Australas Phys Eng Sci Med

DOI 10.1007/s13246-015-0407-9

SCIENTIFIC PAPER

The relationship between interfragmentary movement and cell

differentiation in early fracture healing under locking plate
fixation
Saeed Miramini1 • Lihai Zhang1 • Martin Richardson2 • Priyan Mendis1 •

Adekunle Oloyede3 • Peter Ebeling4

Received: 8 July 2015 / Accepted: 20 November 2015

Ó Australasian College of Physical Scientists and Engineers in Medicine 2015

Abstract Interfragmentary movement (IFM) at the fracture stage, cell differentiation in the fracture callus is highly
site plays an important role in fracture healing, particularly influenced by fracture gap size and IFM, which in turn, is
during its early stage, via influencing the mechanical highly sensitive to locking plate fixation configuration. The
microenvironment of mesenchymal stem cells within the computational model predicted that a small gap size (e.g.
fracture callus. However, the effect of changes in IFM 1 mm) under a relatively flexible configuration of locking
resulting from the changes in the configuration of locking plate fixation (larger bone-plate distances and working
plate fixation on cell differentiation has not yet been fully lengths) could experience excessive strain and fluid flow
understood. In this study, mechanical experiments on surro- within the fracture site, resulting in excessive fibrous tissue
gate tibia specimens, manufactured from specially formulated differentiation and delayed healing. By contrast, a relatively
polyurethane, were conducted to investigate changes in IFM flexible configuration of locking plate fixation was predicted
of fractures under various locking plate fixation configurations to improve cartilaginous callus formation and bone healing for
and loading magnitudes. The effect of the observed IFM on a relatively larger gap size (e.g. 3 mm). If further confirmed by
callus cell differentiation was then further studied using animal and human studies, the research outcome of this paper
computational simulation. We found that during the early may have implications for orthopaedic surgeons in optimising
the application of locking plate fixations for fractures in
clinical practice.
& Saeed Miramini
[email protected]
Keywords Fracture healing  Mesenchymal stem cell
Lihai Zhang
[email protected]
differentiation  Locking plate fixation  Mechanical
testing  Computational simulation  Osteoporosis
Martin Richardson
[email protected]
Priyan Mendis
[email protected]
Introduction
Adekunle Oloyede
[email protected]
Bone fractures, particularly those associated with osteo-
porosis, have become one of the most prevalent trauma
Peter Ebeling
[email protected]
conditions seen daily in clinical practice in an era of
demographic ageing. The costs and impairment in quality
1
Department of Infrastructure Engineering, The University of of life resulting from fractures are significant. The success
Melbourne, Parkville, VIC 3010, Australia of fracture repair is heavily dependent on the balance
2
The Epworth Hospital, Richmond, VIC 3121, Australia between stability and biology at the fracture site. However,
3
Biomedical Engineering and Medical Physics, Queensland current fracture fixation strategies mainly focus on stability
University of Technology, Brisbane, QLD 4001, Australia at the expense of biology, leading to a situation in which
4
Department of Medicine, Monash University, Clayton, the optimal balance between stability and biology remains
VIC 3168, Australia poorly understood [1].

