrous encapsulation of the im-
plant). To this end there has been increasing work on
the influence of surface features on cell behaviour.
Buser et al. [115] compared various surface pre-
parations of CpTitanium (commercially pure titanium)
to an electropolished surface negative control and a
HA-coated positive control group. They observed that
micron-scale roughness could influence cellular acti-
vity. CpTitanium could be modified to enhance bone
accrual and could therefore be considered to be
‘bioactive’.
Implants with a smooth surface at the nanometre
level become surrounded by a fibrous membrane
which resists osseointegration and leads to implant
failure. Implants with increased nanoscale rough-
ness have shown a significantly better affinity with
bone [116], and on some nanotopographies, fibro-
blasts become relatively less adherent when com-
pared to osteoblast cells [117–119]. One study used
three different techniques – electrochemical ma-
chining, anodization, and chemical etching – to
fabricate sub-micron scale features on CpTitanium
surfaces [120]. They discovered that as the size of the
Proc. IMechE Vol. 224 Part H: J. Engineering in Medicine
features decreased, cell proliferation and differentia-
tion increased.
Individual grains of bone are measurable by the
nanometre (average organic grain size of 10–50 nm).
Osteoblasts have cell extensions with , 100 nm
diameter tips that sense features as small as 10 nm
for suitable sites of adhesion [121–123]. In a study
investigating MSC differentiation, isotropic (symme-
trical) and random patterns created by nanotopo-
graphy produced very few osteoblast-like cells [124].
An anisotropic pattern of 120 nm diameter and
100 nm deep pits directed stem cells to become
osteoblasts and produce bone without the use of
osteogenic supplementation [124]. Nanotopography
is a cheap process that has the potential to provide
long-lasting bioactivity.
Surface topography also affects bacterial beha-
viour. This factor is of particular importance in the
surgical setting. Staphylococcus epidermis adhesion
and proliferation is reduced when cultured on TiO2
and ZnO nanotopographies, despite an increase in
osteoblast differentiation and proliferation [125].
Surface modification of materials, destined for or-
thopaedic or dental implantation, may also influence
the other surface characteristics that affect cellular
response. When atomic level control of material as-
sembly is approached, the surface properties are
influenced by quantum phenomena [126]. It is very
difficult, but essential, to distinguish distinct topo-
graphy-related effects from changes in surface energy
or chemical reactivity. It is currently unclear exactly
how topography affects cell behaviour.
9 LOAD-BEARING IMPLANTS
9.1 First-generation implants
Whilst modern cell and tissue engineers are devel-
oping substitutes for porous and highly osteogenic
cancellous bone, orthopaedic surgeons have been
replacing compact load-bearing cortical bone for
many years using bioinert implants.
Traditionally, orthopaedic and dental implants
have been composed of metals such as stainless
steel 316L, cobalt chromium alloy, titanium, or
titanium alloy (Ti-6%Al-4%V) [127]. The ultimate
tensile strength (UTS) and relative inertness of these
materials make them attractive constituents for
load-bearing prostheses or fracture fixation devices.
Metal cannot mechanically replicate bone due to the
dramatically different Young’s moduli (see Table 4).
This creates an unnatural situation and a significant
change in the mechanics of the implicated bone.
JEIM770
 Bone grafting, orthopaedic biomaterials, and bone engineering 1337

