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Engineering Fracture Mechanics 71 (2004) 18091840

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Review

Modelling bone tissue fracture and healing: a review q


M. Doblare *, J.M. Garca, M.J. G
omez
Mechanical Engineering Department, Group of Structures and Material Modelling, Arag
on Institute of Engineering Research (I3A),
University of Zaragoza, Maria de Luna s/n, Zaragoza 50018, Spain
Received 13 November 2002; received in revised form 27 June 2003; accepted 28 August 2003

Abstract
This paper reviews the available literature on computational modelling in two areas of bone biomechanics: fracture
and healing. Bone is a complex material, with a multiphasic, heterogeneous and anisotropic microstructure. The
processes of fracture and healing can only be understood in terms of the underlying bone structure and its mechanical
role.
Bone fracture analysis attempts to predict the failure of musculoskeletal structures by several possible mechanisms
under dierent loading conditions. However, as opposed to structurally inert materials, bone is a living tissue that can
repair itself. An exciting new eld of research is being developed to better comprehend these mechanisms and the
mechanical behaviour of bone tissue.
One of the main goals of this work is to demonstrate, after a review of computational models, the main similarities
and dierences between normal engineering materials and bone tissue from a structural point of view. We also underline
the importance of computational simulations in biomechanics due to the diculty of obtaining experimental or clinical
results.
 2003 Elsevier Ltd. All rights reserved.
Keywords: Biomechanics; Bone fracture; Fracture healing; Computational simulation

Contents
1.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1811

2.

Basic concepts of bone biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1812

3.

Bone mechanical properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1815

4.

Mechanisms of bone fracture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1817

5.

Bone fracture criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1820

Research partially supported by Diputaci


on General de Arag
on, project P-008/2001.
Corresponding author. Tel.: +34-9767-61912; fax: +34-9767-62578.
E-mail address: mdoblare@posta.unizar.es (M. Doblare).

0013-7944/$ - see front matter  2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.engfracmech.2003.08.003

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M. Doblare et al. / Engineering Fracture Mechanics 71 (2004) 18091840

6.

Modelling traumatic and pathologic fractures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1824

7.

Bone fracture healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1825

8.

Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1833

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1834

Nomenclature
elastic modulus
Poissons ratio
compression strength
tension strength
apparent ash density
ash fraction
BV
bone volume fraction
TV
qt
true tissue density
q
bone apparent density
n
bone porosity

n
directional bone porosity dened in Eq. (10)
Xij
symmetric traceless tensor that describes the porosity distribution
a
the crack length
d
the average spacing of bone cement lines
DK
range of cyclic stress density [115]
D
unidimensional damage variable
N
number of cycles
Nf
number of cycles to failure
ri
principal stresses
rij
stress components
Fi ; Fij tensors that dene TsaiWu quadratic failure criterion
A
fabric tensor that takes account the bone mass distribution
Gij ; Fijkm tensors used by Cowin [18] in order to dene the TsaiWu failure criterion
r
ultimate strength in tension along the principal direction i
i
r
ultimate strength in compression along the principal direction i
i
sij
stress deviatoric tensor
Ni
number of cells for each cell type i (where subscripts s, b, f and c indicate stem cells,
osteoblasts, broblasts and chondrocytes respectively)
ci
cell concentration for each cell type i
v
boundary growth rate
tm
time that cells need to dierentiate (maturation time)
w
mechanical stimulus that controls the evolution of the dierent cellular events
fproliferation x; w function that denes the number of stem cells that proliferate and cause the callus
growth
E
m
rc
rt
qa
a

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fproliferation cs ; x; w function that denes the number of stem cells that proliferate causing an increase
of the concentration
fmigration cs ; x function that denes how stem cells migrate
fdifferentiation x; w; tm function that characterizes how stem cells dierentiate into specialized cells
ggrowthx;w;tm function that quanties the change of volume that chondrocytes experiment by swelling
hdifferentiation w; tm function that determines the evolution of osteoblast population produced by intramembranous ossication
hremodelling w function that estimates the rate of osteoblast population by endochondral ossication
pi
proportion in volume of each component i (where each subscript means mi: mineral, cI:
collagen type I, cII: collagen type II, cIII: collagen type III, gs: ground substance)

1. Introduction
The main role of the musculoskeletal system is to transmit forces from one part of the body to another
under controlled strain and to protect vital organs (e.g. lungs, brain). It also performs other important
functions such as serving as mineral reservoir.
Several skeletal tissues participate in this mechanical objective of transmission and protection: bone,
cartilage, tendons, ligaments and muscles. Bone mainly determines global structural stiness and strength,
whereas other tissues transmit loads between bones. The mechanical properties of bone are a result of
a compromise between the need for a certain stiness (to reduce strain and achieve a more ecient kinematics), and the need for enough ductility to absorb impacts (to reduce the risk of fracture and minimize
skeletal weight).
As a result of this compromise, thousands of years of evolution have produced a complex, multiphasic,
heterogeneous, anisotropic microstructure. In the rst section of this paper we present the main aspects of
bone biology in terms of its mechanical properties and constitutive behaviour. Another important aspect of
bone behaviour is its self-adaptive capacity, modifying its microstructure and properties according to the
specic mechanical environment. Bone is not like inert engineering materials. It undergoes substantial
changes in structure, shape and composition according to the mechanical and physiological environment,
an adaptive process known as bone remodelling. A brief explanation of the basic aspects of bone remodelling is included in Section 2.
Bone adaptability allows for ecient repair, which in turn helps to prevent fractures. However, fractures
are still quite common, usually caused by the sudden appearance of a load that exceeds bone strength, or
the cyclic activity of loads (well below bone strength) that gradually accumulate damage at a rate that
cannot be repaired. The stiness and strength of the bone are reduced until a failure of the rst type occurs
under a much lower load. Predicting and preventing bone fractures is an important topic in orthopaedics
due to their high frequency, surgical complications and socio-economic impact. For example, the number
of hip fractures world-wide was estimated to be 1.66 million in 1990 and expected to increase to 6.26 million
by 2050 [1]. In the third section of this paper we review the main studies and models developed to predict
bone fractures.
Once a fracture occurs, the basic healing process is auto-activated naturally to repair the site. Healing
involves the dierentiation of several tissues (cartilage, bone, granulation, etc.), with dierent patterns that
are directly inuenced by the mechanical environment, which is in turn governed by the load applied and
the stability of the fracture site. In fact, not all fractures are completely repaired. Sometimes there are nonunions or delayed fractures depending on specic geometric, mechanical and biological factors, justifying
the many dierent kinds of xations used to improve fracture stabilisation. In Section 4 we review the
fracture healing process and the dierent computer simulation models.

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Finally, the last section includes important conclusions on modelling bone fracture and fracture healing,
indicating the main new trends.

2. Basic concepts of bone biology


Bone tissue has very interesting structural properties. This is essentially due to the composite structure of
bone, composed by hydroxyapatite, collagen, small amounts of proteoglycans, noncollagenous proteins
and water [25]. Inorganic components are mainly responsible for the compression strength and stiness,
while organic components provide the corresponding tension properties. This composition varies with
species, age, sex, the specic bone and whether or not the bone is aected by a disease [6]. Another important aspect that also characterizes this peculiar mechanical behaviour of bone is its hierarchical organization. Weiner and Wagner [2] described this, starting from the nanometric level and ending at the
macroscopic levels, relating the latter to the mechanical properties.
From a macroscopic point of view, bone tissue is non-homogeneous, porous and anisotropic. Although
porosity can vary continuously from 5 to 95%, most bone tissues have either very low or very high porosity.
Accordingly, we usually distinguish between two types of bone tissue (see Fig. 1). The rst type is trabecular
or cancellous bone with 5095% porosity, usually found in cuboidal bones, at bones and at the ends of
long bones. The pores are interconnected and lled with marrow (a tissue composed of blood vessels, nerves
and various types of cells, whose main function is to produce the basic blood cells), while the bone matrix
has the form of plates and struts called trabeculae, with a thickness of about 200 lm and a variable
arrangement [7].
The second type is cortical or compact bone with 510% porosity and dierent types of pores [9].
Vascular porosity is the largest (50 lm diameter), formed by the Haversian canals (aligned with the long
axis of the bone) and Volkmannss canals (transverse canals connecting Haversian canals) with capillaries
and nerves. Other porosities are associated with lacunae (cavities connected through small canals known as
canaliculi) and with the space between collagen and hydroxyapatite (very small, around 10 nm). Cortical
bone consists of cylindrical structures known as osteons or Haversian systems (see Fig. 2), with a diameter
of about 200 lm formed by cylindrical lamellae surrounding the Haversian canal. The boundary between
the osteon and the surrounding bone is know as the cement line.

Fig. 1. Bone section showing cortical and trabecular bone (From [8] with permission).

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Fig. 2. Microscopical structure of cortical bone. (a) 3D sketch of cortical bone, (b) cut of a Haversian system, (c) photomicrograph of
a Haversian system (From [11] with permission).

Cortical bone is usually found in the shafts of long bones and surrounding the trabecular bone forming
the external shell of at bones. This combination of trabecular and cortical bone forms a sandwich-type
structure, well known in engineering for its optimal structural properties [10].
Throughout their useful life, both types of bone are formed by two dierent tissues: woven and lamellar
bone. The skeletal embryo consists of woven bone, which is later replaced by lamellar bone. Normally there
is no woven bone in the skeleton after four or ve years but it reappears during the healing process after
fracture. The two types of bone have many dierences in composition, organization, growth and mechanical properties. Woven bone is quickly formed and poorly organized with a more or less random
arrangement of collagen bers and mineral crystals. Lamellar bone is slowly formed, highly organized and
has parallel layers or lamellae that make it stronger than woven bone.
Bones can grow, modify their shape (external remodelling or modelling), self-repair when fractured
(fracture healing) and continuously renew themselves by internal remodelling. All these processes are
governed by mechanical, hormonal and physiological patterns. Growth and modelling mostly occur during
childhood, fracture healing only occurs during fracture repair and internal remodelling occurs throughout
our lifetime, playing a fundamental role in the evolution of the bone microstructure and, consequently, in
the adaptation of structural properties and microdamage repair.
Bone remodelling only occurs on the internal surfaces of the bone matrix (trabecular surfaces of
cancellous bone and Haversian systems of cortical bone). Bone can only be added or removed by bone
cells on these surfaces. There are four types of bone cells, which can be classied according to their
functions.

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Osteoblasts are the dierentiated mesenchymal cells that produce bone. They are created at the periosteum layer or stromal tissue of bone marrow.
Osteoclasts remove bone, demineralizing it with acid and dissolving collagen with enzymes. These cells
originate from the bone marrow.
Bone lining cells are inactive osteoblasts that are not buried in new bone. They remain on the surface
when bone formation stops and can be reactivated in response to chemical and/or mechanical stimuli [12].
Like bone lining cells, osteocytes are former osteoblasts that are buried in the bone matrix. They are
located in lacunae [9] and communicate with the rest of cells via canaliculi. Many authors [1316] suggest
that osteocytes are the mechanosensor cells that control bone remodelling, but this has not been proven yet.
Furthermore, it is quite reasonable to assume that osteocytes, the only cells embedded in the bone matrix,
are aected by processes that damage the bone matrix. Matrix disruption may be expected to directly injure
osteocytes, disrupting their attachments to bone matrix, interrupting their communication through canalicular or altering their metabolic exchange. Fatigue microdamage may therefore create a situation resembling disuse at the level of the osteocyte cell body and lead to bone remodelling starting with osteoclast
recruitment.
The remodelling process is not performed individually by each cell, but by groups of cells functioning as
organized units, which Frost named basic multicellular units (BMUs) [17]. They operate on bone periosteum, endosteum, trabecular surfaces and cortical bone, replacing old bone by new bone in discrete

Fig. 3. ARF sequence in cortical bone (a) and in trabecular bone (b) (From [11] with permission).

