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Relationship between bone adaptation and in-vivo mechanical stimulus in biological reconstructions after bone tumor: A biomechanical modeling analysis
Accepted Manuscript Relationship between bone adaptation and in-vivo mechanical stimulus in biological reconstructions after bone tumor: A biomechanical modeling analysis
Giordano Valente, Lorenzo Pitto, Enrico Schileo, Sabina Piroddi, Alberto Leardini, Marco Manfrini, Fulvia Taddei PII: DOI: Reference:
S0268-0033(17)30028-1 doi: 10.1016/j.clinbiomech.2017.01.017 JCLB 4278
To appear in:
Clinical Biomechanics
Received date: Accepted date:
7 July 2016 19 January 2017
Please cite this article as: Giordano Valente, Lorenzo Pitto, Enrico Schileo, Sabina Piroddi, Alberto Leardini, Marco Manfrini, Fulvia Taddei , Relationship between bone adaptation and in-vivo mechanical stimulus in biological reconstructions after bone tumor: A biomechanical modeling analysis. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Jclb(2017), doi: 10.1016/ j.clinbiomech.2017.01.017
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ACCEPTED MANUSCRIPT
Relationship between bone adaptation and in-vivo mechanical stimulus
in
biological
reconstructions
after
bone
tumor:
a
biomechanical modeling analysis
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Giordano Valente1*, Lorenzo Pitto1, Enrico Schileo2, Sabina Piroddi1, Alberto Leardini3,
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Marco Manfrini4, Fulvia Taddei1
1. Medical Technology Laboratory, Rizzoli Orthopaedic Institute, Bologna, Italy
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2. Computational Bioengineering Laboratory, Rizzoli Orthopaedic Institute, Bologna, Italy
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3. Movement Analysis Laboratory, Rizzoli Orthopaedic Institute, Bologna, Italy
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4. Orthopedic and Traumatologic Clinic for Musculoskeletal Tumors, Rizzoli
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Orthopaedic Institute, Bologna, Italy
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*CORRESPONDING AUTHOR:
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e-mail: [email protected]
Word Count: Abstract 249, Manuscript 4408
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ACCEPTED MANUSCRIPT ABSTRACT
Background:
Biomechanical
interpretations
of
bone
adaptation
in
biological
reconstructions following bone tumors would be crucial for orthopedic oncologists, particularly if based on quantitative observations. This would help plan for surgical
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treatments, rehabilitative programs and communication with the patients. We aimed to
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analyze the biomechanical adaptation of a femoral reconstruction after Ewing sarcoma according to an increasingly-used surgical technique, and to relate in-progress bone
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resorption to the mechanical stimulus induced by different motor activities.
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Methods: We created a multiscale musculoskeletal and finite element model from CT scans and motion analysis data at a 76-month follow-up of a patient, to analyze muscle
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and joint loads, and to compare the mechanical competence of the reconstructed bone
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with the contralateral limb, in the current real condition and in a possible revision surgery
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that removed proximal screws.
Findings: Our results showed strategies of muscle coordination that led to differences in
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joint loads between limbs more marked in more demanding motor activities, and
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generally larger in the contralateral limb. The operated femur presented a markedly low ratio of physiological strain due to load-sharing with the metal implant, particularly in the lateral aspect. The possible revision surgery would help restore a physiological strain configuration, while the safety of the reconstruction would not be threatened. Interpretation: We suggest that bone resorption is related to load-sharing and to the internal forces exerted during movement, and the mechanical stimulus should be
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ACCEPTED MANUSCRIPT improved by adopting modifications in the surgical treatment and by promoting physical therapy aimed at specific muscle strengthening. KEYWORDS
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biological reconstruction; bone tumor; bone mechanical stimulus; subject-specific
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musculoskeletal modeling; subject-specific finite element modeling
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ACCEPTED MANUSCRIPT
INTRODUCTION
Limb-salvage surgery represents a special operative procedure in orthopedic oncology and has become the accepted standard of treatment for bone tumors of the extremities
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(Aksnes et al., 2008; Kolk et al., 2014). Among limb-salvage surgery options, biological
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reconstruction of long bones after tumor resection through the combination of massive
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bone allograft (MBA) and vascularized fibula autograft (VFA), originally known as Capanna technique (Capanna et al., 2007, 1993), has been increasingly used in several
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orthopedic units around the world since the early 1990s. In this technique, after
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resection of the bone tumor, the VFA is harvested from the contralateral limb and combined with the MBA in a concentric or parallel assembly (Capanna et al., 2007). This
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biological reconstruction combines important advantages implied in the two grafts: the
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mechanical strength of the MBA and the osteogenic potential of the VFA. This facilitates bone healing and union by activation of a remodeling process following hypertrophy of
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the VFA as a reaction to mechanical loading, and helps reduce fracture and infection
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thanks to the MBA support and the vascular nature of the VFA.
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Several studies analyzed the long-term evolution of biological reconstructions from an oncological perspective (Abed, Y.Y. et al., 2009; Bakri et al., 2008; Capanna et al., 2007; Houdek et al., 2015; Innocenti et al., 2009; Jager et al., 2010; Li et al., 2010; Rabitsch et al., 2013), reporting of stable and durable reconstructions, satisfactory results in terms of limb-salvage rates, tumor control, function and manageable complications with acceptable rates. However, complications still include nonunion, fracture and infection, which can be related to the biomechanical behavior of the
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ACCEPTED MANUSCRIPT reconstruction, including response to loading conditions. In this context, only two studies analyzed the long-term biomechanical response to loading (Ceruso et al., 2008; Manfrini et al., 2004), providing only a qualitative description of different remodeling patterns. Therefore, there are no quantitative long-term analyses of mechanical loading in such
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reconstructions, which would instead be crucial, as bone adaptation can evolve towards
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conditions that concern bone resorption and threaten the safety of the bone assembly (Ceruso et al., 2008), and adverse events can still occur as a consequence of
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mechanical loading during the adaptation process. Objective functional results in the long term would be then crucial, to provide feedbacks to clinicians about surgical and
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rehabilitative outcomes, and patient counseling about potential recovery (Ottaviani et al.,
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2009). Currently, computational modeling of the musculoskeletal system is the only viable method to predict internal loads (Erdemir et al., 2007; Pandy and Andriacchi,
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2010) and bone mechanical competence (Keyak et al., 2013; Orwoll et al., 2009) in vivo.
