Influence of fracture geometry on bone healing under locking plate fixations: A comparison between oblique and transverse tibial fractures

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Influence of fracture geometry on bone healing under locking plate fixations: A comparison between oblique and transverse tibial fractures Saeed Miramini a,∗, Lihai Zhang a, Martin Richardson b, Priyan Mendis a, Peter R. Ebeling c a b c

Department of Infrastructure Engineering, The University of Melbourne, Victoria 3010, Australia The Epworth Richmond Hospital, Victoria 3121, Australia Department of Medicine, School of Clinical Sciences, Monash University, Monash Medical Centre, Victoria 3168, Australia

a r t i c l e

i n f o

Article history: Received 10 December 2015 Revised 28 May 2016 Accepted 17 July 2016 Available online xxx Keywords: Bone fracture healing Oblique fracture Interfragmentary movement Mechanical testing Computational modelling Cell differentiation

a b s t r a c t Mechano-regulation plays a crucial role in bone healing and involves complex cellular events. In this study, we investigate the change of mechanical microenvironment of stem cells within early fracture callus as a result of the change of fracture obliquity, gap size and fixation configuration using mechanical testing in conjunction with computational modelling. The research outcomes show that angle of obliquity (θ ) has significant effects on interfragmentary movement (IFM) which influences mechanical microenvironment of the callus cells. Axial IFM at near cortex of fracture decreases with θ , while shear IFM significantly increases with θ . While a large θ can increase shear IFM by four-fold compared to transverse fracture, it also result in the tension–stress effect at near cortex of fracture callus. In addition, mechanical stimuli for cell differentiation within the callus are found to be strongly negatively correlated to angle of obliquity and gap size. It is also shown that a relatively flexible fixation could enhance callus formation in presence of a large gap but could lead to excessive callus strain and interstitial fluid flow when a small transverse fracture gap is present. In conclusion, there appears to be an optimal fixation configuration for a given angle of obliquity and gap size. © 2016 Published by Elsevier Ltd on behalf of IPEM.

Introduction Oblique fracture is one of the most common fracture types among all the long bone fractures, and approximately 30–40% of tibial shaft fractures are oblique [1,2]. Due to the oblique geometry, these fractures are especially susceptible to delayed healing or non-union [2–4]. Although it was suggested that the large bone fragment surface area of an oblique fracture could improve bone healing capacity, the special geometry of oblique fractures could still result in delayed healing or non-union [3]. Aro et al. [3] compared fracture healing between transverse and oblique osteotomy in canine tibia stabilized by external fixation. The right and left tibias of eleven adult dogs were randomly undergone transverse and 60° oblique osteotomy, respectively, and then fixed for healing by the same type of external fixation. The experimental results showed that, at 60 days post-surgery, the bending stiffness of the oblique fractures was 76.8% of that of the ∗

Corresponding author. E-mail addresses: [email protected], [email protected] (S. Miramini), [email protected] (L. Zhang), [email protected] (M. Richardson), [email protected] (P. Mendis), [email protected] (P.R. Ebeling).

transverse fractures. Further, the oblique fractures apparently resulted in delayed healing in comparison to the transverse ones, e.g. the bending stiffness of an oblique fracture generally required 90 days to reach that of an intact bone, whereas a transverse fracture healed much faster taking 60 days to regain full bending stiffness. The excessive shear movement at the fracture site has been identified as an important determinant of instability in oblique fractures, leading ultimately to impaired angiogenesis which prevents normal healing process [4–9]. It was suggested that as angiogenesis is very dependent on the fracture site stability, the excessive shear IFM may impede the longitudinal development of blood vessels in the fracture site, thereby leading to impaired ossification of the callus tissue [9]. A recent computational study has confirmed the negative effect of shear IFM on bone healing [10]. In recent years, application of locking plate fixation has become increasingly popular in clinical practice for internal fixation of fractures [11] and has been particularly promising for the fixation of osteoporotic fractures [11–13]. The locking plate fixation bridges the fracture gap and allows a certain degree of IFM to promote callus formation and indirect bone healing [14]. The clinical application of locking plate fixation requires careful pre-operation planning to maximize its effectiveness [15]. However, the scientific

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Influence of fracture geometry on bone healing under locking plate transverse tibial fractures, Medical Engineering and Physics (2016),