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packets. The BMUs always follow a well-dened sequence of processes, normally known as the ARF
sequence: activationresorptionformation (Fig. 3).
Bone is also anisotropic. Cortical bone has a very low porosity and its anisotropy is mainly controlled by
lamellar and osteonal orientation. On the contrary, trabecular bone has a higher porosity and its anisotropy
is determined by trabecular orientation. It is dicult to quantify anisotropy experimentally. In fact, only
recently have several measures of bone mass directional distribution been proposed for trabecular bone.
Cowin [18] denes bone anisotropy by means of the so-called fabric tensor: a second order tensor that
denes the principal values and directions of the bone mass distribution (for dierent ways of measuring the
fabric tensor see also [1922]).
In fact, structural anisotropy has a direct inuence on stiness properties as well as strength. For
example, the average strength of a compact human bone in Reilly and Burstein [23] was 105 MPa in a
longitudinal compression test, and 131 MPa in a transversal compression test. The average longitudinal
strength in tension in the same experiment was 53 MPa.

3. Bone mechanical properties


As shown in Section 2, the mechanical properties of bone depend on composition and structure.
However, composition is not constant in living tissues. It changes permanently in terms of the mechanical
environment, ageing, disease, nutrition and other factors. Many reports try to correlate mechanical
properties with composition [2429]. Vose and Kubala [30] were possibly the rst to quantify how much
mechanical properties depend on composition, obtaining a correlation between ultimate bending strength
and mineral content. One of the most cited works is Carter and Hayes [24], who found that elastic modulus
and the strength of trabecular and cortical bone are closely related to the cube and square of the apparent
wet bone density, respectively.
Although these preliminary models only took into account the apparent density, several authors [10,31
34] have shown that the mechanical properties of cortical and cancellous bone depend on apparent density
and mineral content. The most representative compositional variable is the ash density with the following
correlation:
E MPa 10500  qa2:570:04

rc MPa 117  qa1:930:04

where qa is ash density. This expression explains over 96% of the statistical variation in the mechanical
behaviour of combined vertebral and femoral data over the range of ash density (0.031.22 g cm3 ).
Keyak et al. [35] also studied the relationship between mechanical properties and ash density for
trabecular bone, obtaining the following expressions with 92% correlation:

E MPa 33900  q2:2
if qa 6 0:27 g cm3
a
2
1:88
rc MPa 137  qa
if qa 6 0:317 g cm3
One limitation of these models is that they do not separate the inuence of bone volume fraction from the
ash fraction. So, Hern
andez et al. [36] express the apparent density as a function of the bone volume
fraction (bone volume/total volume) and the ash fraction (a):
q

BV
BV
q
1:41 1:29a
TV t TV

where qt is the true tissue density of the bone, that is linearly related to the ash fraction a. They determined
the elastic modulus and compressive strength, independently of bone volume fraction and ash fraction, with
a 97% correlation:

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 2:580:02 2:740:13
E MPa 84370 BV
a
TV 1:920:02 2:790:09
rc MPa 749:33 BV
a
TV

In these expressions, the exponent related to ash fraction is larger than that associated with bone volume
fraction, suggesting that a change in mineral content will produce a larger change in mechanical properties.
We have focused on compression strength because the ultimate tension strength of bone tissue is usually
established as a percentage of the compression strength. Dierent values have been used for this ratio, from
0.33 to 0.7 in bovine trabecular bone [37,38], to 0.5 to 0.7 for human cortical bone, depending on the test
direction [23]. Keyak and Rossi [39] performed a FE analysis on the inuence of this parameter and found
that the best agreement was between 0.7 and 1. However, they considered that the parameter was constant,
even though it should also depend on structural variables, as suggested by Keaveny et al. [37,40].
Although all these correlations can predict the main mechanical properties, they do not consider the
inuence of structural and microstructural features or the dierent behaviours in each direction. This aspect
was rst considered by Lotz et al. [41]. They determined the Youngs modulus and the compressive strength
of cortical and trabecular femoral bone in the axial and transversal directions using the apparent density as
a control variable. The elastic modulus and the compressive strength for cortical femoral bone in the axial
direction was approximated by
E MPa 2065  q3:09

rc MPa 72:4  q1:88

and in the transversal direction by the correlation


E MPa 2314  q1:57

rc MPa 37  q1:51

Similarly, the compressive strength for trabecular bone was dened as,

1904  q1:64 axial direction
E MPa
1157  q1:78 transversal direction

rc MPa

40:8  q1:89
21:4  q1:37

axial direction
transversal direction

A dierent idea was suggested by Pietruszczak et al. [42], who included the directional dependence of
strength using the expression:

c
1  nl
9
rc l rc0
1  n0
where n0 , rc0 are reference properties (the rst is the average porosity, and the second the corresponding
strength for this level of porosity), c a constant in the interval 1; 2, and nl is the directional porosity that
can be approximated as
nl  n1 Xij li lj

10

being n the average porosity, li the orientation relative to a xed Cartesian coordinate system and Xij
a symmetric traceless tensor, which describes the distribution of voids.
These mathematical relationships have been used to predict proximal femoral fractures with nite elements. The 3D nite element model is generated from a geometrical model usually recovered from a CT
scan of the specic organ. It is also calibrated in terms of K2 HPO4 equivalent density. Then apparent
density, porosity or apparent ash density are estimated using dierent correlations to model the heterogenous distribution of mechanical properties. Most models consider isotropic behaviour, since it is not
possible to quantify the whole anisotropic structure of a bone organ with current techniques. Only [42]
includes this eect in femoral fracture simulations, but with a spatially constant anisotropy ratio, even

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though it changes widely in the femur at dierent locations [21,43]. One way to overcome this limitation is
to employ anisotropic internal bone remodelling models [4448] that can predict density and anisotropy
distribution, and some of them with sucient accuracy.
Another assumption of most FE analyses in the literature is the linearity of the constitutive behaviour of
bone tissue. This is usually accurate enough, but some authors obtain more accurate results by considering
nonlinear material properties for cortical and trabecular bone [49,50].
An additional limitation is the lack of analyses on fracture initiation and growth until complete failure.
Most studies obtain a stress distribution and a possible fracture load. The extension of the principles of
Fracture Mechanics to bone fracture analysis is clearly underdeveloped, although it will probably be an
important research eld in the near future.

4. Mechanisms of bone fracture


The rst mechanism of bone fracture appears when an accidental load exceeds the physiological range,
inducing stresses over the strength that bone tissue has achieved after adaptation during growth and development (traumatic fracture). Following the clinical literature [5153], there are two main causes for this
type of fracture: an external impact produced, for example, by a fall, or fractures that occur spontaneously by a muscular contraction without trauma (see Fig. 4). The latter are quite common in elderly
people with osteoporosis. Several authors suggest that the main cause of hip fracture is contraction of the
iliopsoas muscle and gluteus medius [53,54].
This kind of fracture is often produced by normal loads acting on a bone that has been weakened by
disease or age [55]. This type of fracture is normally called pathologic. Most are provoked by osteoporosis
in the elderly and are more frequent in women than men. Another important cause of pathologic fractures
are bone tumours, which modify bone mechanical properties and produce stress concentrators. Removing
the tumour usually increases the risk of fracture. In fact, the higher risk of bone fracture in the elderly is not
only due to the progressive reduction of bone consistency (osteoporosis), and therefore strength, but also to
additional factors such as the inability of soft tissues to absorb the energy generated in a fall and the change

Fig. 4. Scheme of two usual mechanisms of bone fracture.

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of the kinematic variables of the gait. Lotz and Hayes [56] report that only a small amount of energy is
needed to break a bone (i.e. 5% of the energy available in a fall), what is due to the energy absorbing action
of soft tissues that are deformed in the impact.
The second type of fracture is produced by creep or fatigue. Bones often support more or less constant
loads for prolonged periods of time and cyclic loads that may produce microdamage. If the accumulation of
microdamage is faster than repair by remodelling, microcracks (or other kinds of microdamage) can
multiply to produce macrocracks and complete fracture. Clinically, this is called a stress fracture. It normally occurs in individuals who have increased repetitive-type physical activities such as soldiers, ballet
dancers, joggers, athletes and racehorses [7,5759]. It also occurs at lower activity levels in bones weakened
by osteoporosis, especially at advanced ages when bone remodelling is almost inactive.
Many experimental [6064] and theoretical [58,59,6571] works have suggested that bone tissue can
repair microdamage by remodelling. Indeed, some authors consider that the accumulation of microdamage
is the mechanical stimulus for remodelling [66,69,70,120,121].
However, the prevention of stress fractures does not only depend on repair by remodelling. It is also
controlled by the specic process of crack initiation and propagation. The microstructure of cortical bone is
similar to ber-reinforced composite materials. Osteons are analogous to bers, interstitial bone tissue is
analogous to the composite matrix and the cement line acts as a weak interface where cracks may initiate
[72]. Many authors have tried to explain the mechanical behaviour of cortical bone tissue through composite models. Katz [73] considers the anisotropy of cortical moduli using a hierarchical composite model
of osteons made of hollow, right circular cylinders of concentric lamellae. Crolet et al. [74] applied
homogenization techniques to develop a hierarchical osteonal cortical bone model with several levels of
microstructure: osteons, interstitial bone, and layers of lamellae with collagen bers and hydroxyapatite.
The results obtained agree well with the experimental data. Other authors suggest that osteons increase the
toughness and fatigue resistance of cortical bone [71,7579]. For example, Corondan and Haworth [79]
found that crack propagation in bone is inhibited by more or larger osteons. Prendergast and Huiskes [80]
also employed microstructural nite element analysis (FEA) to explore the relationship between damage
formation and local strain of osteocyte containing lacunae for various types of damage. The high local
strain around lacuna formed stress bands between lacunae, providing sites for crack nucleation and paths
for crack growth, eectively unloading the lacunae adjacent to the damaged region.
Linear elastic fracture mechanics (LFM) have also been used widely to characterize bone resistance to
fracture [76,8187] by measuring the fracture toughness of cortical bone under various loading modes (see
Table 1). However, changes in fracture toughness with age, microstructure and composition are not always
the same in dierent species or bone locations in the same species, as shown by Yeni and Norman [88]. Only
a few studies have addressed the fracture mechanics of microcracks in osteonal cortical bone [77,89,90]
by analysing the interaction between microcracks and the distribution and type of osteon.
In general, fractures are caused by two main mechanisms: when the damage rate exceeds the remodelling/repair rate (excess damage) or when a normal damage rate is not repaired properly due to a defective
remodelling/repair mechanism (decient repair).
Damage accumulation in bone is similar to articial structural materials. Schaer et al. [93,94] showed
that fatigue damage is similar in vitro and in vivo. The microdamage (related to the load and number of
cycles), may appear in dierent ways at the microstructural level: debonding of the collagenhydroxiapatite
composite [95], slipping of lamellae along cement lines [96], cracking along cement lines or lacunae [97,98],
shear cracking in cross-hatched patterns [99] and progressive failure of the weakest trabeculae [100]. At the
macroscopic level damage is hardly visible before there is a large crack and global failure, even though the
mechanical functionality may have altered substantially in earlier stages. In general, the evolution of microdamage during cyclic loading can be quantied in four ways [101] by measuring: (1) defects at microscale
(number/density of cracks), (2) changes in dierent properties (material density, acoustic emission recordings, electrical resistivity, ultrasonic waves, microhardness measurements, etc.), (3) the remaining life to