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Interfragmentary movement (IFM) and geometry of the However, there are several studies suggesting that the
fracture site both significantly influence fracture healing locking plate fixations are not flexible enough to reliably
[2–5]. The degree of IFM depends on the type and stiffness promote indirect healing [1, 9, 15, 16]. In addition, IFM
of the fracture fixation and the mechanical loading applied induced by locking plate fixation is not uniform across the
to the fracture. While rigid fixation suppresses the IFM and fracture gap [i.e. IFM is much smaller at the near cortex
results in insufficient callus formation and delayed healing, (cortex adjacent to plate) compared with the far cortex], and
a relatively flexible fixation can provide a certain degree of so results in asymmetric and inconsistent tissue formation,
IFM that encourages callus formation [6]. However too which is unfavourable to fracture healing [16].
much flexibility may result in unstable fixation, leading to In this study, we conducted a series of mechanical
excessive IFM and delayed fracture healing [2, 5]. This experiments involving surrogate tibia specimens and
suggests that there should be an optimal balance between locking plate fixations to investigate the characteristics of
stability and biology. In addition, fracture gap size is IFM at fracture site under various locking plate fixation
another important factor that influences the healing process configurations. The effect of experimentally observed IFM
[7]. For a given IFM, the fracture callus between a small on the mesenchymal stem cell differentiation pattern in the
fracture gap size generally experiences a larger stress and early stage of healing was then investigated using our
strain compared with that between a relatively large gap recently developed computational model of fracture heal-
size [8, 9]. ing [17], which has the capability of linking changes in the
IFM is largely controlled by the configuration of fixation configuration of the fixation system to changes in cellular
devices. Recently, the application of locking plate fixation mechanical microenvironments, and ultimately the mes-
has become increasing popular in surgical treatment of enchymal stem cell differentiation pattern in the early stage
fractures [10]. In contrast to the conventional compression of fracture healing.
plate, the locking plate fixation aims to provide the fracture
site with a certain degree of IFM that is essential for indirect
healing, [11]. In addition, locking plate fixation stabilizes the Materials and methods
fracture by means of locking screws, eliminating the
necessity of contact between bone and plate, thereby pre- As illustrated in Fig. 1, firstly, an experimental protocol
serving periosteal blood supply beneath the plate [12]. The was presented to measure the IFM at the near and far cortex
locking plate fixations can be suitable for number of frac- of a transverse fracture under different configurations of
tures including complex periarticular fractures, comminuted locking plate fixation [i.e. namely the Bone-Plate Distance
metaphyseal or diaphyseal fractures, osteoporotic fractures (BPD) and the plate Working Length (WL)]. Secondly, the
as well as fracture mal-union and pathological bones. actual geometry of the fractured surrogate tibia specimens
Locking plate fixations can also be a good option for under locking plate fixation was imported into our devel-
metaphyseal fractures of long bone in which the intrame- oped computational model of fracture healing [17–19]
dullary nailing has a high risk of misalignment [12–14]. using CT scan imaging and 3D model reconstruction