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basis of this pre-operation planning, especially its effect on oblique fractures, has not been well understood to date. We have recently developed a validated computational model to simulate mechanical microenvironment of the fracture callus under locking plate fixation for transverse fractures [16–19]. Through application of the theory of porous media [20] and the mechanoregulation theory of Prendergast et al. [21], the model has the capability of predicting the early stage of bone healing for a transverse fracture under various configurations of locking plate fixation [19] via quantification of both tissue strain and interstitial fluid flow which are two important mechanical stimuli for callus cell differentiation. Although it is widely known that mechanical microenvironment of early callus cells can be influenced by fracture fixation, fracture geometry as well as applied loading [22–25], the influence of fracture obliquity on mechanical microenvironment of bone healing of fractures stabilized by locking plate is still unclear. By using experimental testing in conjunction with computational modelling, in this study, we aimed to investigate the changes in the mechanical microenvironment of fracture callus cells and subsequently cell differentiation, resulting from the changes of the angle of obliquity, fracture gap size and configuration of locking plate fixation. The focus of this study was on the early stage of bone healing as it has been demonstrated that the mechanical condition at this stage is critically important and can influence the entire healing process [22–25]. It was demonstrated that during the early stage of healing, mesenchymal stem cells and osteo-chondroprogenitor cell in the fracture callus commit to chondrogenic or osteogenic fate [24] and consequently they are especially sensitive to their mechanical microenvironment [23].

Fig 1. Mechanical testing of surrogate tibia bone specimens using INSTRON testing machine and 3D optical measurement system (ARAMIS). Table 1 Experimental groups used in the mechanical testing.

To achieve the study aim, firstly the axial and shear IFM of surrogate fractures with different angles of obliquity stabilized by locking plate fixation were measured through mechanical testing involving an INSTRON testing machine and 3D optical measurement system (ARAMIS). Then, the effect of experimentally observed IFM on mechanical microenvironment of fracture callus was investigated using our computational model of fracture healing. 2.1. Mechanical testing Twenty adult human tibia surrogate specimens manufactured by Synbone (Malans, Switzerland) were used in the mechanical experiment. Mechanical testing using Synbone tibia surrogate are widely used to investigate biomechanical behaviour of different fracture fixation methods [26,27]. The surrogates were made of specially formulated polyurethane foam comprising of inner cancellous bone and outer shell of cortical bone which provide similar geometrical and mechanical properties to real adult human tibia with around 1500 MPa average compressive Young’s modulus and 0.25 Poisson’s ratio. The purpose of using surrogate bone tibia instead of cadaver specimens was to eliminate inter-specimen variability in the analysis of the influence of fracture obliquity on the fracture IFM. Standard stainless steel 4.5 mm broad Locking Compression Plate (LCP) with locking screws manufactured and provided by DePuy Synthes (Oberdorf, Switzerland) were applied anteromedially on the tibia surrogate diaphysis. The plates were 206 mm long, 17.5 mm wide and 5.2 mm thick with 11 holes, while the locking screws were 40 mm long with 4.5 mm core diameter. Based on the guideline proposed by Gautier and Sommer [28], the screw holes were produced by a drill bit of Ø4.3 mm and the screws were placed in the first, third and fifth holes from the fracture site and were tightened to 4 Nm. In addition, a bone-plate distance (BPD) of 2 mm was adjusted on the fracture model by cite

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Group

Angle of obliquity (θ )