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Subject-specific musculoskeletal modeling and simulation of movement were used to investigate femoral loads during gait in a patient who underwent a biological
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reconstruction following osteosarcoma (Taddei et al., 2012), and subject-specific finite
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element (FE) modeling of a reconstructed femur following Ewing sarcoma was used to evaluate the risk of fracture of the reconstruction (Taddei et al., 2003). Coupling subjectspecific musculoskeletal and FE models, i.e. multiscale body-organ modeling, would be a powerful computational tool for clinical applications. However, although state-of-the-art methods would allow comprehensive multiscale analyses, a few studies exploited such tools for clinically-driven questions (Martelli et al., 2014b; Vahdati et al., 2014; van der Ploeg et al., 2012), and none was applied to orthopedic oncology yet.
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ACCEPTED MANUSCRIPT The overall aim of this study is to analyze the long-term biomechanical adaptation of a biologically-reconstructed femur following Ewing sarcoma, and to relate the partly adverse bone adaptation to the mechanical stimulus induced by different motor activities. More specifically, we aim to: (i) analyze the internal loads, i.e. muscle and joint
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contact forces, during common motor activities, (ii) evaluate the safety of the
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reconstruction and (iii) compare the mechanical competence of the reconstructed bone
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with the contralateral limb, in the current real condition and in a possible new scenario of minimally-invasive revision surgery that removed the three most proximal screws. We
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hypothesized that this revision surgery could restore a physiological mechanical
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stimulus without threatening the safety of the bone assembly.
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Surgical technique and follow-up
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METHODS
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An 8-year-old male patient received a combination of MBA and VFA for the reconstruction of the intercalary skeletal gap after resection for Ewing sarcoma at the
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right proximal femur (Fig. 1). The affected bone was replaced by a deep-frozen MBA
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and a VFA harvested from the contralateral limb. The MBA was prepared to receive the VFA on its endosteal surface. First, a double osteotomy was performed on the proximal femur: one at the level of the lesser trochanter and another at 13.5 cm distally. Tumor excision was completed by isolating and protecting the deep femoral vascular pedicle. Second, a 15 cm part of the intercalary fibula and the peroneal vascular pedicle were extracted from the contralateral limb. The MBA, previously defrosted and modeled with a distal Z-shape osteotomy, was then prepared with a hole in the antero-superior part to
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ACCEPTED MANUSCRIPT allow passage of the peroneal pedicle. Finally, the fibula was inserted into the graft and the whole system was slotted into both ends of the autologous bone and secured by using a 14-hole titanium alloy plate and nine screws with a diameter of 4.5 mm and different lengths. Two screws were placed in the femoral neck, one in correspondence
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of the graft hole, the other six in the distal femur.
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The implanted VFA in combination with mechanical loading led to a successful longterm reconstruction: no complications or reoperations, nor tumor recurrence during
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follow-up. In addition, osteo-fusion with the autologous bone was observed with an intense remodeling involving both MBA and VFA, which also led to the formation of
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cortical fronts between them. However, there were valgism of the femoral neck,
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decrease in bone density in the femoral head and neck, decrease in MBA cortical thickness, enlargement of the peroneal medullary canal in conjunction with decrease in
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peroneal bone density, formation of cortical rings between MBA and VFA (Taddei et al.,
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Experimental data
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2015) (Fig. 1).
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Lower-body CT scans and motion analysis data of five motor activities were acquired after 76 months of follow-up, when the patient was 15 years old, 48.5 kg and 170 cm (Fig. 1). Before CT scanning, the patient was instrumented with 22 reflective markers on pelvis and lower limbs according to an established protocol (Leardini et al., 2007), which were also visible on the CT images. The patient performed ten walking trials, three stair ascent, stair descent and chair rise/sit trials each, and four squat trials. An additional static posture was acquired in standing position. Stair ascent and descent were
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ACCEPTED MANUSCRIPT performed by using a four-step modular staircase, allowing measurement of also ground reaction forces on the second and third steps. Chair rise/sit was performed by using a swivel stool, with the feet separately over the two force platforms, as well as during squatting. Marker trajectories and ground reaction forces were collected using an 8-
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camera motion capture system (Vicon 612 Motion System, Oxford, UK) and two force
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platforms (Kistler, Winterthur, Switzerland), respectively. The local ethical committee
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approved all procedures, and the parents of the patient provided written informed
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consent for participation.