Fig. 1 Schematic diagram

illustrates methodology of this
study

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techniques to investigate the effect of the changes in the manufactured from surgical grade stainless steel. The LCPs
configuration of the fixation system on the cellular were applied medially on the tibia diaphysis surrogates to
mechanical microenvironments, and ultimately cell differ- stabilize an induced transverse osteotomy. All the screws
entiation pattern in the early stage of healing. This research were tightened to 4 Nm and the BPD was adjusted by
focused on the early stage of bone healing (i.e. first week temporary spacers during the specimen preparation. After
after surgical operation) as studies have suggested that the applying the LCP on the surrogates, a transverse fracture
mechanical conditions at the fracture site in this stage is gap was created in front of the central hole of the plate. A
particularly of critical importance to the entire healing transverse fracture gap was investigated in this study as it is
process [20–25]. During this stage, mesenchymal stem one of the most common types of shaft fractures adopted in
cells in the fracture callus commit to chondrogenic or animal models [3, 4, 26]. As illustrated in Table 1, four
osteogenic fate [22], and are therefore especially sensitive configuration groups of locking plate fixation were studied
to their mechanical microenvironment [21]. to explore the effect of both BPD and WL on the IFM at
the near and far cortex of the fracture site. To compare the
Mechanical testing of surrogate bone specimens different configurations of locking plate fixation, the stan-
dard osteotomy model [27] with the screws placed in the
Surrogate bone specimens first, third and fifth holes from the fracture site and BPD of
2 mm was considered as a control model.
Twenty surrogates of tibial bone specimens manufactured
by Synbone (Malans, Switzerland) were used for Mechanical testing protocol
mechanical testing. The purpose of using surrogate bone
tibia instead of cadaver specimens was to eliminate inter- The fracture models were tested under axial compression
specimen variability in the analysis of the influence of BPD with a material testing system (Instron 5569A; Instron,
and WL on the fracture IFM. As shown in Table 1, the Canton, Massachusetts). The distal end of the tibia surro-
twenty surrogates were divided into four groups (five gate specimens were rigidly fixed by a lathe chuck and the
specimens in each group) with different LCP configura- axial compressive load was applied on the tibia inter-
tions in each group. The surrogates, 387 mm long with condylar eminence to allow free rotation (Fig. 2a). This
27 mm shaft diameter, were manufactured from specially set-up simulates the physiological loading conditions
formulated polyurethane foam comprising an inner can- applied on tibia through knee and ankle [28, 29]. Four
cellous bone and an outer shell of cortical bone, replicating configuration groups of five specimens were tested and a
the geometrical and mechanical properties of real adult quasi-static axial compressive load of 100, 150 and 200N
human tibia (compressive Young’s modulus was around was applied to the specimens respectively. These loading
1500 MPa). The use of surrogates could eliminate the conditions represent the allowable partial weight bearing
effect of bone model sample variability in this study. following surgical operation [30]. The magnitude of IFM at
the near and far cortex of the fracture was measured by two
Implants digital callipers with 0.01 mm resolution (Kincrome, Vic-
toria, Australia).
Twenty DePuy Synthes standard 4.5 mm broad Locking
Compression Plate (LCP) with locking screws (Oberdorf,, Statistical analysis
Switzerland) were used in this study. The plates were
206 mm long, 17.5 mm wide and 5.2 mm thick with 11 For each level of applied load, the IFM at the near and far
holes, while the locking screws were 40 mm long with cortex of the four experimental groups were cross-com-
4.5 mm core diameter. Both the plates and the screws were pared using t test to detect any significant differences. Our
power calculations demonstrated that five tibia surrogate
Table 1 Configurations of locking plate fixation used in the specimens in each sub-group would be able to achieve a
mechanical testing significance level of 0.05 with a power of 98 %. The sta-
Configuration Number of Bone-plate Working tistical analysis was performed using MATLAB (R2010,
surrogate distance length (WL) The MathWorks, Inc., Natick, MA, USA).
specimens (BPD) (mm) (mm)

C1 (control) 5 2 30
Computational modelling of early stage fracture
healing
C2 5 4 30
C3 5 2 100
Our recently developed computational model of fracture
C4 5 4 100
healing [17] was used to investigate the influence of the

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Fig. 2 a Mechanical testing

system used in this study
(Instron 5569A; Instron,
Canton, Massachusetts). b Bone
fracture model geometry
indicating working length (WL),
bone-plate distance (BPD).
c Finite element model of tibia
fracture with the incorporation
of facture callus