Sample size

C1 (control) C2 C3 C4

0° 15° 30° 45°

5 5 5 5

temporary spacers during specimen preparation. After application of locking plate fixations on the surrogates, fractures with different angles of obliquity (i.e. θ = 0°, 15°, 30° and 45°) were created on the surrogates. Figs. 1 and 2a illustrate mechanical testing set-up and geometry of the fracture model respectively. The fracture models were tested under axial compression by a material testing system (INSTRON 5569A, Canton, Massachusetts). The distal fragment of the tibia was fixed in a lathe chuck and the axial compressive load was applied on the tibia intercondylar eminence to allow free rotation (Fig. 1). This set-up simulates the physiological loading conditions applied on tibia through knee and ankle [29,30]. As illustrated in Table 1, four groups of five specimens were tested and an axial compressive load of 100, 150 and 200 N in 0.5 s was applied to the specimens. These loading conditions represent the partial weight bearing situation following surgical operation [31]. As shown in Fig. 2a, the axial IFM (i.e. IFM component in z-direction which is normal to the fracture line) and the shear IFM (i.e. IFM component in x-direction which is parallel to the fracture line) were measured using 3D optical measurement system ARAMIS (GOM, Braunschweig, Germany). A two-factor ANOVA test was conducted to analyse the effect of angle of obliquity and applied loading, and their interaction on axial and shear IFM. In addition, for each magnitude of loading, the axial and shear IFMs were cross-compared using unpaired t-test to detect differences resulting from different angles of obliquity. A significance level of 5% was used in the statistical analysis. Our pilot study conducted before the main experiments indicted that a sample size of 5 in each group is required to provide a statistical power of 89% with a significance level of 5% to detect significant differences resulting from different angles of obliquity and magnitudes of applied loading. The statistical analysis was performed using MATLAB (R2010, The MathWorks, Inc., Natick, MA, USA).

2. Material and methods

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2.2. Computational modelling of early stage of healing In this research step, the influence of IFMs (observed in the mechanical testing of Section 2.1) on the early stage of healing was of

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Fig 2. (a) Construction of 3D geometry of bone fracture model consisting of fractured tibia bone, fracture callus and locking plate fixation. (b) The developed finite element model of the fracture. Table 2 Material properties of tissues applied in the computational model. Parameter

Granulation tissue

Young’s modulus (MPa) Poisson’s ratio Porosity Permeability (m4 /N s) Fluid compression modulus (MPa) Solid compression modulus (MPa) a b

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0.05 0.17b 0.8b 10−14 b 2300b 2300b

20 0 0 0b 0.3b 0.04b 10−17 b 2300b 13920b

2 0.17b 0.8b 10−14 b 2300b 2300b

McCartney et al. [48]. Lacroix and Prendergast [33].

studied by employing our previously developed and validated computational model of fracture healing [16–19]. The tibia surrogate model used in the experiments was firstly scanned by a CT scanner with 0.7 mm resolution. The CT scanned images were then imported into commercial medical image processing software Mimics (Materialise, Belgium) to reconstruct a 3D geometry of tibia model (Fig. 2). By using commercial CAD software Solidworks (Dassault Systemes, USA), the 3D geometry of locking plate fixation was constructed on the model. In addition, a fracture with different gap sizes (i.e. 1 mm and 3 mm) and angles of obliquity (i.e. θ = 0°, 15°, 30° and 45°) was created in the tibia model. A 3D soft fracture callus was also created at the fracture site by assuming a callus index of 1.1 (i.e. the callus diameter divided by bone diameter). The callus index of 1.1 was selected following the study of Horn et al. [32] who measured the callus size of a group of patients with tibial fracture stabilized by locking plates. Finally, the complete 3D geometry of bone fracture was imported into our previously developed computational model [16] for numerical analysis. The cortical bone, marrow and callus tissues were treated as a biphasic mixture with a solid phase and an incompressible fluid phase [21], while their mechanical behaviour were modelled using the theory of porous media [16]. The material properties of the tissues applied in the computational model were taken from published sources and can be found in Table 2. In addition, the stainless steel locking plate and locking screws were modelled as linear elastic materials with Young’s modulus and Poisson’s ratio of 220 GPa and 0.34 rePlease

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spectively. It was assumed that the external boundaries of fracture callus, cortical bone and marrow are impermeable to fluid flow [33], and that there was a perfect bond between locking screws and the bone, as well as between locking screws and locking plate. To replicate the experimental conditions of the mechanical testing, the distal fragment of the fracture was fixed in the computational model while the proximal fragment was subjected to an axial compressive loading of 10 0–20 0 N, ramped over 0.5 s. The numerical analysis was performed using commercial finite element software COMSOL MULTIPHYSICS (COMSOL AB, Sweden) [34]. The cortical bone, marrow, fracture callus and locking plate fixation were meshed with 13,603, 6535, 14,335 and 15,683 second-order tetrahedral elements respectively in the finite element model as shown in Fig. 2b. The mesh sizes were determined based on a mesh sensitivity analysis that is in turn defined by when the difference between the current and subsequent solution, after doubling the mesh density in fracture callus, was less than 2%. The axial and shear IFM was numerically computed by the model and compared with the results of mechanical experiments. It can be reasonably assumed that the IFM measured in the mechanical experiments is approximately equal to the IFM of the fracture during the early stage when the callus is composed of granulation tissue with very low stiffness. After reproducing the mechanical experiments results, the computational model was employed to calculate the mechanical microenvironment of of