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Table 1
Experimental measures of Kc and Gc for cortical bone (from [7,10])
Bone type

Kc (MPa m1=2 )

Gc (J m2 )

Mode I: Transverse fracture


Bovine femur [81]
Bovine tibia [82]
Equine metacarpus [83]
Human tibia [84]

5.49
2.24.6
7.5
2.25.7

31005500
7801120
23402680
350900

Mode I: Longitudinal fracture


Bovine femur [81]
Bovine femur [91]
Bovine tibia [85]
Human femur [84]
Human tibia [76]
Human tibia [92]

3.21
2.45.2
2.86.3
2.25.7
4.324.05
3.7

13882557
9202780
6302238
350900
897595
360

Mode II
Human tibia [84]

2.22.7

365

failure, and (4) variations of macromechanical behaviour (changes in elastic, plastic or viscoplastic properties). The last measurement is often used to quantify fatigue cycling by a macroscopic analysis of stiness,
strength and creep relaxation [93,94,102110], in addition to other methods [103,109114].
Taylor and Prendergast [115] express the crack growth rate in terms of the cyclic stress intensity and
crack length, concluding that the crack growth rate decreases rapidly with increasing length. This behaviour
is typical of short-crack fatigue in many materials and can be interpreted in terms of microstructural
barriers to growth. They propose the following equation for compact bone:

m 

da
d a
0
fCDK  DKth n g C 0 DK n
11
dN
d
where symbols {} means

A for A P 0
fAg
0 for A < 0

12

and a is the crack length, d the average spacing of cement lines, DK is the range of cyclic stress density and
the rest of parameters are constants determined by Prendergast and Taylor [115]. The rst term describes
the behaviour of cracks when they are long, and the second one is used for short cracks.
Carter and Caler [109,110,116] propose a damage variable, D, between 0 and 1, that increases at a rate
inversely proportional to the number of cycles to failure Nf :
dD
1

dN Nf

13

that is, a remaining lifetime criterion that identies the damage level with proximity to failure. One of the
main disadvantages is that it does not account for the current damage state or stress history.
Several years later, Zioupos et al. [117] and Pattin et al. [118] dened damage as the ratio between the
elastic modulus in the current and the initial state:
D1

E
E0

14

depending on the stress history and the mechanical properties of the material. In fact, the accumulated
damage at each stress level is a non-linear function of the number of cycles [117,118].

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Many theoretical models have been developed in order to predict the accumulation of microdamage in
bone. Recently Davy and Jepsen [119] have performed a detailed revision of the most important contribution in this eld.
It is important to understand that fatigue failure is not only prevented by lamellar structure but also by
remodelling. Several theories have been developed to explain how bone remodelling is activated by damage
and mechanical load. The models hypothesise that bone tries to optimise strength and stiness by regulating porosity and local damage generated by fatigue or creep.
Martin and co-workers have proposed several models where bone remodelling is activated by damage
produced by fatigue or creep [66,70,120]. In their last work [66], a more realistic theory is proposed that
includes the most important mechanical and biological processes. It assumes that bone remodelling is
controlled by packets of cells, so-called BMUs. The BMUs act in a sequence of events that require three to
four months based on measurements from biopsies. The events control the remodelling response and depend on the mechanical environment, microdamage accumulation and the surface available for remodelling.
Prendergast and Taylor [69] proposed a full bone internal remodelling model where damage occurs as a
microcrack distribution even in the equilibrium situation. The stimulus that controls repair is the dierence
between the actual damage and the damage in the equilibrium situation. Ramtani and Zidi [121] also
propose a model to explain the physiological process of couple damaged-bone remodelling, following the
general framework of continuum thermodynamics.
Skeletal biomechanics is more and more focused on how skeletal tissues are produced, maintained and
adapted as an active response to biophysical stimuli in their environment, currently known as mechanobiology [122]. Now that the human genome has been sequenced, it is apparent that the genetic code is only
the beginning. It provides few answers about how skeletal tissues are generated and maintained. This
emphasises the importance of understanding the role of environmental inuence, especially mechanical
factors. The development of mechanobiology will bring great benets to tissue engineering and to the
treatment and prevention of dierent skeletal problems, such as congenital deformities, osteoporosis,
osteoarthritis and bone fractures.

5. Bone fracture criteria


Dierent fracture criteria have been proposed for bone tissue and many experiments have been performed to validate them [37,40,123127]. Many reports use FE models to evaluate fracture patterns and
loads in terms of fracture criteria, especially in the proximal femur [39,125,128131]. Here we review the
most important criteria and their limitations.
The Von MisesHencky formula is an isotropic criterion traditionally used to predict yielding of ductile
materials like metals. It assumes equal strength (ultimate stress) in tension and compression, which is not
very realistic in bone tissue. Failure results when the equivalent Von MisesHencky stress equals the
ultimate strength of the material
q
r2  r3 2 r3  r1 2 r1  r2 2 rc
15
with ri principal stresses and rc the ultimate strength in compression (or tension).
Although this criterion is not very realistic, it has been widely used for estimating proximal femoral
fracture load and assessing hip fracture risk [39,126,128,129,132]. In fact, Keyak et al. [39] analysed that,
when isotropic material properties are used, the Von MisesHencky criterion may be the most accurate for
predicting fracture location, even after accounting for dierences in the tensile and compressive strength
of bone.

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1821

However, the experimental results obtained by Fenech and Keaveny [123] for bovine trabecular bone
indicated that the Von MisesHencky criterion was not a good predictor of fracture load in trabecular
bone, particularly when the stress state was dominated by shear.
Homan (1967) [164] proposed a fracture criterion for brittle materials that also takes into account the
dierent strength in tension and compression. Nevertheless, it assumes the same behaviour in all directions:
2

C1 r2  r3 C2 r3  r1 C3 r1  r2 C4 r1 C5 r2 C6 r3 1

16

where ri are the principal stresses, Ci material parameters dened as C1 C2 C3 2r1t rc ; C4 C5 C6


1
 r1c , and rc , rt are the ultimate strengths in compression and in tension, respectively. In expression (16),
rt
the linear terms represent the dierence between tension and compression. The Homan criterion is
equivalent to the Von MisesHencky criterion when rc rt .
This criterion has been also used to predict load and pattern of proximal femoral fractures [39,132]
obtaining results slightly worse than the Von MisesHencky criterion.
The maximum stress criterion (Rankine criterion) was initially introduced to predict failure of brittle
materials. It assumes that failure takes places when the highest principal stress exceeds the ultimate strength
in tension or compression. Keyak and Rossi [39] used it to predict the ultimate fracture load of bone tissue
with less than 30% error in all cases. The parallel criterion in strains (SaintVenant criterion) is even more
correlated with the experimental data (less than 20% error), which is also a well-known situation in brittle
materials. Fenech and Keaveny [123] were able to predict the failure of trabecular bone reasonably well
using the principal strain criterion.
Keyak and Rossi [39] also obtained reasonably accurate results with the maximum shear stress (also
known as the Tresca theory) and the maximum shear strain criteria.
The MohrCoulomb criterion is commonly used for materials with dierent behaviour in tension and
compression, such as soils [133]. It is an isotropic criterion that is expressed as follows for non-cohesive
materials, in the space of principal stresses:
r1 r3
 1
rt rc

17

where r1 P r2 P r3 are the principal stresses and rc , rt the ultimate strengths in compression and tension
(rt arc ), respectively. Keyak and Rossi [39] used this criterion to predict the ultimate fracture load of
bone tissue. It agreed well with the experimental data when coecient a tended to one. For smaller values,
the results are on the safety side, that is, the predicted fracture load is always lower than the experimental
one [128].
The modied MohrCoulomb criterion solves some of the original problems [133]. It is expressed as
 rt
1
when rr13 6  1
r1
18
r3
rc rt
 r1  rc 1 otherwise
rc rt
This criterion was used to predict fracture load due to a fall [39]. The results were better than the standard
MohrCoulomb when coecient a was low, but worse when a was above 0.5.
Other authors have tried to validate experimental tests using cellular solid multiaxial criteria [123,127].
These models are better than their predecessors but very dicult to implement in a general way for FE
analyses of whole bones. They could be very useful to validate other more phenomenological criteria.
The TsaiWu quadratic criterion [134] is an obvious candidate for a multiaxial anisotropic failure criterion since it accounts for strength asymmetry (dierent tensile and compressive strengths) and anisotropy,
as well as interactions between strengths under dierent loading conditions. Tsai and Wu [134] expressed
this criterion in terms of the stress tensor and two material dependent tensors. The basic hypothesis is the
existence of a failure surface in the stress space of the following form:

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M. Doblare et al. / Engineering Fracture Mechanics 71 (2004) 18091840

f rk Fi ri Fij ri rj 1

for i; j; k 1; 2; . . . ; 6

19

being Fi and Fij tensors of material dependent constants of second and fourth rank respectively and ri the
principal stresses. The interaction terms must verify:
Fii Fjj  Fij2 P 0

20

which implies that all the diagonal terms of Fij must be positive. The inequality guarantees that each
principal stress axis intersects with the fracture surface. The linear terms in (19) take into account the
dierence between positive and negative ultimate stresses. Finally, it is interesting to remark that the Von
MisesHencky and Homan criteria are particular cases of the TsaiWu criterion. The main disadvantage
of the latter is the high number of constants that have to be determined by multiple experimental tests and
the subsequent correlation procedure. For instance, for orthotropic material this number goes up to 12 and
for a heterogeneous anisotropic material the correlation is almost impossible. However, the TsaiWu
criterion has been used as the point of departure for simplied criteria [18,123], which strongly reduces the
number of constants. Fenech and Keaveny [123] used a simplied TsaiWu criterion to predict the fracture
load on trabecular bovine femurs with less than 20% error. Keaveny et al. [127] estimated the TsaiWu
coecients as a functions of apparent density, using uniaxial strength-density data from 139 bovine tibial
specimens and multiaxial data from 9 similar specimens. So they predicted the failure criterion at dierent
apparent densities indicating that the orientation of this surface depended on apparent density and was
relatively well aligned with the principal material directions (see Fig. 5). This TsaiWu criterion has been
also applied with varying degrees of success to cortical bone [135137], and has been formulated in terms
of the fabric tensor [18], as will be shown below.
Cowin [18] proposed a fracture criterion useful for porous materials and/or composites, based on the
properties of the homogenized microstructure. The fracture criterion is a function f of the stress state, the
porosity n and the fabric tensor A as follows:
f A; r; n f QAQT ; QrQT ; n 1;

8Q orthogonal tensor

21

Cowin [18] considers that a quadratic function obtains a good compromise between reliability and computational cost, with the criterion expressed as
Gij rij Fijkm rij rkm 1

22

where rij are the stress components and Gij , Fijkm functions of A, n.
Eq. (22) may be simplied by working in the space of principal stresses and considering a symmetrical
criterion with respect to the principal axes. It then depends on only three constants Gii and six Fiikk of the
material as follows:

Fig. 5. TsaiWu failure criterion for general triaxial normal loading for an apparent density of 0.6 g/cc. (From [127] with permission).