change of IFM (measured at ‘‘Mechanical testing of sur- commercial medical image processing soft-
rogate bone specimens’’ section) resulting from the change ware Mimics 14.11 (Materialise, Haasrode,
of fixation configuration, on the cellular mechanical Belgium) [34].
microenvironment and ultimately cell differentiation pat- Step 3: The 3D geometry of locking plate fixations
tern during the early stage of healing. As shown in Fig. 2b, used in the mechanical testing was recon-
the 3D geometry of the bone fracture model used in the structed and applied on the tibia model
computational analysis consisted of a fractured tibia spec- created in Step 2 by using commercial CAD
imen with different gap sizes (i.e. 1 mm and 3 mm), software Solidworks (Dassault Systemes,
locking plate fixation with various configurations (i.e. MA, USA). In addition, a 1 mm and 3 mm
BPD = 0, 2, 4 mm and WL = 30, 65, 100 mm) and a soft transverse fracture gap were applied in the 3D
fracture callus. The construction of a complete 3D geom- model to investigate the effect of different gap
etry of bone fracture model involved the following steps: sizes on the mechanical microenvironment of
the fractures. A 3D fracture callus was also
Step 1: The 2D CT scan images of the surrogate tibia
created at the fracture site by assuming a
used in the mechanical testing were obtained
callus index of 1.1 (i.e. the callus diameter
by using a CT scanner (Siemens definition
divided by bone diameter). The callus index
flash dual source dual energy) at Epworth
of 1.1 was selected following the study of
Richmond Hospital (Richmond, Victoria,
Horn et al. [35] who measured the callus size
Australia) with 0.6 pitch number and 0.7 mm
of a group of patients with tibial fracture
resolution. The effective slice spacing (reso-
stabilized by locking plates.
lution) of 0.7 mm to 1 mm is commonly
Step 4: Finally, the complete 3D geometry of bone
applied for CT scan images acquisition
fracture model constructed in Step 3 was
required for 3D geometry reconstruction of
imported into our previously developed com-
macroscopic tissues such as bone [31, 32],
putational model [17] for numerical analysis.
since it can result in high quality 3D geometry
without leading to computational instability. The fracture callus was modelled using the Theory of
Applying higher resolutions can result in Porous Media [36–38] which is commonly used to simulate
creation of unsmooth surfaces leading to the mechanical behaviour of soft biological tissues (e.g.
unnecessary small mesh sizes resulting in cartilage) [38–40]. In addition to the fracture callus, bone
computational instability in the finite element marrow and cortical bone were also modelled as a poroe-
model [33]. lastic tissue [41]. The material properties of the tissues
Step 2: The 3D geometry of the tibia was recon- applied in the computational model are presented in
structed from the CT scan images by using Table 2. The external boundaries of all the tissues, i.e. the

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Table 2 Material properties of

Parameter Granulation tissue Marrow Cortical bone
tissues used in this study
Young’s modulus (MPa) 0.05a 2b 2,0000b
b b
Poisson’s ratio 0.17 0.17 0.3b
b b
Porosity 0.8 0.8 0.04b
4 -14b -14b
Permeability (m /Ns) 10 10 10-17b
b b
Fluid compression modulus (MPa) 2300 2300 2300b
Solid compression modulus (MPa) 2300b 2300b 13920b
a
McCartney et al. [49]
b
Lacroix, Prendergast [41]

fracture callus, cortical bone and marrow, were assumed to stabilized by rigid configurations of locking plate fixation
be impermeable to fluid flow [41]. The interface between could potentially result in delayed healing [9].
the screw and the bone was defined fully bonded in the In addition, the non-uniform gap motion (i.e. the dif-
finite element model. ferent IFM at the near and far cortex) can result in asym-
The cortical bone, marrow and callus were meshed with metric and inconsistent callus formation which is
11446, 6115 and 2595 second-order tetrahedral elements unfavourable for healing [16]. In order to quantify and
respectively (Fig. 2c). The relative tolerance of 10-4 m for compare the uniformity of IFM between the fractures under
displacement and 10 Pa for pressure was applied in the different fixation configurations, the ratio of IFM at the far
solver. The values of tolerances and mesh sizes were cortex (IFMFC) to IFM at the near cortex (IFMNC) is
obtained by a convergence analysis when the difference illustrated in Fig. 4. A smaller ratio of IFMFC/IFMNC
between current and subsequent solutions was less than indicates that the IFM is more uniform across the fracture
2 %. The total Lagrange formulation with material coor- gap. The mechanical testing results show that the increase
dinate system was applied in the model to account for large of BPD and WL in combination with axial loading mag-
strains. nitude could not only increase the IFM at both the near and
To replicate the experiment, the protocol used in the far cortex (Fig. 3, Table 3) but also decrease their differ-
mechanical testing was adopted in the computational ence (Fig. 4, Table 4), resulting in a more uniform IFM.
model. The distal part of the tibia was fixed in the model The results show that the increase of BPD alone (C2,
and the proximal part was subjected to 100, 150 and 200N 100N) could increase IFM at the near cortex by 46 %
axial compressive ramp load in 0.5 s.The IFM at the near (p \ 0.05) and the increase of WL alone (C3, 100N)
and far cortex was numerically calculated and compared increases the IFM by 130 % (p \ 0.05). Furthermore,
with results of the mechanical testing. It is reasonable to simultaneous increase of BPD and WL (i.e. C4, 100N) has
assume that the IFM measured in the experiments is a collective effect, resulting in 218 % increase in IFM at
approximately equal to in vivo IFM in the early stages of the near cortex (p \ 0.05). Most importantly, the increase
callus formation when callus is composed of granulation becomes more significant when the external loading is high
tissue. After reproducing the mechanical testing results, the (C4, 200N), i.e. increasing IFM at the near cortex by
mechanical microenvironment of early fracture callus (i.e. 668 % and decreasing the ratio of IFMFC/IFMNC by 25 %
octahedral shear strain and fluid flow) was calculated and at the same time (p \ 0.05).
finally the initial cell differentiation was predicted. The mechanical testing results from our study suggest
that the adjustment of the configuration of internal fixation
(e.g. BPD and WL) in conjunction with the magnitude of
Results and discussion loading could alter the IFM distribution at fracture site. The
influence of the IFM distribution on the mesenchymal stem
Figure 3 illustrates the IFM at the near and far cortex of the cell differentiation pattern within the fracture callus was
four configuration groups obtained in the mechanical test- further investigated using the developed computational
ing. For all the four configurations under external loading model. Although the fracture callus was not included in the
from 100–200N, it can be seen that IFM is much smaller at mechanical experiments, it can be reasonably assumed that
the near cortex in comparison with that at the far cortex the IFM observed in the experiments is approximately
(p \ 0.001). For example, as shown in Fig. 3a, for control equal to the IFM of the fracture during the early stage when
model (C1) and 100N applied loading, IFM at the far the callus is composed of granulation tissue with very low
cortex is more than four times larger than that at the near stiffness. Figure 5a compares the IFM at the near cortex
cortex. The small IFM at the near cortex of the fractures and far cortex between the mechanical testing