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Musculoskeletal model
A subject-specific musculoskeletal model of the lower limbs was created from CT by
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using a previously developed workflow (Valente et al., 2014) (Fig. 2). The model
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included nine rigid bodies (pelvis, thighs, shanks, tali, feet), articulated by 12 degrees of freedom (DOF) and actuated by 85 musculotendon units. Body volumes and inertial
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properties were derived from the CT images. Each hip was modeled as a 3-DOF ball-
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and-socket joint, each knee as a 1-DOF hinge joint, and each ankle as a 2-DOF universal joint including two non-intersecting hinges at the tibiotalar and subtalar joints
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(Valente et al., 2015). Body and joint coordinate systems were defined according to the recommendations of the International Society of Biomechanics (Wu et al., 2002). The number and paths of the musculotendon actuators were defined according to a generic model (Delp et al., 1990). Additional wrapping surfaces were included to represent the ankle capsule to prevent soleus, medial and lateral gastrocnemius from penetrating the tibia during dorsiflexion. According to the reconstruction surgery, the right vastus intermedius was not included in the model, and the origin of the right vastus lateralis 8
ACCEPTED MANUSCRIPT was moved distally. The maximum isometric force (Fmax) of each musculotendon unit (i) was calculated as follows (Valente et al., 2014):
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i
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Fmax i
Vol Vol ( PCSA)i l ( gen ) lMT l0 i ( gen ) 0 lMT
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where PCSA is the muscle physiological cross-sectional area, Vol is the muscle volume
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calculated from CT, l0 and lMT are the optimal fiber length (unknown) and the musculotendon length (calculated from CT) for the subject-specific model, respectively,
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( gen ) are the corresponding quantities for a generic model (Delp et al., 1990), l0( gen ) and lMT
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and σ is the maximum muscle tension set to 61 N/cm 2 according to Arnold et al (Arnold et al., 2010). The subject-specific musculoskeletal model was created in the OpenSim
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file format (Delp et al., 2007) using NMSBuilder (Valente et al., 2014). All motor activities
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were simulated using this musculoskeletal model and the motion analysis data to calculate joint angles, joint moments, muscle forces and activations, and joint contact
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forces, leveraging OpenSim. Joint angles describing the motion were calculated from
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the experimental marker trajectories through Inverse Kinematics, minimizing errors between the experimental marker positions and the corresponding markers on the model. Joint moments were calculated from the joint angles and the ground reaction forces through Inverse Dynamics. Muscle forces were calculated by decomposing the joint moments among musculotendon units through Static Optimization, minimizing the sum of muscle activations squared and neglecting the force-length-velocity relationships
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ACCEPTED MANUSCRIPT of muscle (Anderson and Pandy, 2001). Joint contact forces were calculated from the instantaneous force equilibrium through Joint Reaction Analysis. Finite Element model
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FE models of both femurs were generated from CT by using a previously validated
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procedure (Schileo et al., 2014) (Fig. 2). Bone, plate and screws volumes obtained from
advancing
front
algorithm
(Hypermesh
v.10,
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image segmentation were meshed with 10-node tetrahedral elements using an Altair
Engineering
Inc.,
USA).
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Inhomogeneous isotropic material properties were mapped from CT onto the mesh
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elements using the Bonemat algorithm (Taddei et al., 2007), which allows conversion of Hounsfield Units (HU) values of CT data into elastic modulus values for each mesh
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element (Schileo et al., 2008). Poisson’s ratio of 0.3 was assumed for all materials.
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Metal artifacts on CT images due to titanium alloy plate and screws were reduced before performing material mapping, by assigning a 1600 HU threshold to all values greater
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than 1600 HU, i.e. the maximum value detected in the cortical bone of the contralateral
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femur. The sets of loading for each motor activity applied to the femurs were selected from the trials presenting the highest peak in hip contact force. These sets of forces
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allowed representation of the maximum physiological loading conditions in the different motor activities. Muscle forces were applied on either origin/insertion or intermediate via points of the muscle paths, to account for the correct directions of the muscle forces. In the origin/insertion points, the forces were applied to the mesh node closest to the muscle attachment point. In the intermediate via points (i.e. gluteus maximus anterior, middle and posterior, iliacus, vastus lateralis, intermedius and medialis, gastrocnemius lateralis and medialis), the forces were applied to rigid beam elements (i.e. MPC184 10
ACCEPTED MANUSCRIPT element type in Ansys) that connected the origin/insertion on the femur to the consecutive intermediate via point. Force directions were defined as the vector connecting the application point belonging to the femur to the consecutive point in the muscle path belonging to the other body segment (i.e. pelvis or shank). The hip contact
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forces were applied on the center of the femoral head. The femurs were physiologically
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constrained by applying displacement constraints at three nodes on the femur to prevent
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rigid body motion (Speirs et al., 2007): a node placed on the intercondylar fossa was fully constrained, a node on the center of the femoral head was constrained in the
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antero-posterior and medio-lateral directions, and a third node on the lateral epicondyle
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was constrained in the antero-posterior direction. FE linear-elastic simulations were
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performed using Ansys (v. 14, Ansys Inc., USA).
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Biomechanical analyses
To analyze the internal loads during the different motor activities, joint contact forces
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and the most influential muscle forces (i.e. gluteus medius, iliacus, psoas, medial and
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lateral hamstrings, rectus femoris, vasti, gastrocnemius and soleus) were first expressed in percentage of motor activity cycle and normalized to the subject body-weight (BW).
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Then mean and maximum differences in joint contact forces between the operated and the contralateral limb over the activity cycles were calculated, and Wilcoxon signed rank tests (p < 0.01) were performed to evaluate significant differences. In addition, Pearson correlation coefficients (R) were calculated to quantify similarities in force patterns between limbs.
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ACCEPTED MANUSCRIPT The safety of the reconstruction and the bone mechanical competence in both femurs were evaluated in the loading configurations corresponding to the maximum peak of hip contact force among all trials for each motor activity. To evaluate the safety of the reconstruction, von Mises stress in the plate and screws and the principal tensile and
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compressive strain in the bone, excluding the region distal to the reconstruction (Fig. 2),
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were calculated, in the current configuration and in the configuration that simulated
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removal the three most proximal screws. Element-wise stresses and strains, calculated at the element centroid including the stress and strain distribution in the neighboring
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elements (ETABLE in Ansys), were considered in the analysis. The safety factor was
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determined as σlim/σmax for the plate and screws and εlim/εmax for the bone, where σlim is the fatigue limit of 240 MPa for titanium alloy in the most conservative condition
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(accounting for a stress concentration factor of 3.3)a, σmax is the maximum stress
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recorded in the femur, εlim is the limit strain of 1.04% compressive and 0.73% tensile (Bayraktar et al., 2004), εmax is the maximum strain recorded in the femur. To avoid
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boundary condition artifacts, the finite elements lying inside 10 mm spheres centered in
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the points of application of muscle forces and hip contact force were excluded from the calculations. To avoid metal artifacts, elements in contact with the metal components
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were also excluded.