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early fracture callus (i.e. octahedral shear strain and fluid flow) and subsequently to predict the initial cell differentiation for fractures with different gap sizes (i.e. 1 mm and 3 mm) and angles of obliquity (i.e. θ = 0°, 15°, 30° and 45°), stabilized by various configurations of locking plate fixation [i.e. BPD = 0, 2, 4 mm and the plate working length (WL) = 30, 65, 100 mm].

The effect of the experimentally observed IFM on cell differentiation within the callus was further investigated by using the developed computational model. It can be reasonably assumed that the IFM measured in the mechanical experiments is approximately equal to the IFM of the fracture during the early stage when the callus is composed of granulation tissue with very low stiffness. The computational model was employed to investigate the changes in the mechanical microenvironment of the cells within the fracture callus resulting from the changes in fracture gap size, angle of obliquity and fixation configuration. Fig. 5 illustrates the effects of fracture gap size and angle of obliquity on the callus octahedral shear strain and interstitial fluid flow (i.e. the two mechanical stimuli which modulate cell differentiation within the callus [21]). As it can be seen from Fig. 5, under both 1 mm and 3 mm gap sizes, the magnitude of mechanical stimuli (i.e. octahedral shear strain and fluid flow) across the callus decrease with increase in angle of obliquity. The decrease in mechanical stimuli predicted by the model is due to the reduction in axial IFM in oblique fractures in comparison with transverse fracture as observed in mechanical experiments. The implication of this simulation result is that, under the same loading conditions, the mechanical stimuli in the fracture site of an oblique fracture is relatively weaker in comparison with those of a transverse fracture, and therefore an increase in the flexibility of the fixation system becomes necessary. Furthermore, Fig. 5 shows that the mechanical stimuli in the callus are largely dependent on the fracture gap size; and the magnitude of both octahedral shear strain and interstitial fluid flow across the fracture site is strongly negatively correlated with the fracture gap size. This simulation outcome is consistent with the finding of Perren [42] which suggested that the fracture callus within a relatively smaller gap generally experiences relatively larger strain. Fig. 6 shows the model prediction of cell differentiation at the near cortex (NC) and far cortex (FC) of the early fracture callus under various fracture gap sizes, angles of obliquity and configurations of locking plate fixation. The prediction is based on the mechanoregulation theory proposed by Prendergast et al. [43] which simulates cell differentiation based on the mechanical γ stimuli index “S” (S = a + vb ; a = 0.0375, b = 3 μsm ); where γ is octahedral shear strain and v is interstitial fluid flow. Based on this mechanoregulation theory, cell differentiation pattern at a particular region of callus during the early stage of healing could be predicted as follows:

3. Results and discussion Figs. 3 and 4 show the comparison of the numerical predictions of the axial and shear IFMs with the mechanical experiments. It can be seen that the computational model can reasonably reproduce the experimental results very well. The two-factor ANOVA test of the experimental results indicated that both angle of obliquity and magnitude of applied loading influence axial IFM significantly (p < 0.001). In addition, there is a significant interaction between these two variables indicating that the level of applied loading affects the influence of angle of obliquity on axial IFM (p < 0.001). Further, significant difference in shear IFM was detected as a result of change in angle of obliquity and magnitude of applied loading (p < 0.001), while no significant interaction was detected between loading level and obliquity angle (p = 0.46). For each magnitude of applied loading, the axial and shear IFMs were cross-compared using t-test to detect differences resulting from different angles of obliquity. As illustrated in Fig. 3, for small angles of obliquity (i.e. θ varies from 0° to 15°), there is a little difference in axial IFM (p = 0.1 for applied load = 150 N), whereas a significant decrease in axial IFM is seen at the near cortex when θ reaches from 0° to 30°, and this decrease in axial IFM could be over 50% in comparison to transverse fracture (p < 0.0 0 03 for applied load = 150 N). Most importantly, for very large fracture obliquity (i.e. θ ≥ 45°), the positive axial IFM (in Fig. 3) indicates the callus tissue at the near cortex is under tension. The clinical studies and animal experiments have shown axial IFM that are too small at the near cortex of fractures stabilized by a locking plate can suppress callus formation, and so may result in delayed healing [35–38]. Therefore, a relatively small axial IFM at the near cortex as a result of a large angle of obliquity (i.e. θ ≥ 30º) could make the oblique fractures more susceptible to insufficient and inconsistent callus formation with resultant delayed healing. Most importantly, the tensile axial IFM at the near cortex resulting from a large angle of obliquity (e.g. θ ≥ 45°) could have negative effect on healing based on the histological study of Pauwels [39], who correlated the histological architecture of a pseudarthrosis tissue of an oblique fracture with the tissue distortion at the fracture site. He suggested that in the area of the fracture callus where tensile stress predominates (i.e. within the fracture gap), long cells of connective tissue are developed, therefore leading to bony non-union. These observations are supported by other similar studies suggesting that tensile IFM may have negative impact on bone healing [40,41]. Fig. 4 shows the result of shear IFM for fractures with different angles of obliquity. It can be seen that shear IFM increases with fracture obliquity significantly (p < 0.001). In comparison to transverse fracture (i.e. θ = 0°), a large fracture obliquity (e.g. θ = 45°) could lead to over a four-fold increase in shear IFM. In addition, for a constant θ , shear IFM increases with increase in loading. It has been proposed that delayed healing and non-union might occur in oblique fractures, when the shear IFM is over a certain threshold (i.e. 2 mm) [6]. Thus, the configuration of locking plate fixation and the allowable partial weight-bearing post-operation have to be carefully chosen and controlled in the treatment of oblique fractures to minimize the negative impact of shear IFM on the fracture angiogenesis and bone healing [9]. Please

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•

Osteoblast differentiation at a low level of mechanical stimuli (S ≤ 1).

The design concept of locking plate fixation is to enhance indirect healing through encouraging chondroblast differentiation and subsequently formation of cartilaginous callus in the early stage using flexible fixation techniques [14,36]. However, the high level of osteoblast differentiation (low level of mechanical stimuli) in the fracture gap during the early stage of healing could inhibit cartilaginous callus formation and delay the healing of fractures under locking plate fixations [37,38,44]. •

Chondroblast differentiation at a medium level of mechanical stimuli (1 < S ≤ 3).

As the early soft callus growth is driven by chondroblasts with cartilaginous tissues forming 2–3 weeks after fracture [45], a medium level of mechanical stimuli could enhance the healing process through increasing soft callus size and cartilaginous tissue content. •

of

Fibroblast differentiation at a high level of mechanical stimuli (S > 3).

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Fig 3. Comparison of numerical predictions of axial IFM at both near and far cortex with experimental results. (a) Applied axial load = 100 N; (b) applied axial load = 150 N; and (c) applied axial load = 200 N. The fracture was stabilized by a locking plate system with BPD = 2 mm and WL = 30 mm.

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Fig 4. Comparison of numerical predictions of shear IFM with experimental results. (a) Applied axial load = 100 N; (b) applied axial load = 150 N; and (c) applied axial load = 200 N. The fracture was stabilized by a locking plate system with BPD = 2 mm and WL = 30 mm.

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Fig 5. The effects on fracture gap size and angle of obliquity on the octahedral shear strain and interstitial fluid flow at near cortex (NC) and far cortex (FC) of the fracture plane. The fractured bone was stabilized by a locking plate fixation with BPD = 2 mm and WL = 30 mm and the applied axial load was 150 N.

It is suggested that certain amount of fibrous tissue formation through fibroblasts differentiation can stiffen the fracture site and result in healing in the next stages [37,38]. •

Interestingly, the simulation results suggest that there should be an optimal configuration of locking plate fixation for each angle of obliquity. For example, for a 3 mm gap size, chondroblast differentiation could happen at both near and far cortex when WL = 65 mm, BPD = 2 mm for θ = 0°; WL = 65 mm, BPD = 2 or 4 mm for θ = 15°; and WL = 65 mm, BPD = 4 mm for θ = 30°.

Excessive strain and interstitial fluid flow (S > 6).