M. Doblare et al. / Engineering Fracture Mechanics 71 (2004) 18091840

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G11 r11 G22 r22 G33 r33 F1111 r211 F2222 r222 F3333 r233 2F1122 r11 r22 2F1133 r11 r33
2F2233 r22 r33 1

23

Cowin [18] gives some indications to determine the constants from the ultimate strengths of the material
in the dierent directions and orientations. Thus
Gii

Fiijj

1
1
 
r
r
i
i

Fiiii

1

r
i ri

1
1
1
  
ri ri
rj rj
2r2ij

24
!
 gA

25


where r
i , ri , rij are the ultimate strengths in tension, compression and in shear, respectively, along each
direction and plane and gA is a function of the fabric tensor. The main innovation with respect to Tsai
Wu is the assumption that the tensors Fijkm , Gij are functions of the porosity and the fabric tensor, that is,
of the properties of the homogenized microstructure of the material.
Although this criterion has been cited by several authors [42,138], it has not been used in computational
simulations due to the diculty of determining all the parameters involved. Only Gomez et al. [131] correlated the dierent directional parameters of the Cowin criterion with the apparent density and the fabric
tensor, that were obtained after simulating the anisotropic bone remodelling and computing the density and
fabric tensor distribution on femoral bone. The approach was used to predict hip fractures and the results
were in accordance with the experimental work of Yang et al. [53].
Pietruszczak formulated a theory to explain fractures in concrete [139]. It has also been applied to
frictional materials [140] and bone tissue [42], with behave dierently in terms of tension and compression.
This criterion takes into account the stress state rij , the fabric tensor Aij and the porosity n that denes the
failure criterion:
!
!2 

I
r
r
 b3
F b1
b2
0
26
rc
gh  rc
gh  rc
s s 1=2
where I rii is the (negative) trace of the stress tensor (negative rst stress invariant);
r ij2 ij
(rep


lated to the second stress invariant) being sij the stress deviatoric tensor, h sen1 3sij sjk skl =2
r3 =3
(related to the third stress invariant), b1 , b2 , b3 are adimensional material constants and rc the ultimate
uniaxial compression strength. The g function of the third invariant is expressed as
p p
1 b  1  bK
p
gh p p
27
K 1 b  1  b 1  K 1 b  sin 3h

with b a constant close to 1, K a material dependent constant that represents the ratio between the ultimate
value of r in compression and in tension. This criterion was used by Pietruszcak et al. [42] to determine the
risk of fracture in human femurs, simulating the fracture produced by a fall. G
omez et al. [131] obtained
similar results when they compared this criterion with Cowins criterion.
Finally, we can observe that there is a lack of agreement between dierent studies. Several authors
[37,125] suggest that strain-based failure theories are better than stress-based ones, but others indicate the
opposite [39]. For example, Keyak and several collaborators [39,49,129] mostly use distortion energy
theories (Von MisesHencky or Tresca criterion) to represent femoral bone fracture. But Fenech and
Keaveny [123], prefer maximum normal strain criterion in their study of trabecular bovine bone for uniaxial tensile or compressive loading along the principal trabecular direction combined with torsional
loading about the same direction.

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M. Doblare et al. / Engineering Fracture Mechanics 71 (2004) 18091840

There may be several causes for this discrepancy. Most computational simulations do not dierentiate
between cortical and trabecular bone (only in porosity), but their structure is completely dierent, which
could aect their failure mechanisms. Also, most of the criteria assume isotropic behaviour, which is unrealistic. All this controversy suggests that we are still far from getting a mechanobiologically based failure
criterion for bone and that more experimental, analytical and simulation works should be performed in
order to determine the appropriate bone failure theory. Some of the available results on the simulation of
bone fractures according to the previously explained criteria are shown in Section 6.

6. Modelling traumatic and pathologic fractures


The importance and high cost of treating bone fractures has promoted the development of non-invasive
methods of assessing fracture risk and prevention. The methods usually involve radiographic techniques to
measure bone mineral density, such as dual-energy X-ray absorptiometry (DXA) or quantitative computed tomography (QCT) [56,141147]. The methodology has been somewhat successful but it is still limited by a more precise estimation of fracture load and the identication of subjects with a high risk of
fracture. It does not take into account dierent loading conditions, the distribution of bone material within
the entire structure and the properties of the distributed bone material [148]. In order to solve some of
these limitations, FEA have been widely used to predict and prevent the occurrence of hip fractures
[39,42,49,50,126,128,129,132,138,149151]. FEA helps to identify the most probable fracture mechanisms, the regions where the fracture initially appears and the forces and orientations needed to produce
them.
All these models have similarities and dierences that must be analysed in order to perform a comparative analysis that highlights their main limitations and the ideal properties that should be veried in
future developments.
Lotz et al. [132] studied the stress distributions in the proximal femur during a one-legged stance and for
a fall to the lateral greater trochanter. In the rst case, the peak stresses were in the subcapital region. For
the simulated fall, the peak stresses appeared in the intertrochanteric region. Cheal et al. [138] studied the
fracture strength of the proximal femur with a lesion in the femoral neck due to a tumor. They considered
four loading conditions corresponding to level gait and stair climbing. Lotz et al. [151] also examined the
evolution of stress distribution in the proximal femur during the three phases of the gait cycle, but they did
not compute fracture loads. Ford et al. [126] analyzed the eect of internal/external rotations on femoral
strength for loading that represented impact from a fall onto the hip. Sabick and Goel [150] compared the
failure loads for a posterolateral impact on the greater trochanter with a fall onto the buttocks, but they did
not study other load directions. Keyak et al. [129] analysed the ability of nite element models to predict the
fracture location and/or type for two dierent loading conditions: one similar to joint loading during singlelimb stance and one simulating impact from a fall (the same fall that was simulated by Lotz et al. [132]). In
the rst condition, the FE models predicted that only cervical fractures occurred (72% agreement with
experimental results). In the second case they predicted trochanteric and cervical fractures, obtaining a 79%
agreement with laboratory tests. Keyak et al. [152] also determined the force directions associated with the
lowest fracture loads for two types of loading: one simulating the impact from a fall and the other corresponding to joint loading during daily activities (atraumatic condition). For the fall, the force direction
with lowest fracture load was an impact onto the greater trochanter at an angle of 60 or 70 respect to the
shaft. For atraumatic loading, the lowest fracture load was determined in conditions very similar to
standing on one leg or climbing stairs.
Gomez et al. [131] reproduced the experimental work performed by Yang et al. [53] using FEA. A
computational simulation was developed to characterize the heterogenous structural distribution in the

M. Doblare et al. / Engineering Fracture Mechanics 71 (2004) 18091840

1825

Fig. 6. (a) Factor of risk to fracture in the case of iliopsoas contraction; (b) X-ray of neck fracture (From [53] with permission).

femur and determine porosity and anisotropic properties. They were able to use the Cowin criterion as a
function of the porosity and fabric tensor [18], obtaining promising results that will be below reviewed.
They examined hip fracture patterns due to two possible contractions: iliopsoas and gluteus medius
muscle, in order to obtain a risk factor that is dened by the ratio between the Cowin equivalent stress and
the considered ultimate stress.
In the case of psoas-iliac contraction, a high risk factor is obtained in the neck area (Figs. 6 and 7). The
results obtained indicate that a neck fracture probably occurs since the risk factor is over the limit value 1 in
this area, in a similar way that happened in Yangs experiments for which all the seven femurs supporting
this type of load broke along the neck zone.
They [131] also studied hip fracture patterns due to contractions of the gluteus medius muscle and were
able to predict dierent subtrochanteric or intertrochanteric fractures (Figs. 8 and 9). It appears that
subtrochanteric fracture (or fracture in region D) is the most probable, although neck and trochanteric
fracture can also occur. Similar results were obtained in the Yangs tests [53], where three femurs suered
intertrochanteric fracture and four of them were subtrochanteric.
7. Bone fracture healing
Bone is a living material that is routinely exposed to mechanical environments that challenge its
structural integrity. As explained above, there are several causes of bone fractures. However, in contrast
with inert materials, bone can regenerate to form new osseous tissue where it is damaged or missing. In fact,
the healing of a fracture is one of the most remarkable of all the biological processes in the body.
Understanding tissue regeneration is also essential to explain similar biological processes such as skeletal
embriogenesis and growth.
Bone ossication in the embryo and the growing child can occur in dierent forms: endochondral, intramembranous or appositional ossication. In the rst, cartilage is formed, calcied and replaced by bone.

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M. Doblare et al. / Engineering Fracture Mechanics 71 (2004) 18091840

Fig. 7. (a) Regions of proximal femur; (b) volume percentage of factor of risk for dierent femoral regions in the case of iliopsoas
contraction.

Fig. 8. (a) Factor of risk to fracture due to contractions of the gluteus medius muscle; (b) X-ray of intertrochanteric fracture (From [53]
with permission).

M. Doblare et al. / Engineering Fracture Mechanics 71 (2004) 18091840

1827

Fig. 9. Factor of risk in dierent regions in the case of gluteus medium contraction.

In the second, bone is formed directly by osteoblasts (at bones like skull or pelvis). In the third, ossication is adjacent to membrane layers of mesenchymal cells that dierentiate into osteoblasts. When
osteoblasts are not part of a membrane (i.e., endosteal, trabecular or Haversian canal surface) ossication
is called appositional. The last type of ossication is normally the only one found in healthy adults but
the two types can be activated during the fracture healing process. Therefore, this process is important to
understand tissue repair as well as tissue generation.
Fracture healing is a natural process that can reconstitute injured tissue and recover its original function
and form. It is a very complex process that involves the coordinated participation of immigration, dierentiation and proliferation of inammatory cells, angioblasts, broblasts, chondroblasts and osteoblasts
which synthesize and release bioactive substances of extracellular matrix components (e.g., dierent types
of collagen and growth factors).
We can dierentiate between primary or secondary fracture healing. Primary healing occurs in cases of
extreme stability and negligible gap size, involving a direct attempt by the bone to form itself directly [153].
Secondary healing occurs when there is not enough stabilisation and gap size is moderate. In this case,
healing activates responses within the periosteum and external soft tissues that form an external callus,
which reduces the initial movement by increasing stiness. Most fractures are repaired by secondary
healing, which does a more thorough job of replacing old and damaged bone.
Secondary fracture healing has a series of sequential stages than can overlap to a certain extent, including inammation, callus dierentiation, ossication and remodelling.
The rst stage begins after bone fracture. Blood emanates from the ruptured vessels and a hemorrhage
quickly lls the fracture gap space. Macrophages remove the dead tissue and generate initial granulation
tissue for the migration of undierentiated mesenchymal cells, originating an initial stabilizing callus. These
cells proliferate and migrate from the surrounding soft tissue [153156].
In the next stage, mesenchymal cells may dierentiate into chondrocytes, osteoblasts or broblasts (Fig.
10), depending on the biological and mechanical conditions. These dierentiated cells begin to synthesize
the extracellular matrix of their corresponding tissue. Intramembranous woven bone is produced by direct
dierentiation of the stem cells into osteoblasts and appears adjacent to each side of the gap site, advancing
to the center of the callus. At the same time, at the center of the callus, cartilage is formed by chondrogenesis, except right beside the gap where the stability is still very small and high relative displacement
prevents the dierentiation of mesenchymal cells (Fig. 11).
Once the callus is lled (mainly by cartilage), endochondral ossication begins following a complex
sequence of cellular events including cartilage maturation and degradation, vascularity and osteogenesis.