To compare the bone mechanical competence between limbs, the principal tensile and compressive strain distributions were evaluated in five transverse sections of the proximal reconstruction (Fig. 2). The analysis of results was then focused on the
a
http://www.matweb.com/
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ACCEPTED MANUSCRIPT representative section at half implant, where higher stress and strain due to bending were expected, and on the corresponding section in the contralateral limb. Mean and maximum values of principal strains for all motor activities were calculated in the lateral and medial portions of the sections, to identify the clearest trends observable in a
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complex structural configuration including MBA and VFA. For the operated limb, the
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calculations were also performed after simulation of the screws-removal configuration. RESULTS
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Internal loads during motor activities
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Overall, there were differences in lower-limb joint contact forces between the operated
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and contralateral limb in all motor activities (Fig. 3, Table 1). The differences were less marked during walking, and were more marked during more demanding activities,
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particularly during double-support ones (i.e. chair rise/sit and squat). The loads were
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generally larger in the contralateral limb, with a peak difference of 3.4 BW at the knee during squat (Fig. 3, Table 1). This was mostly induced by a muscle compensation
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strategy from the vasti, gastrocnemius and hamstrings of the contralateral limb (Fig. 4).
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However, the hip loads were slightly larger in the operated limb during gait activities (i.e. walking, stair ascent and stair descent), as a result of different strategies of muscle coordination (Fig. 3, Table 1, Fig. S-1). Particularly, during stair descent, the gluteus medius, psoas and hamstrings exerted larger forces in the operated limb during stance, as well as gastrocnemius during early stance (Fig. 4), which led to also have a higher first peak in knee contact force in the operated limb. Although marked differences in joint
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ACCEPTED MANUSCRIPT contact forces occurred, there were similarities in force patterns confirmed by the high correlation values (R) in almost all cases (Table 1). Safety of the reconstruction
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The reconstruction was mechanically safe, as safety factors in both the metal implant
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and bone were never below unity (Table 2). Overall, the most demanding activities were
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stair descent and walking. In the current configuration, the minimum bone safety factor (1.67) was found in the reconstruction, close to the MBA hole. However, most of the
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bone volume showed significantly larger safety factors, with levels of 3-5 at the proximal
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femur (Fig. 5). In the screws-removal configuration, safety was not threatened (Table 2). However, consistently with the increased load-sharing in the bone, there was a general
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decrease in the safety factor (Fig. 5), especially during stair descent, although the
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minimum values (1.61) did not change markedly.
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Comparison of bone mechanical competence between limbs
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The different motor activities resulted in different distributions of tensile and compressive strains in the selected femur sections (Figs. 6 and S-2). In the contralateral limb,
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assumed as physiological reference condition, the lateral aspect was mainly subjected to tensile strain in all motor activities, while the medial aspect to compressive strain (Fig. 6). In the operated limb in the current configuration, the lateral aspect was markedly shielded from tensile strain, to the extent that compressive strain was larger in all motor activities (Fig. 6). The tensile strain in the lateral aspect was always less than half of the corresponding values in the contralateral limb (Table 3). Conversely, the medial aspect was less shielded from compressive strain during gait activities (Fig. 6), where the ratio 14
ACCEPTED MANUSCRIPT of the compressive strain in the operated limb could even exceed 100% during stair descent (Table 3). However, the ratios were lower during double-support activities, where markedly lower loads were applied compared to the contralateral limb (see internal loads during motor activities). In the screws-removal configuration, all values of
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tensile and compressive strains increased compared to the current configuration (Fig.
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6). In gait activities, a contralateral-like strain configuration could be restored, as the
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tensile strain in the lateral aspect and the compressive strain in the medial aspect were close to the corresponding strains in the contralateral limb (Table 3). Particularly, in stair
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descent, the tensile strain markedly increased in the lateral side, whose mean value
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passed from 48% to 131%. Conversely, in double-support activities where markedly lower loads were applied, a contralateral-like strain configuration could not be restored
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(Fig. 6, Table 3).
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DISCUSSION
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Biomechanical interpretations of bone adaptation in biological reconstructions following
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bone tumors would be crucial for clinicians, particularly if based on quantitative data, to plan for surgical treatments and rehabilitative programs, as well as for communication
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with the patients. The aim of this study was to analyze, by using a multiscale musculoskeletal and finite element model, the biomechanical adaptation of a femoral reconstruction after bone tumor resection, and to relate the bone adaptation observed to the mechanical stimulus induced by different motor activities. Our results indicate that the long-term adaptation resulted in strategies of muscle coordination that generally led to larger joint contact forces in the contralateral limb, particularly at the knee. We raise a concern for the future safety of the reconstructed bone assembly, as the combination of 15
ACCEPTED MANUSCRIPT lower internal loads and the presence of a stiff metal plate makes the bone share loadbearing with the metal implant to the extent that the ratio of physiological strain with respect to the intact contralateral bone is markedly low. This evidence possibly explains the bone adaptation during the follow-up analyzed, which shows a decrease in allograft
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cortical thickness, enlargement of the peroneal medullary canal and decrease in
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peroneal bone density. In the perspective of bone adaptation, the removal of the three
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most proximal screws would still preserve the safety of the reconstruction and would help restore a physiological configuration thanks to the increased mechanical stimulus in
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the bone.