Table 4 Comparative stiffness of bone and other rele-
vant materials [127]
Material Young’s modulus (GPa) UTS (MPa)
Cortical bone 7–25 50–150
Cancellous bone 0.1–1 ,1
Stainless steel 316L 200 207–1160
CoCrMo alloy 230 430–1028
Ti-6%Al-4%V 105 780–1050
Alumina ceramic 365 1138
HA 85 40–100
PMMA (bone cement) 770 1.5
PE 1 20–30
UHMWPE 1 46
Subsequent bone remodelling leads to bone resorp-
tion in such areas (stress shielding) and the potential
for fracture through the weakened bone.
Titanium has long been appreciated for its bio-
compatible nature [128]. The low inflammatory
response exhibited by tissues adjacent to titanium,
is considered advantageous and necessary for osteo-
integration [129]. The biocompatibility of Ti-6%Al-
4%V is considered by most groups to be superior to
CoCrMo [130]. Adverse effects of cobalt [130],
chromium [131], and molybdenum [132] on other
cell types have been identified. CoCrMo alloy parti-
cles have been shown to be toxic, with cell death
increasing as the particle dosage increases [133, 134].
9.2 Second-generation implants
To enable osseointegration, metal-stemmed pros-
theses used in orthopaedics are modified with
surface treatments or coatings. The FurlongH HA-
coated femoral prosthesis (JRI, London, UK), intro-
duced in 1985, was the first implant in the world to
use HA. A study reviewed the 331 consecutive
Furlong HA-coated femoral components implanted
between 1986 and 1991. After a mean follow-up of
17.5 years, the survival rate (for all causes of revision)
was 97.4 per cent. No stems were revised for aseptic
loosening [135].
In an effort to improve bone ingrowth, porous metal
implants inspired by the structure of bone have been
developed. Trabecular MetalTM (Zimmer Ltd, Swindon,
UK) is fabricated in elemental tantalum metal using
vapour deposition techniques that create an 80 per cent
porous biomaterial with a crystalline microtexture that
is structurally similar to trabecular bone [136]. A
transcortical animal study demonstrated 4 weeks after
surgery there was 42 and 53 per cent ingrowth in the
two porosities of tantalum metal investigated. Mechan-
ical tests indicated the shear fixation strength was
considerably higher than materials with less volumetric
porosity [136].
Methods for fabricating nanoscale topographies are
now being utilized to create commercially available
implants with bioactivity. The OsseoSpeedTM surface
(Astra Tech AB, Molndal, Sweden) has nanofeatures
created by grit blasting titania (TiO2), followed by
hydrofluoric acid (HF) treatment. Its surface has
microscale variations of CpTitanium, with random
50–100 nm features imparted by the HF [137, 138]. It
caused greater expression of the osteoblast markers
Runx, Osterix, alkaline phosphatize, and bone sialo-
protein. Furthermore, canine models compared Os-
seoSpeedTM (which exhibits micron- and nano-
topographies) with grit-blasted CpTitanium (that
only had micron-scale roughness) [139, 140]. They
found increased production of bone at the implant
interface after using OsseospeedTM.
NanotiteTM (BIOMET 3i Implant Innovations, Palm
Beach Gardens, Florida) is another metal implant that
exhibits nanoscale features. It involves a CaP nano-
particle modification of a titanium alloy implant
using discrete crystalline deposition (DCD) methods
[141]. The tightly adherent 50–100 nm CaP DCD
crystal is deposited over 50 per cent of the implant
surface. In a rat tibia model, bone ingrowth was 27%
(CpTi) and 30% (Ti alloy) for the metals with
nanotopography compared to 12% (CpTi) and 17%
(Ti alloy) for the unmodified and surfaces [142].
Attention is now turning from metal to ceramics and
composite materials. Surface-modified and bioactive
zirconia (e.g. ZiUniteTM, NobelBiocare, Gothenburg,
Sweden) and alumina/zirconia dental implants are
now being used clinically [143].
10 FUTURE POSSIBILITIES IN ORTHOPAEDIC
BIO-ENGINEERING
10.1 Third-generation implants
Third-generation materials are both bioactive and
resorbable. They gradually degrade and are replaced
by host tissues – thereby facilitating repair in situ.
Engineers should be inspired by the natural compo-
sition and structure of bone. The use of natural ma-
terials (e.g. HA, collagen, and glycosaminoglycans) is
more appealing than synthetic materials. In parti-
cular, attention must be paid to the bioactivity and
potential toxic reactions of degradation products.
10.2 Load-bearing bone graft substitutes
Injectable bone graft substitutes can resist compres-
sive forces, but are susceptible to shear forces. Cor-
tical strut grafts, provide more mechanical stability,

JEIM770 Proc. IMechE Vol. 224 Part H: J. Engineering in Medicine

1338 A S Brydone, D Meek, and S Maclaine
but exhibit little osteoconduction and no osteoin-
duction. Alternatively, metal implants can support
the load while a cancellous-type bone graft is used to
restore bone stock. Ideally, a composite of at least
two bone types would exist. The outermost layer
could provide mechanical support and the inner
layer (similar to immature bone) would allow
vascular ingrowth and bone repair.
10.3 Massive bone graft substitutes
A good vascular supply is a prerequisite for the
successful integration of a bone graft. Histological
analysis of bone graft substitutes demonstrates only
2–3 mm of vascular invasion into the material. To
enable the success of massive bone graft substitutes
– the vascular supply must be maintained. This may
be possible by either implantation of a blood vessel
[144] or the incorporation of vascular channels and
the necessary growth factors into the scaffold.
10.4 Antibacterial implants
Nanotopography enables engineers to create a surface
in a non-resorbable implant (e.g. titanium) with per-
manent bioactivity. Current techniques to immobilize
antibiotics in implant coatings can provide long acting
but finite effects [145]. It may be possible to create a
surface in an orthopaedic implant using nanotopo-
graphy that will be resistant to bacterial adhesion and
proliferation. Alternatively, antimicrobial agents can
be attached to implants and only become activated
when in contact with infecting organisms.
10.5 Articular cartilage restoration
Autologous chondrocyte implantation offers some
hope of hyaline cartilage regeneration in joints. This
could potentially reduce the need for joint replace-
ment in the future. Currently, joints cannot be
restored to be ‘as good as new’ [146]. Continued
research is required to improve biomaterials (e.g.
collagen bilayers) that can be glued or stapled (with
resorbable staples) to areas of cartilage loss. A very
viscous hydrogel may provide an even more con-
venient delivery technique. Ideally, autologous cells
could be isolated from simple blood samples and the
cells could be introduced arthroscopically.
11 CONCLUSIONS
There are many clinical conditions which result in
bone loss and create defects which require recon-
Proc. IMechE Vol. 224 Part H: J. Engineering in Medicine
struction. Currently, no prevention has been devel-
oped for aseptic loosening and osteolysis affecting
implants. Further problems faced by orthopaedic
surgeons due to insufficient bone regeneration in-
cludes non-union of fractures, high failure rates for
fusion procedures, and inadequate bone stock in
bone tumour and revision surgery. Thus, there is
considerable interest in the development of the
next generation of osteoinductive materials that
can repair the body in situ whilst permitting
mobilization.
F Authors 2010
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