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M. Doblare et al. / Engineering Fracture Mechanics 71 (2004) 18091840

Fig. 10. The mesengenic process (From [157] with permission).

Fig. 11. Callus at day 9 after fracture showing more mature bone under the periosteum (intramembranous ossication) and an
abundance of chondroid tissue adjacent to the fracture site (chondrogenesis) (From [153] with permission).

The ossication continues until all the cartilage has been replaced by bone and a bony bridge surrounds the
fracture gap, achieving a good stabilization and sucient stiness. When the fracture is completely stabilized, mesenchymal cells begin to invade the gap (Fig. 11). Once the gap has ossied, remodelling of the
fracture site begins gradually in order to restore the original internal structure and shape (internal and

M. Doblare et al. / Engineering Fracture Mechanics 71 (2004) 18091840

1829

Fig. 12. Pauwels concept of tissue dierentiation (From [158] with permission).

external bone remodelling). The last stage is much longer than the previous one (1 year compared to several
weeks, depending on the animal species).
This summarizes the most important stages of bone fracture healing, although the evolution depends on
many factors such as mechanical, type of fracture, gap size, blood supply, hormones, growth factors, etc.
Fracture healing is an important topic of research in biomechanics. During the last years, many theories
and simulation models have been proposed to develop a comprehensive view of the mechanisms that
control bone morphogenesis. Pauwels [158] was one of the rst authors to propose a theory of tissue
dierentiation in response to local mechanical stress and strain (Fig. 12). He assumed that deviatoric
stresses are the specic stimulus for the formation of brous connective tissue or bone, whereas hydrostatic
stresses control the formation of cartilaginous tissue.
Perren and Cordey [159,160] proposed that tissue dierentiation is controlled by the resistance of various
tissues to strain. Their main idea is that a tissue that ruptures or fails at a certain strain level cannot
be formed in a region experiencing strains greater than this level. This theory is normally know as the
interfragmentary strain theory [161].
Carter et al. [162,163] developed a new tissue dierentiation theory, which correlates new tissue formation with the local stress/strain history. They described qualitatively the relationship between the ossication pattern and the loading history, using nite elements to quantify the local stress/strain level,
assuming that the tissue in the callus is formed by a single solid phase. They proposed several interesting
dierentiation rules that are graphically summarized in Fig. 13. In this gure there are two lines that
separate the dierent tissue regions. On the contrary, to the left of the pressure line, the tissue is supporting
a high hydrostatic pressure, which serves as stimulus for the production of cartilaginous matrix, to the right

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M. Doblare et al. / Engineering Fracture Mechanics 71 (2004) 18091840

Fig. 13. Relationship between mechanical stimuli and tissue dierentiation (From [162] with permission).

of this line the hydrostatic pressure is very low, causing the production of bone matrix. There is a limit from
which this tissue is not dierentiated, this one is limited by the boundary line of the right. When the tissue is
subjected to high tensile strains (above the tension line) brous matrix is produced with cartilage or bone
depending on the hydrostatic pressure level.
Many authors have also used computational models (mainly based on nite elements), to estimate local
strains and stresses during the dierent stages of fracture healing [161163,165168], since there is experimental evidence [156,169] that tissue dierentiation is mechanically dependent.
Kuiper et al. [170172] developed a dierentiation tissue theory using the tissue shear strain and uid
shear stress as the mechanical stimuli regulating tissue dierentiation and the strain energy as the mechanical stimulus regulating bone resorption. They used an axisymmetric biphasic model of nite elements
of a fracture and applied movements on the cortical bone in an attempt to predict typical healing patterns
including callus growth. The results were that larger movements increased callus size and delayed bone
healing.
Lacroix et al. [161,173,174] used the dierentiation rules proposed by Prendergast et al. [175] (see Fig. 14)
in combination with FEA to predict dierent fracture healing patterns depending on the origin of the
stem cells. The model can predict the callus resorption produced in the last stage of the fracture healing
process, but cannot predict callus growth during the initial reparative phase (assuming a determined callus
size).
Ament and Hofer [176] proposed a tissue regulation model based on a set of fuzzy logic rules derived
from medical experiments, using the strain energy density as the mechanical stimulus that controls the
process of cell dierentiation.

Fig. 14. Tissue dierentiation law based on mechanical strain and uid ow (From [174] with permission).

M. Doblare et al. / Engineering Fracture Mechanics 71 (2004) 18091840

1831

Bailon-Plaza and Van der Meulen [177] studied the fracture healing process produced by growth factors.
They used the nite dierences method to simulate the sequential tissue regulation and the dierent cellular
events, studying the evolution of the several cells that exists in the callus.
More recently, Garca et al. [178] developed a continuum mathematical model that simulates the process
of tissue regulation and callus growth, taking into account dierent cellular events (i.e., mesenchymal cell
migration, mesenchymal cell, chondrocyte, broblast and osteoblast proliferation, dierentiation and
dead), and matrix synthesis, degradation, damage, calcication and remodelling over time. They also
analysed the evolution of the main components that form the matrix of the dierent tissues (i.e., dierent
collagen types, proteoglycans, mineral and water) to determine mechanical properties and permeability
according to this composition.
In order to dene all these processes, the fundamental variables were the number of cells N and the
concentration c of each cell type (independent variables), with subscripts s, b, f and c indicating stem
cells, osteoblasts, broblasts and chondrocytes respectively. They used the second invariant of the deviatoric strain tensor w as the mechanical stimulus that controls the dierentiation process, which also depends
on location and time. The rate of change of the number of cells in a control volume V of tissue at a point is
dened via the continuity equation to take into account changes in concentration and boundary growth v
along the surface normal:


oci x; t
_
Ni
28
grad ci v ci x; tdivv V
ot
where they assume that each term evolves dierently for each cell type, inuenced by mechanical conditions. When no growth occurs, cell concentration only changes by proliferation, migration, dierentiation
or cell death. However, stem cells proliferate so much that a saturation concentration csat can be reached.
In that case, the boundary has to move to give space for the extra cells, which is described as
(
0
if cs < csat
divv fproliferation x;w
29
if cs csat
csat
ocs x; t
fproliferation cs ; x; w fmigration cs ; x  fdifferentiation x; w; tm
ot

30

being tm the maturation time. Growth also occurs when cartilage cells (chondrocytes) swell. In that case, the
number of cells in the volume does not change, but their concentration decreases:
divv 

1
occ x; t
cc x; t
ot

1
ggrowthx;w;tm
cc x; t

31

32

During osteoblast and broblast dierentiation we assume a constant volume. The evolution of number
of osteoblasts depends on whether intramembranous or endochondral ossication 1 is produced:

hdifferentiation w; tm intramembranous ossification
_
Nb
33
hremodelling w
endochondral ossification

1
In intramembranous ossication osteoblasts appear directly by dierentiation from stem cells, while in endochondral ossication
osteoblasts appear as consequence of calcication of cartilage and replacement by bone.

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M. Doblare et al. / Engineering Fracture Mechanics 71 (2004) 18091840

The dierent functions fproliferation , fmigration , fdifferentiation , ggrowth , hdifferentiation and hremodelling have to be dened
according to specic physiological features [178]. The underlying assumption in this work is that the level
of mechanical deviatoric strains in dierent regions of the callus is the main factor determining dierentiation of mesenchymal cells and consequently the process of tissue regeneration. It is very interesting
that the hypothesis used by Garca et al. [178] agrees with the experimental work by Bishop et al. [179],
who concluded that deviatoric strains may stimulate ossication more than volumetric strains.
Garca et al. [178] also characterized the composition and density of the extracellular matrix, assuming
that composition is independent of density and the main components are water, minerals, ground substances and dierent types of collagen. With these hypotheses and assuming all tissues are isotropic and
linear elastic, they evaluated the mechanical properties of the tissues using the next mixture rule depending
on the proportion of each component pi :


E MPa 20000pmi 430pcI 200pcII 100pcIII 0:7pgs


m 0:33pmi 0:48pcoll 0:49pgs

34

However the mechanical properties in the lamellar bone are computed using the following structural rule
where each subscript means mi: mineral, cI: collagen type I, cII: collagen type II, cIII: collagen type III, gs:
ground substance:


E 2014q2:5 ;
E 1763q3:2 ;

m 0:2
m 0:32

if q 6 1:2 g cm3
if q P 1:2 g cm3

35

The rate of matrix production and degradation depends directly on the cell population, except for the
lamellar bone that is controlled by bone remodelling.
This model has been implemented in a nite element code Marc. It correctly predicts tissue dierentiation and callus shape during fracture healing and quanties the regulatory role of mechanical inuences.
For example, Fig. 15 summarizes the evolution of the bone cells predicted by the model (human tibia with a
2 mm fracture), after applying a typical pattern of fracture movement. The model also predicts the damage
that is generated in soft tissues during fracture healing, which allows the study of pathological conditions
such as non-unions.
Although the model is a good predictor of qualitative tissue dierentiation and callus growth, it still
involves many simplications that must be improved in the future. One example is the combination of
mechanical and growth factors and the role of vascularisation [170172,180] and macrophages [181].
Most of the models analyze the course of dierentiation tissue from a known interfragmentary movement, which seems to be the main stimuli under sucient vascularity [167,170172,182184]. However, this
movement depends on the applied load and the stability of the xation used in the treatment. The load
sharing mechanism between the fractured bone and stiness of the xation should also be considered. Most
fracture healing models only analyze fractures under compression, while there are some important situations (distraction osteogenesis) where tension is the main acting load.
Anisotropy should also be included in computational models, distinguishing between woven (more
isotropic) and lamellar bone (more anisotropic).
From a purely numerical point of view, mesh evolution should also be treated correctly, including
remeshing, rezoning and smoothing approaches. More recently, meshless methods that are less sensitive,
such as natural elements, have been used on similar problems [185].
Several authors [122,186] have also remarked that computer models evaluate mechanical stimuli from a
macroscopic (homogenized) continuum level. However, physiological cellular mechanisms are not yet well
understood and it is not clear whether the continuum approach is completely valid.

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Fig. 15. Bone cell population: (a) initial condition, (b) 8 days, (c) 2 weeks, (d) 4 weeks, (e) 6 weeks and (f) 8 weeks after fracture.