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Comparing the differences in joint contact forces between the operated and contralateral
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limb, we found larger contralateral loading that was increasingly evident with more demanding motor activities (Figs. 3 and 4, Table 1). Hip contact forces in the three gait
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activities were instead larger in the operated limb, particularly during stair descent.
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During this activity, the patient seemed to have less control on the operated limb at heelstrike and in the single-support phase, in accordance also with larger knee loads in the
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first peak (Figs. 3 and 4, Table 1). When we applied these internal forces to the organ-
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level models of the femurs, we found a clearly polarized situation. In the representative section at mid-diaphysis, while the compressive strain in the medial aspect was not markedly different from that in the contralateral bone, the mean tensile strain in the lateral aspect (where the screws were implanted) was only the 17% of the corresponding contralateral value during walking, and even during stair descent where the applied forces were indeed larger, did not exceed 48% (Fig. 6, Table 3). This mechanical effect known as strain shielding, which typically occurs when stiff and more
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ACCEPTED MANUSCRIPT flexible materials are combined, led to strain levels below the percentage of physiological strain deemed necessary for bone formation (Martelli et al., 2014a). The strain shielding in the lateral aspect was mildened in the simulated screws-removal configuration during gait activities, even peaking 131% during stair descent (Fig. 6,
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Table 3). However, during double-support activities, the mean tensile strain was up to
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62%, which can be explained by markedly lower forces exerted on the operated femur.
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In this described scenario, which is likely to re-establish a mechanical environment compatible with bone homeostasis (Martelli et al., 2014a), the safety of the
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reconstruction was not threatened, showing small changes with respect to the current
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configuration (Table 2, Fig. 5).
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This is the first study that predicted muscle and joint forces and stress and strain conditions during different motor activities of a long-term biological reconstruction
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through subject-specific multiscale modeling of the musculoskeletal system. Therefore,
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a direct comparison with previous studies was not possible. Muscle and joint forces during walking in a biological reconstruction following osteosarcoma were investigated
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previously (Taddei et al., 2012), showing peak joint forces comparable with the present
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findings but different strategies of muscle coordination due to the specificity of the case regarding surgical details, follow-up and motor function. Our findings of bone strains in the contralateral limb in all activities and in the screws-removal configuration of the operated limb in gait activities are consistent with previous computational (Duda et al., 1998; Martelli et al., 2014b) and experimental (Aamodt et al., 1997) studies showing the lateral aspect of the diaphysial femur subjected to tensile strain and the medial aspect to compressive strains in daily activities, and are also in a comparable range of strain level.
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ACCEPTED MANUSCRIPT This agreement further confirms the hypothesis that the bone adaptation during followup was related to the effect of proximal screws and muscle loading, although we need to consider two aspects. First, the cited studies include subjects that are not age-matched with our case. However, reference data for bone strains in healthy children are lacking
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because of ethical reasons. Second, the contralateral limb in our case may not be
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equivalent to a healthy control, as a 15 cm part of the fibula was harvested from that
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limb. However, regarding bone structure, this generates a high adaptive effort in the tibia to replace the mechanical function of the fibula (Taddei et al., 2009), suggesting that the
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femoral structure is preserved. Regarding motor function, a recent gait study in adults
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warns about an average long-term gait morbidity after fibula harvesting (Feuvrier et al., 2016), but this seemed not the case in the subject studied, possibly thanks to his young
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age and the extensive rehabilitation performed.
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The analysis of the fate of such femoral reconstructions was limited to a single, although
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exemplary, case. As similar bone adaptive mechanisms were shown (Ceruso et al., 2008; Manfrini et al., 2004), and still occur, applying the computational modeling
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workflow to other cases would provide general conclusions about potential revision
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surgery, suggestions about different solutions in plate and screws to be used, and support in the development of physical therapy protocols. Although musculoskeletal and FE models involve unavoidable simplifications and assumptions, we included the strengths of the subject-specific nature of the musculoskeletal modeling, whose robustness has been recently tested with good results (Valente et al., 2014), and the extensive experimental and clinical validation performed on the FE models of bone strength (Falcinelli et al., 2014; Schileo et al., 2014). In addition, the adoption of elastic
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ACCEPTED MANUSCRIPT limits for bone tissue that were derived from bone samples of adults or elderly may be challenged. This choice was however corroborated by the few data available on children, showing substantial invariance of bone elastic limit strain (Currey, 2004; Öhman et al., 2011).
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Our findings demonstrated a close interaction between the predicted internal loads
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during motor activities and the bone mechanical competence when providing a biomechanical interpretation of the long-term adaptation of biological reconstructions.
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We confirm such a surgical approach as a valuable solution for limb-salvage surgery, as we observed that the vascularized autograft contributes to bone union when there is
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mechanical stimulus. However, there is a caveat concerning the long-term evolution, as
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stiff metal implants can have a negative influence on the bone mechanical stimulus. We can also speculate that the parallel bone assembly could be a valuable alternative to the
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concentric assembly in femoral reconstructions, to improve mechanical stimulus that
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would avoid autograft resorption by promoting its enlargement instead. A favorable sideconsequence would be to avoid holes in the allograft, which hosted the minimum safety
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factor in our analysis. To evaluate the efficacy of the present computational modeling
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workflow as a clinical decision-making tool, research trials should be performed that apply the proposed analysis at different timepoints of the follow-up to a population of biological reconstructions. This would eventually allow to establish which diagnostic tools and biomechanical indicators are relevant in the clinical practice. In summary, our study provided a biomechanical interpretation of the bone adaptation of a femoral reconstruction after bone tumor using a vascularized fibula autograft inlaid in a massive bone allograft. The novelty of our study resided in the multiscale approach in 19
ACCEPTED MANUSCRIPT subject-specific computational modeling applied to orthopedic oncology. Our results demonstrated a relationship between bone adaptation and in-vivo mechanical stimulus, suggesting that bone resorption is related to load-sharing with the metal implant and to the internal forces exerted during movement. In the long-term evolution of these bone
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reconstructions, the mechanical stimulus should be promoted to avoid possible safety
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threatening of the bone assembly, by planning for additional surgical treatment, new
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designs of metal implants and physical therapy aimed at specific muscle strengthening.