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Fig. 3 The experimental measurements for IFM at the near and far 4 mm, WL = 30 mm (C2), c BPD = 2 mm, WL = 100 mm (C3)
cortex of the fractures stabilized by different configurations of locking and d BPD = 4 mm, WL = 100 mm (C4)
plate fixation: a BPD = 2 mm, WL = 30 mm (control), b BPD =

Fig. 4 The ratio of IFM at far

cortex (IFMFC) to IFM at near
cortex (IFMNC) for different
configurations of locking plate
fixation

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Table 3 Percent increase of IFM relative to control (C1, 100 N) for different configurations of locking plate fixation and load magnitudes
Configuration Percent increase of IFM relative to control (C1, 100N)
Near cortex Far cortex
100N 150N 200N 100N 150N 200N

C1 Control 40 % (p \ 0.05) 119 % Control 26 % 82 %

(p \ 0.05) (p \ 0.05) (p \ 0.05)
C2 46 % (p \ 0.05) 148 % (p \ 0.05) 255 % No significant 53 % 113 %
(p \ 0.05) increase (p = 0.07) (p \ 0.05) (p \ 0.05)
C3 130 % (p \ 0.05) 305 % (p \ 0.05) 438 % 38 % 130 % (p \ 0.05) 200 % (p \ 0.05)
(p \ 0.05) (p \ 0.05)
C4 218 % (p \ 0.05) 412 % 668 % 80 % 169 % (p \ 0.05) 295 % (p \ 0.05)
(p \ 0.05) (p \ 0.05) (p \ 0.05)

Table 4 Percent decrease of

Configuration Percent decrease of IFMFC/IFMNC relative to control (C1, 100N)
IFMFC/IFMNC relative to
control (C1, 100N) for different 100N 150N 200N
configurations of locking plate
fixation and load magnitudes C1 Control No significant decrease No significant
(p = 0.07) decrease (p = 0.06)
C2 10 % (p \ 0.05) 15 % (p \ 0.05) 18 % (p \ 0.05)
C3 21 % (p \ 0.05) 23 % (p \ 0.05) 20 % (p \ 0.05)
C4 23 % (p \ 0.05) 24 % (p \ 0.05) 25 % (p \ 0.05)