The excessive strain and interstitial fluid flow (S > 6) can lead to very high level of fibrous tissue formation and potentially delayed healing or non-union [37]. Fig. 6 summarizes the dominant cell differentiation pattern during the early stage of healing at the near cortex (NC) and far cortex (FC) of the fracture gap under different combinations of gap sizes, angles of obliquity, BPD and WL of locking plate fixation. The model prediction shows that, for transverse fracture with a small gap size (i.e. 1 mm), the increase of the flexibility of locking plate fixation via increasing BPD and WL will have a negative effect on healing by inducing excessive strain and fluid flow. In addition, the computational simulation results suggest that for all the fractures with a large gap size (i.e. 3 mm) an increase in the flexibility of locking plate fixation is necessary. Otherwise, the mechanical stimuli at the fracture site would be too low to promote cartilaginous callus formation and indirect healing. The simulation results are consistent with the study of Perren [42] which showed that the cells within a relatively smaller gap generally experiences relatively larger strain than those within a large fracture gap. Clinical data suggest that a very small fracture gap (e.g. 10 μm) experiences very large strain even under a rigid fixation and consequently delayed healing (i.e. longer than 20 weeks) or non-union [46]. Consistent with clinical studies [46,47], the model results suggest that an improved callus formation and bone healing is achievable by wide bridging of the fracture using a relatively flexible fixation. Please

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3.1. Limitations It should be mentioned that, to simplify the complexity of the mechanical experiments and computational model, muscle loadings were not included; and only the effect of knee joint loading, as the largest load applied on the bone during the postoperative partial weight bearing [29], was considered as an axial load. In addition, the load was applied on tibia intercondylar eminence in the mechanical experiments and computational model while in-vivo bodyweight loading is primarily applied on tibia through its condylar surfaces. Since the intercondylar eminence is located in the middle of the two condylar surfaces, the experimental loading is expected to generate a similar resultant load as the in-vivo loading condition. Further the fibula was not included in the experiments and computational model. Moreover, the computational model result should be further validated against animal experiments and clinical investigations data before it can be implemented for development of surgical treatment strategies. 4. Conclusion In this paper, we investigated the influence of fracture geometry, especially the angle of obliquity and fracture gap size, on of

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Fig 6. The average mechanical stimuli index (S) and dominant cell differentiation pattern during the early stage of healing at the near cortex (NC) and far cortex (FC) of the fracture site under different combinations of gap sizes, angles of obliquity, BPD and WL of locking plate fixation.

the early stage of bone healing through mechanical testing in conjunction with computational modelling. The main findings of this study can be summarized as follows: •

•

•

•

flow. In contrast, for a large oblique fracture gap size (i.e. gap size = 3 mm, θ ≥ 30°), increasing the flexibility of locking plate fixation could enhance cartilaginous callus formation and improve fracture healing. Furthermore, there should be an optimal configuration of locking plate fixation for each angle of obliquity.

A large angle of obliquity (i.e. θ ≥ 30º) can significantly decrease the magnitude of axial IFM at the near cortex. In addition, for a very large fracture obliquity (i.e. θ ≥ 45°), the callus tissue at the near cortex could be under tension. There is a strongly positive correlation between the shear IFM and angle of obliquity. A very large angle of obliquity (i.e. θ ≥ 45º) could lead to more than four-fold increase of shear IFM in comparison to that of a transverse fracture (i.e. θ = 0°). The magnitude of mechanical stimuli at the fracture site (i.e. octahedral shear strain and interstitial fluid flow) decreases with the increase of angle of obliquity. In addition, the mechanical stimuli are strongly negatively correlated with the fracture gap size. Under a small transverse fracture gap size (i.e. gap size = 1 mm), an increase of the flexibility of locking plate fixation could lead to excessive strain and interstitial fluid

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If confirmed by animal and human studies, this research may lead to useful guidelines that could potentially assist orthopaedic surgeons in application of locking plate fixation in clinical practice. Conflict of interest No conflict of interest to declare. Acknowledgments The authors would like to thank Johnson & Johnson Medical, AOTRAUMA Asia Pacific (AOTAP14-02), Victorian Orthopaedic of

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Research Trust (2015–2016), Epworth HealthCare and the University of Melbourne for their support.

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