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ACKNOWLEDGEMENTS
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This study was supported by the project “Biological bone reconstruction in children skeleton after sarcoma resection. Validation of the technique through CT scan analysis
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and histological evaluation of the retrieved cases” (RF-2010-2321501), funded by the
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CONFLICT OF INTEREST
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Italian Ministry of Health.
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The authors do not have any financial or personal relationships with other people or
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organization that could inappropriately influence their work. REFERENCES
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ACCEPTED MANUSCRIPT Rabitsch, K., Maurer-Ertl, W., Pirker-Frühauf, U., Wibmer, C., Leithner, A., 2013. Intercalary Reconstructions with Vascularised Fibula and Allograft after Tumour Resection in the Lower Limb. Sarcoma 2013, 1–8. Schileo, E., Balistreri, L., Grassi, L., Cristofolini, L., Taddei, F., 2014. To what extent can
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Bioscientifica, Salzburg, Austria, p. P158.
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Taddei, F., Viceconti, M., Manfrini, M., Toni, A., 2003. Mechanical strength of a femoral reconstruction in paediatric oncology: a finite element study. Proc. Inst. Mech.
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Eng. [H] 217, 111–119.
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Vahdati, A., Walscharts, S., Jonkers, I., Garcia-Aznar, J.M., Vander Sloten, J., van Lenthe, G.H., 2014. Role of subject-specific musculoskeletal loading on the
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Biomed. Mater. 30, 244–252.
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prediction of bone density distribution in the proximal femur. J. Mech. Behav.
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Valente, G., Pitto, L., Stagni, R., Taddei, F., 2015. Effect of lower-limb joint models on subject-specific musculoskeletal models and simulations of daily motor activities.
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J. Biomech. 48, 4198–4205.
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Valente, G., Pitto, L., Testi, D., Seth, A., Delp, S.L., Stagni, R., Viceconti, M., Taddei, F., 2014. Are Subject-Specific Musculoskeletal Models Robust to the Uncertainties in Parameter Identification? PLoS ONE 9, e112625. van der Ploeg, B., Tarala, M., Homminga, J., Janssen, D., Buma, P., Verdonschot, N., 2012. Toward a more realistic prediction of peri-prosthetic micromotions. J. Orthop. Res. 30, 1147–1154.
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ACCEPTED MANUSCRIPT Wu, G., Siegler, S., Allard, P., Kirtley, C., Leardini, A., Rosenbaum, D., Whittle, M., D’Lima, D.D., Cristofolini, L., Witte, H., Schmid, O., Stokes, I., 2002. ISB recommendation on definitions of joint coordinate system of various joints for the reporting of human joint motion--part I: ankle, hip, and spine. International Society
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of Biomechanics. J Biomech 35, 543–548.
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FIGURE LEGENDS
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Figure 1. Details of the surgical technique and the experimental data used in this study.
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Left panel: particulars of the biological reconstruction from the CT after surgery, including the section at half implant. Right panel: lower-body CT and motion analysis
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data after 76 months of follow-up used to create the multiscale body-organ models.
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adaptation.
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Bottom panel: 8 CT follow-up of the representative section at half implant showing bone
Figure 2. Workflow for the present subject-specific body-organ modeling and simulation. Left panel: creation of the body-level musculoskeletal model from CT using NMSBuilder(Valente et al., 2014), and simulations of the five motor activities using OpenSim(Delp et al., 2007) to calculate the internal loads (muscle forces and joint contact forces). Right panel: creation of the organ-level finite element models of both femurs, application of the loads from the musculoskeletal model and the physiological
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ACCEPTED MANUSCRIPT constraints(Speirs et al., 2007); linear-elastic simulation using Ansys to evaluate the safety of the reconstruction (excluding the region distal to the reconstruction) and compare the femurs in the current and screws-removal configurations in five transverse sections of the proximal reconstruction (with particular focus on the representative
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section at half implant).
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Figure 3. Joint contact forces in the operated and contralateral limbs during the different motor activities, expressed in body-weight (BW) as mean and standard deviation among
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the trials.
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Figure 4. The most influential muscle forces in the operated and contralateral limbs during stair descent (left panel) and squat (right panel), expressed in body-weight (BW)
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as mean and standard deviation among the trials. Muscle forces during the other motor
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activities are available in the Supplementary Figure S-1.
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Figure 5. Safety factor distribution in the operated femur during walking (top panel) and stair descent (bottom panel), in the current configuration (left panel) and in the screws-
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removal configuration (right panel).
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Figure 6. Comparison of the bone mechanical competence of the selected section between the operated and contralateral limbs at the peak hip contact forces of the different motor activities, in the current real configuration and in the simulated configuration of possible removal of the three most proximal screws. Tensile (ε1) and compressive (ε3) strain distributions are presented, with the corresponding mean and maximum values in the lateral and medial aspect of the section. Principal strain
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panel), expressed in body-weight (BW) as mean and standard deviation among the
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trials.
Figure S-2. Tensile (ε1) and compressive (ε3) strain distributions in the additional
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selected sections of the operated limb at the peak hip contact forces of the different
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motor activities, in the current real configuration and in the simulated configuration of
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possible removal of the three most proximal screws.