measurements and computational model predictions for that the developed model could predict the spatial depen-
control group (C1). It can be seen that the numerical results dency of cell differentiation across the fracture gap. Fig-
fit the experimental data very well, with normalized root- ure 6 illustrates the computational model prediction of the
mean-square deviation (NRMSD) of 2.8 and 4.2 % for near mechanical stimuli index (S) and dominant cell differen-
cortex and far cortex respectively. tiation at the near and far cortex of the fractures stabilized
After validation of the computational model prediction by different configurations of the locking plate fixation
of IFM against the mechanical experiment results, the under physiological loading conditions post-surgery. It can
model was employed to investigate the effect of flexibility be seen that the magnitude of S as well as the callus cell
of locking plate fixation on bone healing. The model differentiation are highly dependent on both the fracture
simulated the early stage of bone healing based on gap size and the flexibility of locking plate fixation.
mechanoregulation theory proposed by Prendergast, et al. Locking plate fixation aims at indirect fracture healing
[42, 43]. According to this mechanoregulation theory, cell with callus formation [14, 16]. Therefore, during the early
differentiation within the callus is modulated by two stage of healing, chondroblast differentiation in the fracture
mechanical stimuli [i.e. octahedral shear strain of the tissue site is favourable as it results in cartilaginous callus for-
(c) and interstitial fluid flow (v)], and has been shown to mation and subsequently indirect healing in the next stages
have the most accurate prediction of cell differentiation [45]. In addition, the differentiation of osteoblasts in the
among the proposed theories [44]. This theory predicts cell fracture gap under the locking plates might not result in
differentiation pattern based on mechanical stimuli index direct osteonal bone union (i.e. direct healing) [9, 45, 46],
‘‘S’’ ðS ¼ c=a þ v=b ; a ¼ 0:0375and b ¼ 3lm=s ). A high as this requires the degree of interfragmentary motion to be
magnitude of mechanical stimuli in the early stage (S [ 3) kept as low as possible during the period of fracture
results in fibroblast differentiation. An intermediate S healing, and this can only reliably be achieved by inter-
(1 \ S B 3) favours chondroblast differentiation, and low fragmentary compression and using a rigid fixation system
mechanical stimuli S B 1 leads to osteoblast differentia- (i.e. compression plating). Further, the study of Mckibbin
tion. Figure 5.b illustrates the computational model pre- [47] showed that direct osteonal bone union is an extremely
diction of early-stage cell differentiation at transverse slow and mechanically inferior healing process involving
cross-section of the callus (i.e. section A–A indicated in cortical bone remodelling. Thus, under locking plate fixa-
Fig. 2b) for C1, 150N, gap size = 3 mm. It demonstrates tions, the early-stage differentiation of osteoblasts in the

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Fig. 5 a Comparison of the

computational model result with
that from the experimental
measurements (C1, control).
b Computational model
prediction of cell differentiation
at transverse cross-section of the
callus during the early stage of
healing depending on octahedral
shear strain and interstitial fluid
flow of the granulation tissue
(C1, 150 N, gap size = 3 mm)

fracture gap may result in delayed healing. Furthermore, fibrous tissue differentiation and delayed healing. By
although certain amounts of fibrous tissue formation contrast, a relatively flexible configuration of locking plate
through fibroblast differentiation can stiffen the fracture fixation seems to benefit fracture healing under a relatively
callus, and so stabilize the fracture site [9, 45], too much large gap size (e.g. 3 mm). The computational simulation
fibrous tissue formation, resulting from excessive strain results are consistent with the study of Perren [8], which
and interstitial fluid flow may result in delayed healing or shows that cells within a small fracture gap experience
non-union [45]. larger strain than those within a large fracture gap. Clinical
It can be seen from Fig. 6 that a small fracture gap size studies indicate that a very small fracture gap experiences
(e.g. 1 mm) under relatively flexible configurations of very large strain and consequently delayed healing or non-
locking plate fixation could lead to excessive strain and union [11]. Consistent with clinical data [11, 48], our
fluid flow within the fracture site resulting in excessive computational simulation results suggest that a successful