8. Conclusions
More and more departments of Continuum Mechanics are becoming involved in orthopaedic research,
especially in the analysis of mechanical behaviour of living tissues (bone, ligaments and tendons) and the
design of implants. Both areas require in depth understanding of the behaviour of bone as a structural
material, especially the mechanisms of bone failure under dierent loading conditions and how the
mechanical factors aect bone fracture treatment.
It is very important to develop clinical and research tools to assess bone failure and healing in order to
improve the treatment and diagnoses of skeletal diseases. At the same time this helps to unravel the
interaction between mechanical and biochemical regulatory pathways.
Many experiments on skeletal failure and repair have been performed in the last century that include a
range of factors (biological, mechanical, hormonal, sex, age, etc.). Despite this eort, there are still many
unanswered questions. Some of the challenges arise from the diculty of performing in vivo experiments
and interpreting their results, which are very dicult to compare across species, ages, patients, geometries,
bones, loading conditions and so on. All these facts indicate the complexity of the biological problems and
have stimulated the development of computational models that can analyze the inuence of all factors and
make predictions under dierent conditions. These models must also be validated with experimental work.
However, in many cases the computational models cannot be validated directly because some measurements cannot be performed in vivo. Despite this, indirect validations can be performed if the conclusions of the computer simulations are similar to the experimental or clinical results. Indeed, simulations

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of fracture healing are one of the clearest examples of this situation since it is impossible to measure the
stress or strain level in each tissue during dierentiation. But most computational works reviewed here has
been helpful to study the inuence of mechanical factors in this complex process.
Despite the limitations of computer models (e.g., lack of validation and biological information) much
progress has been made on a clinical level, for example:
Many designs of joint replacement prostheses have been studied using nite element models, either by
the manufacturer or by university institutes [187].
Automated patient-specic nite element models have been useful in the assessment of femur and spine
fracture risk [188].
Well-constructed computer models of bones have been used to investigate the eects of regional dierences in age-related bone loss under dierent loading conditions [188].
Nevertheless, it is very dicult to obtain quantitative conclusions from computer simulations because of
anthropometric and metabolical dierences between patients and animal species. Thus, research groups
should make an eort to quantify the range of variability of physiological parameters between individuals
and animals species.
Moreover, most computational models make important simplications, especially in terms of the
characterization of material and boundary/loading conditions. Many computer analyses proceed without a
precise determination of material behaviour. So, we believe that the critical task for biomechanics is to
determine constitutive laws for living tissues. In particular, biomechanical models can be most improved by
including time-dependent mechanical properties, damage and repair of living tissues. In this paper, we have
focused on comparing the current theories of bone fracture and healing, indicating the fundamental considerations to take into account for future improvements.
In the near future, it will be important to focus research on the integration of simulations, experiments
and theoretical aspects [122].
Use of computational simulations for the parametric examination of factors that are dicult or impossible to examine experimentally will contribute to the advance of biomechanics, as other authors have
also indicated [187,189].
All these facts suggest that future research programs in bone biomechanics will probably use more
complex and realistic computer simulations to reduce animal experimentation and clinical trials, with
important economic benets. Perhaps it will be possible to develop computer analysis as a methodology to
perform realistic preoperative mechanical analysis of musculoskeletal disruptions, their prevention and
clinical treatment.

References
[1] Cooper C, Melton LJ. Hip fractures in the elderly: a world-wide projection. Osteoporosis Int 1992;2:2859.
[2] Weiner S, Wagner HD. The material bone: structure-mechanical function relations. Ann Rev Mater Sci 1998;28:27198.
[3] Robinson RA, Elliot SR. The water content of bone. I. The mass of water, inorganic crystals, organic matrix, and CO2 space
components in a unit volume of dog bone. J Bone Joint Surg 1957;39A:16788.
[4] Martin RB. Porosity and specic surface of bone. CRC Critical Reviews in Biomedical Engineering, 1984.
[5] Lucchinetti E. Composite models of bone properties. In: Bone mechanics handbook, 2nd ed. Boca Raton, FL: CRC Press; 2001.
p. 12.119 [chapter 3].
 n M, Aparicio C. Structure and mechanical properties of cortical bone. In: Structural biological
[6] Ginebra MP, Planell JA, Onta~
no
materials. New York: Pergamon Press; 2000. p. 3371 [chapter 3].
[7] Martin RB, Burr DB, Sharkey NA. Skeletal tissue mechanics. New York: Springer-Verlarg; 1998.
[8] Williams PL. Grays anatomy. 38th ed. Churchill Livingstone; 1995.
[9] Cowin SC. Bone poroelasticity. J Biomech 1999;32(3):21738.

M. Doblare et al. / Engineering Fracture Mechanics 71 (2004) 18091840


[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41]
[42]
[43]
[44]
[45]
[46]
[47]
[48]

1835

Currey JD. Bones. Structure and mechanics. Princeton, NJ: Princeton University Press; 2002.
Fridez P. Modelisation de ladaptation osseuse externe. PhD thesis, In Physics Department, EPFL, Lausanne, 1996.
Miller SC, Jee WSS. Bone lining cells. In: Bone, vol. 4. Boca Raton, FL: CRC Press; 1992. p. 119.
Cowin SC, Moss-Salentijn L, Moss ML. Candidates for the mechanosensory system in bone. J Biomech Engng 1991;113(2):191
7.
Lanyon LE. Osteocytes, strain detection and bone modelling and remodeling. Calcied Tiss Int 1993;53:1027.
Burger EH. Experiments on cell mechanosensivity: bone cells as mechanical engineers. In: Bone mechanics handbook. Boca
Raton, FL: CRC Press; 2001 [chapter 28].
Skerry TM, Bitensky L, Chayen J, Lanyon LE. Early strain-related changes in enzyme activity in osteocytes following bone
loading in vivo. J Bone Miner Res 1989;4(5):7838.
Frost HM. Bone remodeling dynamics. Springeld, IL: Charles C. Thomas; 1963.
Cowin SC. Fabric dependence of an anisotropic strength criterion. Mech Mater 1986;5:25160.
Odgaard A, Jensen EB, Gundersen HJG. Estimation of structural anisotropy based on volume orientation. A new concept.
J Microscopy 1990;157:14982.
Whitehouse WJ. The quantitative morphology of anisotropic trabecular bone. J Microscopy 1974;101:15368.
Whitehouse WJ, Dyson ED. Scanning electron microscope studies of trabecular bone in the proximal end of the human femur.
J Anatomy 1974;118:41744.
Odgaard A. Quantication of cancellous bone architecture. In: Bone mechanics handbook, 2nd ed. Boca Raton, FL: CRC Press;
2001. p. 14.114.19 [chapter 3].
Reilly DT, Burstein AH. The elastic and ultimate properties of compact bone tissue. J Biomech 1975;8:393405.
Carter DR, Hayes WC. The compressive behavior of bone as a two-phase porous structure. J Bone Joint Surg 1977;59A:95462.
Carter DR, Spengler DR. Mechanical properties and composition of cortical bone. Clin Orthop Rel Res 1978;135:192217.
Gibson LJ. The mechanical behaviour of cancellous bone. J Biomech 1985;18:31728.
Goldstein SA. The mechanical properties of trabecular bone: dependence on anatomic location and function. J Biomech
1987;20:105561.
Rice JC, Cowin SC, Bowman JA. On the dependence of the elasticity and strength of cancellous bone on apparent density.
J Biomech 1988;21:15568.
Martin RB. Determinants of the mechanical properties of bones. J Biomech 1991;24(S1):7988.
Vose GP, Kubala AL. Bone strengthits relationship to X-ray-determined ash content. Human Biol 1959;31:26170.
Currey JD. The mechanical consequences of variation in the mineral content of bone. J Biomech 1969;2:111.
Currey JD. The eect of porosity and mineral content on the Youngs modulus of elasticity of compact bone. J Biomech
1988;21:1319.
Schaer MB, Burr DB. Stiness of compact bone: eects of porosity and density. J Biomech 1988;21:136.
Keller TS. Predicting the compressive mechanical behavior of bone. J Biomech 1994;27:115968.
Keyak JH, Lee I, Skinner HB. Correlations between orthogonal mechanical properties and density of trabecular bone: use of
dierent densitometric measures. J Biomech Mater Res 1994;28:132936.
Hern
andez CJ, Beaupre GS, Keller TS, Carter DR. The inuence of bone volume fraction and ash fraction on bone strength
and modulus. Bone 2001;29(1):748.
Keaveny TM, Wachtel EF, Ford CM, Hayes WC. Dierences between the tensile and compressive strengths of bovine tibial
trabecular bone depend on modulus. J Biomech 1994;27:113746.
Stone JL, Beaupre GS, Hayes WC. Multiaxial strength characteristics of trabecular bone. J Biomech 1983;9:74352.
Keyak JH, Rossi SA. Prediction of femoral fracture load using nite elements models: an examination of stress- and strain-based
failure theories. J Biomech 1983;33:20914.
Keaveny TM. Strength of trabecular bone. In: Bone mechanics handbook. Boca Raton, FL: CRC Press; 2001 [chapter 16].
Lotz JC, Gerhart TN, Hayes WC. Mechanical properties of metaphyseal bone in the proximal femur. J Biomech 1991;24:31729.
Pietruszczak S, Inglis D, Pande GN. A fabric-dependent fracture criterion for bone. J Biomech 1999;32(10):10719.
Wirtz DC, Schiers N, Pandorf T, Radermacher K, Weichert D, Forst R. Critical evaluation of known bone material properties
to realize anisotropic Fe-simulation of the proximal femur. J Biomech 2000;33(10):132530.
Doblare M, Garca JM. Anisotropic bone remodelling model based on a continuum damagerepair theory. J Biomech
2002;35(1):117.
Doblare M, Garca JM. Application of an anisotropic bone-remodelling model based on a damagerepair theory to the analysis
of the proximal femur before and after total hip replacement. J Biomech 2001;34(9):115770.
Jacobs CR, Simo JC, Beaupre GS, Carter DR. Adaptive bone remodeling incorporating simultaneous density and anisotropy
considerations. J Biomech 1997;30(6):60313.
Fernandes P, Rodrigues H, Jacobs CR. A model of bone adaptation using a global optimisation criterion based on the
trajectorial theory of wol. Comput Methods Biomech Biomed Engng 1999;2(2):12538.
Bagge M. A model of bone adaptation as an optimization process. J Biomech 2000;33(11):134957.