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ACCEPTED MANUSCRIPT Table 1. Differences in joint contact forces between the operated and contralateral limb during the different motor activities. Mean and maximum differences over the motor activity cycle are reported in body-weight (BW). Significant differences (Wilcoxon signed rank tests, p < 0.01) are
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highlighted in bold. Pearson correlation coefficients (R) are also reported.
-0.29
-0.23
Mean Diff (BW)
1.07
-2.28
-0.67
Max Diff (BW)
0.77
0.92
0.83
0.95
R
-0.83
-0.24
-0.70
-1.65
Mean Diff (BW)
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0.85
1.60
0.89
0.55
-2.13
-1.61
-2.93
-3.40
Max Diff (BW)
0.96
0.81
0.65
0.69
0.84
R
-0.17
-0.50
-0.69
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Mean Diff (BW)
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Max Diff (BW)
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Ankle Contact Forces
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Squat
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Stair Ascent Stair Descent Chair Rise/Sit
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Joint Contact Forces: Operated vs Contralateral Limb
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ACCEPTED MANUSCRIPT Table 2. Safety factors of the metal implant (σlim/σmax, where σlim is the fatigue limit) and the operated femur bone (εlim/εmax, where εlim is the elastic limit) in the current configuration and in the simulated configuration of removal of the three most proximal
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screws, at the peak hip contact forces of the different motor activities.
2.19
Bone
1.67
Configuration
Screws-Removal
Bone
1.89
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Configuration
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Ascent 1.91
Stair
Chair
Descent
Rise/Sit
Squat
1.46
1.83
1.62
2.27
1.71
1.91
2.69
2.44
1.61
1.86
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Metal Implant
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Safety Factor
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Table 3. Mean and maximum ratio (%) of the strains in the operated limb with respect to the corresponding strains in the contralateral limb, calculated at the peak hip contact forces of the different motor activities in the lateral and medial aspect of the selected
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Principal Strains: Operated vs Contralateral Limb Current Configuration
Screws-Removal Configuration
Medial Slice
Lateral Slice
Medial Slice
Tensile
Compressive
Tensile
Compressive
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Lateral Slice
Mean
17%
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88%
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Max
18%
61%
135%
106%
Mean
22%
76%
60%
94%
Max
27%
70%
136%
108%
Mean
48%
118%
131%
149%
Max
34%
116%
186%
174%
Mean
40%
40%
50%
51%
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Stair Ascent
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Walking
Stair Descent
Chair Rise/Sit
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Max
48%
70%
62%
92%
Mean
39%
57%
62%
74%
Max
42%
85%
84%
123%
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HIGHLIGHTS
Long-term biomechanical adaptation of a femoral reconstruction after bone tumor
Muscle coordination depends on motor activity and leads to larger joint loads in
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Load-sharing with the metal implant leads to markedly low ratio of physiological
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contralateral limb
strain
Bone resorption is related to load-sharing and to internal forces during movement
Mechanical stimulus should be improved though surgery modifications and
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specific physical therapy
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Giordano Valente, Lorenzo Pitto, Enrico Schileo, Sabina Piroddi, Alberto Leardini, Marco Manfrini, Fulvia Taddei PII: DOI: Reference:
S0268-0033(17)30028-1 doi: 10.1016/j.clinbiomech.2017.01.017 JCLB 4278
To appear in:
Clinical Biomechanics
Received date: Accepted date:
7 July 2016 19 January 2017
Please cite this article as: Giordano Valente, Lorenzo Pitto, Enrico Schileo, Sabina Piroddi, Alberto Leardini, Marco Manfrini, Fulvia Taddei , Relationship between bone adaptation and in-vivo mechanical stimulus in biological reconstructions after bone tumor: A biomechanical modeling analysis. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Jclb(2017), doi: 10.1016/ j.clinbiomech.2017.01.017
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Relationship between bone adaptation and in-vivo mechanical stimulus
in
biological
reconstructions
after
bone
tumor:
a
biomechanical modeling analysis
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Giordano Valente1*, Lorenzo Pitto1, Enrico Schileo2, Sabina Piroddi1, Alberto Leardini3,
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Marco Manfrini4, Fulvia Taddei1
1. Medical Technology Laboratory, Rizzoli Orthopaedic Institute, Bologna, Italy
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2. Computational Bioengineering Laboratory, Rizzoli Orthopaedic Institute, Bologna, Italy
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3. Movement Analysis Laboratory, Rizzoli Orthopaedic Institute, Bologna, Italy
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4. Orthopedic and Traumatologic Clinic for Musculoskeletal Tumors, Rizzoli
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Orthopaedic Institute, Bologna, Italy
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*CORRESPONDING AUTHOR:
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e-mail: [email protected]
Word Count: Abstract 249, Manuscript 4408
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ACCEPTED MANUSCRIPT ABSTRACT
Background:
Biomechanical
interpretations
of
bone
adaptation
in
biological
reconstructions following bone tumors would be crucial for orthopedic oncologists, particularly if based on quantitative observations. This would help plan for surgical
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treatments, rehabilitative programs and communication with the patients. We aimed to
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analyze the biomechanical adaptation of a femoral reconstruction after Ewing sarcoma according to an increasingly-used surgical technique, and to relate in-progress bone
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resorption to the mechanical stimulus induced by different motor activities.
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Methods: We created a multiscale musculoskeletal and finite element model from CT scans and motion analysis data at a 76-month follow-up of a patient, to analyze muscle
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and joint loads, and to compare the mechanical competence of the reconstructed bone
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with the contralateral limb, in the current real condition and in a possible revision surgery
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that removed proximal screws.