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Fig. 6 The average mechanical

stimuli index (S) and dominant
cell differentiation during the
early stage of healing, at near
cortex (NC) and far cortex (FC)
for the fractures with 1 and
3 mm gap size respectively
stabilized by 4.5 mm broad
locking plate fixation

indirect healing is achievable when: (1) a relatively flexible computational model results need to be further validated by
fixation is applied on the fracture and (2) a relatively large animal experiments and clinical studies before it can be
fracture gap (i.e. 2–3 mm) is left after fracture reduction. implemented for the development of patient-specific sur-
The computational simulation results suggest a correlation gical treatment strategies. Moreover, it should be men-
between fracture gap size and flexibility of locking plate tioned that the influence of patient age and genetic factors
fixation, indicating that a relatively flexible configuration were not specifically included in this study.
of locking plate fixation is favourable for a relatively larger
fracture gap. The results suggest that there should be an
optimal fracture gap size and configuration of locking plate Conclusion
fixation for better healing outcomes. For example, chon-
droblast differentiation could happen at both the near and In this study, we investigated the effect of the flexibility of
far cortex of the fracture with 3 mm gap size stabilized by locking plate fixation on callus mesenchymal stem cell
4.5 mm broad LCP with WL = 65 mm and BPD = 2 mm. differentiation in the early stage of fracture healing using
Studies show that the differentiation of chondroblast in the mechanical testing in conjunction with computational
early stage of healing encourages cartilage tissue forma- modelling. The mechanical testing results suggest that the
tion, which promotes indirect bone union [45]. IFM at the near cortex of the fractures under rigid con-
figurations of locking plate fixation can be too small to
Limitations promote callus formation and bone healing. The results of
the computational model suggest that the early-stage
The current study has some limitations. For example, an mesenchymal stem cell differentiation is highly influenced
axial compressive load of 100N–200N was applied on the by the fracture gap size and locking plate fixation
proximal end of the fractured tibia (i.e. knee joint load). configuration.
This loading condition represents the allowable partial Our simulation results indicated that the combination of
weight bearing following surgical operation in the early gap size and fixation configuration has to be carefully
stage of healing [30]. To simplify the complex problem, the chosen for fracture healing treatment. For example, under a
muscle loadings were not included in the mechanical small gap size (e.g. 1 mm), a relatively flexible fixation
testing and the computational model, and only the effect of configuration (e.g. BPD = 2 mm and WL = 65 mm)
knee joint loading as the largest load applied on the bone could lead to excessive stress and strain at fracture site,
during walking [28] were considered. In addition, the whereas the same configuration would benefit callus

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formation through endochondral bone formation under a to inconsistent and asymmetric callus formation. J Orthop
large gap size (i.e. 3 mm). The developed model will allow Trauma 24(3):156–162
17. Miramini S, Zhang L, Richardson M, Pirpiris M, Mendis P,
orthopaedic surgeons to design patient-specific surgical Oloyede K, Edwards G (2015) Computational simulation of the
solutions by establishing a rigorous scientific relationship early stage of bone healing under different locking compression
between the configuration of the fixation system and the plate configurations. Comput Methods Biomech Biomed Eng
biological processes of healing, and thereby achieve opti- 18(8):900–913
18. Miramini S, Zhang L, Richardson M, Mendis P (2014) Compu-
mal fracture healing outcomes. tational simulation of mechanical microenvironment of early
stage of bone healing under locking compression plate with
Acknowledgments The authors would like to thank AOTRAUMA dynamic locking screws. Appl Mech Mater 553:281–286
Asia Pacific (AOTAP14-02), DePuy Synthes, Victorian Orthopaedic 19. Zhang L, Miramini S, Mendis P, Richardson M, Pirpiris M,
Research Trust (2014–2015), Epworth HealthCare and the University Oloyede K (2013) The effects of flexible fixation on early stage
of Melbourne for their support. bone fracture healing. Int J Aerosp Lightweight Struct 3(2):
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