1836

M. Doblare et al. / Engineering Fracture Mechanics 71 (2004) 18091840

[49] Keyak JH. Improved prediction of proximal femoral fracture load using nonlinear nite element models. Med Engng Phys
2001;23:16573.
[50] Lotz JC, Cheal EJ, Hayes WC. Fracture prediction for the proximal femur using nite element models: Part IINonlinear
analysis. J Biomech Engng 1991;113:3615.
[51] Sloan J, Holloway G. Fractured neck of femur: the cause of the fall. Injury 1981;13:2302.
[52] Horiuchi T, Igarashi M, Karube S, Oda H, Tokuyama H, Huang T, et al. Spontaneous fractures of the hip in the elderly.
Orthopedics 1988;11(9):127780.
[53] Yang KH, Shen KL, Demetropoulos CK, King AI. The relationship between loading conditions and fracture patterns of the
proximal femur. J Biomech Engng 1996;118:5758.
[54] Smith LD. Hip fractures. The role of muscle contraction on intrinsic force in the causation of fractures of femoral feck. J Bone
Joint Surg 1953;35A:36783.
[55] Zioupos P, Currey JD. Changes in the stiness, strength, and toughness of human cortical bone with age. J Biomech
1998;22(1):5766.
[56] Lotz JC, Hayes WC. The use of quantitative computed tomography to estimate risk of fracture of the hip from falls. J Bone Joint
Surg 1990;72a:689700.
[57] Burr DB, Forwood MR, Schaer MB, Fyhrie DP, Martin RB, Turner CH. Bone microdamage and skeletal fragility in
osteoporotic and stress fractures. J Bone Miner Res 1997;12:615.
[58] Schaer MB, Jepsen JJ. Fatigue and repair in bone. Int J Fatigue 2000;22:83946.
[59] Lee TC, OBrien FJ, Taylor D. The nature of fatigue damage in bone. Int J Fatigue 2000;22:84753.
[60] Hsieh YF, Silva MJ. In vivo fatigue loading of the rat ulna induces both bone formation and resorption and leads to time-related
changes in bone mechanical properties and density. J Orthop Res 2002;22:76471.
[61] Verbogt O, Gibson GJ, Schaer MB. Loss of osteocyte integrity in association with microdamage and bone remodelling after
fatigue in vivo. J Bone Miner Res 2000;15:607.
[62] Muir P, Johnson KA, Ruaux-Mason CP. In vivo matrix microdamage in a naturally occurring canine fatigue fracture. Bone
1999;25:5716.
[63] Bentolila V, Boyce TM, Fyhrie DP, Drumb R, Skerry TM, Schaer MB. Intracortical remodeling in adult rat long bones after
fatigue loading. Bone 1998;23(3):27581.
[64] Burr DB, Martin RB, Schaer MB, Radin EL. Bone remodeling in response to in vivo fatigue microdamage. J Biomech
1985;18:189200.
[65] Martin RB. Is all cortical bone remodelling initiated by microdamage? Bone 2002;30(19):813.
[66] Hazelwood SJ, Martin RB, Rashid MM, Rodrigo JJ. A mechanistic model for internal bone remodeling exhibits dierent
dynamic responses in disuse and overload? J Biomech 2001;34(3):299308.
[67] Martin RB. Toward a unifying theory of bone remodelling. Bone 2000;26:16.
[68] Martin RB. A theory of fatigue damage accumulation and repair in cortical bone. J Orthop Res 1992;10:81825.
[69] Prendergast PJ, Taylor D. Prediction of bone adaptation using damage accumulation. J Biomech 1994;27:106776.
[70] Martin RB, Burr DB. A hypothetical mechanism for the simulation of osteonal remodelling by fatigue damage. J Biomech
1982;15:1379.
[71] Carter DR, Hayes WC. Compact bone fatigue damage: a microscopic examination. Clin Orthop 1977;127:26574.
[72] Burr DB, Schaer MB, Frederickson RG. Composition of the cement line and its possible mechanical role as a local interface in
human compact bone. J Biomech 1988;21:93945.
[73] Katz JL. Composite material models for cortical bone. In: Mechanical properties of bone. New York: Americal Society of
Mechanical Engineers; 1981. p. 17184.
[74] Crolet JM, Aoubiza B, Meunier A. Compact bone: numerical simulation of mechanical characteristics. J Biomech
1993;26(6):67787.
[75] Carter DR, Hayes WC. Fatigue life of compact bone. I. Eects of stress amplitude, temperature and density. J Biomech
1976;9(1):2734.
[76] Norman TL, Vashishth D, Burr DB. Fracture toughness of human bone under tension. J Biomech 1995;28(3):30920.
[77] Guo XE, Liang LC, Goldstein SA. Micromechanics of osteonal cortical bone fracture. J Biomech Engng 1998;120:1127.
[78] Martin RB, Burr DB. Structure function and adaptation of compact bone. New York: Raver Press; 1989.
[79] Corondan G, Haworth WL. A fractographic study of human long bone. J Biomech 1986;19(3):20718.
[80] Prendergast PJ, Huiskes R. Microdamage and osteocyte-lacuna strain in bone: a microstructural nite element analysis. J
Biomech Engng 1996;118(2):2406.
[81] Melvin JW, Evans FG. Crack propagation in bone. Biomaterials Symposium, Americal Society of Mechanical Engineers, 1973.
[82] Boneld W, Datta PK. Fracture toughness of compact bone. J Biomech 1976;9(3):1314.
[83] Alto A, Pope MH. On the fracture toughness of equine metacarpi. J Biomech 1979;12:41521.
[84] Norman TL, Vashishth D, Burr DB. Eect of groove on bone fracture toughness. J Biomech 1992;25:148992.

M. Doblare et al. / Engineering Fracture Mechanics 71 (2004) 18091840

1837

[85] Behiri JC, Boneld W. Fracture mechanics of bonethe eects of density, specimen thickness and crack velocity on longitudinal
fracture. J Biomech 1984;17:2534.
[86] Moyle DD, Gavens AJ. Fracture properties of bovine tibial bone. J Biomech 1986;19(11):91927.
[87] Wright TM, Hayes WC. Fracture mechanics parameters for compact boneeects of density and specimen thickness. J Biomech
1977;10(7):41930.
[88] Yeni YN, Norman TL. Fracture toughness of human femoral neck: eect of microstructure, composition and age. Bone
2000;26(5):499504.
[89] Lakes RS, Nakamura S, Behiri JC. Fracture mechanics of bone with short cracks. J Biomech 1990;23:96775.
[90] Advani SH, Lee TS, Martin RB. Analysis of crack arrest by cement lines in osteonal bone. In: Proc ASME Annual Winter
Meeting, vol. 3, 1987. p. 578.
[91] Grynpas MD, Boneld W, Young RJ. Crack velocity and the fracture of bone. J Biomech 1978;11:4739.
[92] Vashishth D, Norman TL, Burr DB. Mode I fracture toughness of human bone. Advances in bioengineering, vol. 20. New York:
BED, ASME, 1991. p. 3614.
[93] Schaer MB, Radin EL, Burr DB. Mechanical and morphological eects of strain rate on fatigue of compact bone. Bone
1989;10:20714.
[94] Schaer MB, Radin EL, Burr DB. Long-term fatigue behaviour of compact bone at low strain magnitude and rate. Bone
1990;11:3216.
[95] Mammone JF, Hudson SM. Micromechanics of bone strength and fracture. J Biomech 1993;26:43946.
[96] Lee TC. Detection and accumulation of microdamage in bone. PhD thesis, University of Dublin, 1997.
[97] Lakes RS, Saha S. Cement line motion in bone. Science 1979;204:5013.
[98] Reilly GC. Observations of microdamage around osteocyte lacunae in bone. J Biomech 2000;33:11314.
[99] Choi K, Godstein SA. A comparison of the fatigue behaviour of human trabecular and cortical bone tissue. J Biomech
1992;25:137181.
[100] Choi K, Fyhrie DP, Schaer MB. Failure mechanisms of compact bone in bending: a microstructural analysis. In: Trans 40th
Orthop Res Soc, 1994. p. 425.
[101] Zioupos P, Casinos A. Cumulative damage and the response of human bone in two-step loading fatigue. J Biomech
1998;31(9):82533.
[102] Yeni YN, Fyhrie DP. Fatigue damage-fracture mechanics interaction in cortical bone. Bone 2002;30(3):50914.
[103] Arthur Moore TL, Gibson LJ. Microdamage accumulation in bovine trabecular bone in uniaxial compression. J Biomech Engng
2002;124(1):6371.
[104] Reilly GC, Currey JD. The eects of damage and microcracking on the impact strength of bone. J Biomech 2000;33:33743.
[105] Taylor D. Fatigue of bone and bones: an analysis based on stressed volume. J Orthop Res 1998;16:1639.
[106] Burr DB, Turner CH, Naick P, Forwood MR, Ambrosius W, Hasan MS, et al. Does microdamage accumulation aect the
mechanical properties of bone? J Biomech 1998;31:33745.
[107] Martin RB, Stover SM, Gibson VA, Gibeling JC, Grin LV. In vitro fatigue behaviour of the equine third: remodelling and
microcrack damage analysis. J Orthop Res 1996;14:794801.
[108] Schaer MB, Pitchford WC, Choi K, Riddle JM. Examination of compact bone microdamage using back-scattered electron
microscopy. Bone 1994;15:4838.
[109] Carter DR, Caler WE. Cycle-dependent and time-dependent bone fracture with repeated loading. J Biomech Engng
1983;105:16670.
[110] Carter DR, Caler WE. A cumulative damage model for bone fracture. J Orthop Res 1985;3:8490.
[111] Vashishth D, Tanner KE, Boneld W. Contribution, development and morphology of microcracking in cortical bone during
crack propagation. J Biomech 2000;33:116974.
[112] Taylor D, Prendergast PJ. A model for fatigue crack propagation and remodelling in compact bone. Proc Inst Mech Engng
1997;211(5):36975.
[113] Zioupos P, Currey JD, Sedman AJ. An examination of the micromechanics of failure of bone and antler by acoustic emission
tests and laser scanning confocal microscopy. Med Engng Phys 1994;16(3):20312.
[114] Taylor D, Lee TC. Measuring the shape and size of microcracks in bone. J Biomech 1998;31:117780.
[115] Taylor D, Prendergast PJ. Damage accumulation in compact bone: a fracture mechanics approach to estimate damage and repair
rates. Adv Bioeng BED 1995;13:3378.
[116] Caler WE, Carter DR. Bone creep-fatigue damage accumulation. J Biomech 1989;22:62535.
[117] Zioupos P, Wang TW, Currey JD. Experimental and theoretical quantication of the development of damage in fatigue tests of
bone and antler. J Biomech 1996;29:9891002.
[118] Pattin CA, Caler WE, Carter DR. Cyclic mechanical property degradation during fatigue loading of cortical bone. J Biomech
1996;29(1):6979.
[119] Davy DT, Jepsen KJ. Bone damage mechanics. In: Bone mechanics handbook, 2nd ed. Boca Raton, FL: CRC Press; 2001.
p. 18.118.125 [chapter 3].

1838

M. Doblare et al. / Engineering Fracture Mechanics 71 (2004) 18091840

[120] Martin RB. A mathematical model for fatigue damage repair and stress fracture osteonal bone. J Orthop Res 1995;13:30916.
[121] Ramtani S, Zidi M. A theoretical model of the eect of continuum damage on a bone adaptation model. J Biomech
2001;34(4):4719.
[122] van der Meulen MCH, Huiskes R. Why mechanobiology? A survey article. J Biomech 2002;35:40114.
[123] Fenech CM, Keaveny TM. A cellullar solid criterion for predicting the axial-shear failure properties of bovine trabecular bone.
J Biomech Engng 1999;121:41422.
[124] Fenech CM, Keaveny TM. Successful prediction of axial-shear failure properties of bovine trabecular bone using simple
mechanistic criteria. In: Transactions of the Orthopaedic Research Society, vol. 22, 1997. p. 38.
[125] Ford CM, Keaveny TM. The dependence of shear failure properties of trabecular bone on apparent density and trabecular
orientation. J Biomech 1996;29:130917.
[126] Ford CM, Keaveny TM, Hayes WC. The eect of impact direction on the structural capacity of the proximal femur during falls.
J Bone Miner Res 1996;11:37783.
[127] Keaveny TM, Wachtel EF, Zadesky SP, Arramon YP. Application of the TsaiWu quadratic multiaxial failure criterion to
bovine trabecular bone. J Biomech Engng 1999;121(1):99107.
[128] Keyak JH, Rossi SA, Jones KA, Skinner HB. Prediction of femoral fracture load using automated nite elements modeling.
J Biomech 1998;31:12533.
[129] Keyak JH, Rossi SA, Jones KA, Les CM, Skinner HB. Prediction of fracture location in the proximal femur using nite element
models. Med Engng Phys 2001;23(9):65764.
[130] Oden ZM, Selvitelly DM, Bouxsein ML. Eect of local density changes on the failure load of the proximal femur. J Orthop Res
1999;17(5):6617.
[131] G
omez MJ, Garca JM, Doblare M. Prediction of bone femoral fractures by means of the nite element method: 2nd European
Conference on Computational Mechanics. Cracow (Poland), 2001 (Proceedings in CD-Rom).
[132] Lotz JC, Cheal EJ, Hayes WC. Fracture prediction for the proximal femur using nite element models: Part ILinear analysis.
J Biomech Engng 1991;113:35360.
[133] Shigley JE. Mechanical engineering design. New York: Raver Press; 1977.
[134] Tsai SW, Wu EM. A general theory of strength for anisotropic materials. J Compos Mater 1971;5:5880.
[135] Hayes WC, Wright TM. An empirical strength theory for compact bone. Fracture 1977;3:11739.
[136] Cowin SC. On the strength anisotropy of bone and wood. J Appl Mech 1979;4:13747.
[137] Cezayirlioglu H, Bahniuk E, Davy DT, Heiple KG. Anisotropic yield behaviour of bone under combined axial force and torque.
J Biomech 1985;18:619.
[138] Cheal EJ et al. Evaluation of nite element analysis for prediction of strength reduction due to metastatic lesions in femoral neck.
J Biomech 1993;26(3):25164.
[139] Pietruszczak S, Jiang J, Mirza FA. An elastoplastic constitutive model for concrete. Int J Solids Struct 1988;24(7):70522.
[140] Pietruszczak S. An inelastic behaviour of anisotropic frictional materials. Mech Cohesive Frictional Mater 1999;4:28193.
[141] Cummings SR, Black DM, Nevitt MC, Browner W, Cauley J, Ensrud K, et al. Bone density at various sites for prediction of hip
fractures. Lancet 1993;341:725.
[142] Gluer CC, Cummings SR, Pressman A, Li J, Gluer K, Faulkner KG, et al. Prediction of hip fractures from pelvic radiographs:
the study of osteoporotic fractures. The study of osteoporotic fractures research group. J Bone Miner Res 1994;9(5):6717.
[143] Melton LJ, Wahner HW, Richelson LS, OFallon WM, Riggs BL. Osteoporosis and the risk of hip fracture. Am J Epidemiol
1986;124(2):25461.
[144] Perlo JJ, McDermott MT, Perlo KG, Blue PW, Enzenhauer R, Sieck E, et al. Reduced bone-mineral content is a risk factor
for hip fractures. Orthop Rev 1991;20:6908.
[145] Beck TJ, Ru CB, Warden KE, Scott WW, Rao GU. Predicting femoral neck strength from bone mineral data. A structural
approach. Invest Radiol 1990;25:618.
[146] Esses SI, Lotz JC, Hayes WC. Biomechanical properties of the proximal femur determined in vitro by single-energy quantitative
computed tomography. J Bone Miner Res 1989;4:71522.
[147] Lang P, Steiger P, Faulkner K, Gluer C, Genant HK. Osteoporosis. Current techniques and recent developments in quantitative
bone densitometry. Radiol Clin North Am 1997;29:4976.
[148] Cody DD, Gross GJ, Hou FJ, Spencer HJ, Goldstein SA, Pyhrie DP. Femoral strength is better predicted by nite element
models than QCT and DXA. J Biomech 1999;32:101320.
[149] Keyak JH. Relationships between femoral fracture loads for two load congurations. J Biomech 2000;33(4):499502.
[150] Sabick MS, Goel VK. Force needed to fracture and location of fracture region for two simulated fall positions. Trans Orthop Res
Soc 1997;22:833.
[151] Lotz JC, Cheal EJ, Hayes WC. Stress distributions within the proximal femur during gait and falls: implications for osteoporotic
fracture. Osteoporos Int 1995;5:25261.
[152] Keyak JH, Skinner HB, Fleming JA. Eect of force direction on femoral fracture load for two types of loading conditions.
J Orthop Res 2001;19:53944.

M. Doblare et al. / Engineering Fracture Mechanics 71 (2004) 18091840

1839

[153] Einhorn TA. The cell and molecular biology of fracture healing. Clin Orthop Rel Res 1998;355:S7S21.
[154] McKibbin B. The biology of fracture healing in long bones. J Bone Joint Surg 1978;60B(2):15062.
[155] Iwaki A, Jingushi S, Oda Y, Izumi T, Shida JI, Tsuneyoshi M, et al. Localization and quantication of proliferating cells during
rat fracture repair: detection of proliferating cell nuclear antigen by immunochemistry. J Bone Miner Res 1997;12:96102.
[156] Sandberg MM, Aro HT, Vuorio EI. Gene expression during bone repair. Clin Orthop Rel Res 1993.
[157] Caplan AI, Boyan BD. Endochondral bone formation: the lineage cascade. In: Mechanism of bone development and growth.
Boca Raton, FL: CRC Press; 1994.
ber den einub mechanischer reize auf die dierenzierung der st
[158] Pauwels F. Eine neue theorie u
utzgewebe. Z Anat
Entwicklungsgeschichte 1960;121:478515.
[159] Perren SM. Physical and biological aspects of fracture healing with special reference to internal xation. Clin Orthop Rel Res
1979;138:17596.
[160] Perren SM, Cordey J. The concept of interfragmentary strain. In: Current concepts of internal xation of fractures. Berlin:
Springer-Verlarg; 1980. p. 6377.
[161] Lacroix D. Simulation of tissue dierentiation during fracture healing. PhD thesis, University of Dublin, 2000.
[162] Carter DR, Beaupre GS, Giori NJ, Helms JA. Mechanobiology of skeletal regeneration. Clin Orthop Rel Res 1998;S355:S4155.
[163] Carter DR, Blenman PR, Beaupre GS. Correlations between mechanical stress history and tissue dierentiation in initial fracture
healing. J Orthop Res 1988;6:73648.
[164] Homan O. The brittle strength of orthotropic materials. J Compos Mater 1967;1:200.
[165] Blenman PR, Carter DR, Beaupre GS. Role of mechanical loading in the progressive ossication of a fracture callus. J Orthop
Res 1989;7:398407.
[166] Cheal EJ, Mansmann KA, DiGioia AM, Hayes WC, Perren SM. Role of interfragmentary strain in fracture healing: ovine model
of a healing osteotomy. J Orthop Res 1991;9:13142.
[167] Claes LE, Heigele CA. Magnitudes of local stress and strain along bony surfaces predict the course and type of fracture healing.
J Biomech 1999;32:25566.
[168] Gardner TN, Stoll T, Marks L, Mishra S, Knothe Tate M. The inuence of mechanical stimulus on the pattern of tissue
dierentiation in a long bone fracture-an FEM study. J Biomech 2000;33:41525.
[169] Ashhurst DE. The inuence of mechanical stability on the healing of experimental fractures in the rabbit: a microscopical study.
Series B 313 (1986) 271302.
[170] Kuiper JH, Richardson JB, Ashton BA. Mechanical signals in early fracture callus. In: Vander Sloten J, Lowet G, Van
Audekercke R, Van der Perre G, editors. Proc 10th Europ Soc Biomech, 1996. p. 154.
[171] Kuiper JH, Ashton BA, Richardson JB. Computer simulation of fracture callus formation and stiness restoration. In:
Prendergast PJ, Lee TC, Carr AJ, editors. Proc 12th Europ Soc Biomech, 2000. p. 61.
[172] Kuiper JH, Richardson JB, Ashton BA. Computer simulation to study the eect of fracture site movement on tissue formation
and fracture stiness restoration. In: European Congress on Computational Methods in Applied Sciences and Engineering
ECCOMAS, 2000.
[173] Lacroix D, Prendergast PJ, Marsh D, Li G. Simulation of tissue dierentiation during fracture healing. Trans Orthop Res Soc
2000;25:869.
[174] Lacroix D, Prendergast PJ. A mechano-regulation model for tissue dierentiation during fracture healing: analysis of gap size
and loading. J Biomech 2002;35:116371.
[175] Prendergast PJ, Huiskes R, Soballe K. Biophysical stimuli on cells during tissue dierentiation at implant interfaces. J Biomech
1997;6:53948.
[176] Ament Ch, Hofer EP. A fuzzy logic model of fracture healing. J Biomech 2000;33:9618.
[177] Bail
on-Plaza A, Van Der Meulen MCH. A mathematical framework to study the eects of growth factor inuences on fracture
healing. J Theor Biol 2001;212:191209.
[178] Garca JM, Kuiper JH, Doblare M, Richardson JB. A numerical model to study the mechanical inuences on bone fracture
healing. Acta of Bioengineering and Biomechanics, 4(S1), pp. 394395, 2002 (Proceedings of the 13th Conference of European
Society of Biomechanics).
[179] Bishop NE, Tami I, Schneider E, Ito K. In vivo comparison of early fracture healing under deviatoric and volumetric
deformation. Acta Bioeng Biomech 2002;4(S1):7545.
[180] Simon U, Augat P, Utz M, Claes L. Dynamical simulation of the fracture healing process including vascularity. Acta Bioeng
Biomech 2002;4(S1):7723.
[181] Hankemeier S, Gr
assel S, Plenz G, Spiegel HU, Bruckner P, Probst A. Alteration of fracture stability inuences chondrogenesis,
osteogenesis and immigration of macrophages. J Orthop Res 2001;19:5318.
[182] Goodship AE, Kenwright J. The inuence of induced micromovement upon the healing of experimental tibial fractures. J Bone
Joint Surg 1987;20:105561.
[183] Claes LE, Wilke HJ, Augat P, R
ubenacker S, Margevicius K. Eect of dynamization of gap healing of diaphyseal fractures under
external xation. Clin Biomech 1995;8:22734.

1840

M. Doblare et al. / Engineering Fracture Mechanics 71 (2004) 18091840

[184] Gardner TN, Evans M, Simpson H. Temporal variation of applied inter fragmentary displacement at a bone fracture in harmony
with maturation of the fracture callus. Med Engng Phys 1998;20:4804.
[185] Doblare M, Cueto E, Cego~
nino J, Garca JM. On the use of meshless methods in numerical biomechanical simulation. Acta
Bioeng Biomech 2002;4(S1):1267.
[186] Humphrey JD. Stress, strain and mechanotransduction in cells. J Biomech Engng 2001;123:63841.
[187] Prendergast PJ. Finite element models in tissue mechanics and orthopaedic implant design. Clin Biomech 1997;12(6):34366.
[188] Villarraga ML, Ford CM. Applications of bone mechanics. In: Bone mechanics handbook. Boca Raton, FL: CRC Press; 2001
[chapter 33].
[189] Huiskes R. The law of adaptive bone remodelling: a case for crying Newton? In: Structure and remodelling. Singapore: Wold
Scientic; 1995. p. 1524.