Findings: Our results showed strategies of muscle coordination that led to differences in
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joint loads between limbs more marked in more demanding motor activities, and
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generally larger in the contralateral limb. The operated femur presented a markedly low ratio of physiological strain due to load-sharing with the metal implant, particularly in the lateral aspect. The possible revision surgery would help restore a physiological strain configuration, while the safety of the reconstruction would not be threatened. Interpretation: We suggest that bone resorption is related to load-sharing and to the internal forces exerted during movement, and the mechanical stimulus should be
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ACCEPTED MANUSCRIPT improved by adopting modifications in the surgical treatment and by promoting physical therapy aimed at specific muscle strengthening. KEYWORDS
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biological reconstruction; bone tumor; bone mechanical stimulus; subject-specific
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musculoskeletal modeling; subject-specific finite element modeling
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INTRODUCTION
Limb-salvage surgery represents a special operative procedure in orthopedic oncology and has become the accepted standard of treatment for bone tumors of the extremities
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(Aksnes et al., 2008; Kolk et al., 2014). Among limb-salvage surgery options, biological
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reconstruction of long bones after tumor resection through the combination of massive
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bone allograft (MBA) and vascularized fibula autograft (VFA), originally known as Capanna technique (Capanna et al., 2007, 1993), has been increasingly used in several
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orthopedic units around the world since the early 1990s. In this technique, after
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resection of the bone tumor, the VFA is harvested from the contralateral limb and combined with the MBA in a concentric or parallel assembly (Capanna et al., 2007). This
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biological reconstruction combines important advantages implied in the two grafts: the
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mechanical strength of the MBA and the osteogenic potential of the VFA. This facilitates bone healing and union by activation of a remodeling process following hypertrophy of
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the VFA as a reaction to mechanical loading, and helps reduce fracture and infection
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thanks to the MBA support and the vascular nature of the VFA.
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Several studies analyzed the long-term evolution of biological reconstructions from an oncological perspective (Abed, Y.Y. et al., 2009; Bakri et al., 2008; Capanna et al., 2007; Houdek et al., 2015; Innocenti et al., 2009; Jager et al., 2010; Li et al., 2010; Rabitsch et al., 2013), reporting of stable and durable reconstructions, satisfactory results in terms of limb-salvage rates, tumor control, function and manageable complications with acceptable rates. However, complications still include nonunion, fracture and infection, which can be related to the biomechanical behavior of the
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reconstructions, which would instead be crucial, as bone adaptation can evolve towards
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conditions that concern bone resorption and threaten the safety of the bone assembly (Ceruso et al., 2008), and adverse events can still occur as a consequence of
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mechanical loading during the adaptation process. Objective functional results in the long term would be then crucial, to provide feedbacks to clinicians about surgical and
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rehabilitative outcomes, and patient counseling about potential recovery (Ottaviani et al.,
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2009). Currently, computational modeling of the musculoskeletal system is the only viable method to predict internal loads (Erdemir et al., 2007; Pandy and Andriacchi,
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2010) and bone mechanical competence (Keyak et al., 2013; Orwoll et al., 2009) in vivo.
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Subject-specific musculoskeletal modeling and simulation of movement were used to investigate femoral loads during gait in a patient who underwent a biological
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reconstruction following osteosarcoma (Taddei et al., 2012), and subject-specific finite
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element (FE) modeling of a reconstructed femur following Ewing sarcoma was used to evaluate the risk of fracture of the reconstruction (Taddei et al., 2003). Coupling subjectspecific musculoskeletal and FE models, i.e. multiscale body-organ modeling, would be a powerful computational tool for clinical applications. However, although state-of-the-art methods would allow comprehensive multiscale analyses, a few studies exploited such tools for clinically-driven questions (Martelli et al., 2014b; Vahdati et al., 2014; van der Ploeg et al., 2012), and none was applied to orthopedic oncology yet.
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ACCEPTED MANUSCRIPT The overall aim of this study is to analyze the long-term biomechanical adaptation of a biologically-reconstructed femur following Ewing sarcoma, and to relate the partly adverse bone adaptation to the mechanical stimulus induced by different motor activities. More specifically, we aim to: (i) analyze the internal loads, i.e. muscle and joint
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contact forces, during common motor activities, (ii) evaluate the safety of the
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reconstruction and (iii) compare the mechanical competence of the reconstructed bone
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with the contralateral limb, in the current real condition and in a possible new scenario of minimally-invasive revision surgery that removed the three most proximal screws. We
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hypothesized that this revision surgery could restore a physiological mechanical
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stimulus without threatening the safety of the bone assembly.
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Surgical technique and follow-up
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METHODS
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An 8-year-old male patient received a combination of MBA and VFA for the reconstruction of the intercalary skeletal gap after resection for Ewing sarcoma at the
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right proximal femur (Fig. 1). The affected bone was replaced by a deep-frozen MBA
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and a VFA harvested from the contralateral limb. The MBA was prepared to receive the VFA on its endosteal surface. First, a double osteotomy was performed on the proximal femur: one at the level of the lesser trochanter and another at 13.5 cm distally. Tumor excision was completed by isolating and protecting the deep femoral vascular pedicle. Second, a 15 cm part of the intercalary fibula and the peroneal vascular pedicle were extracted from the contralateral limb. The MBA, previously defrosted and modeled with a distal Z-shape osteotomy, was then prepared with a hole in the antero-superior part to
6
ACCEPTED MANUSCRIPT allow passage of the peroneal pedicle. Finally, the fibula was inserted into the graft and the whole system was slotted into both ends of the autologous bone and secured by using a 14-hole titanium alloy plate and nine screws with a diameter of 4.5 mm and different lengths. Two screws were placed in the femoral neck, one in correspondence
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of the graft hole, the other six in the distal femur.
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The implanted VFA in combination with mechanical loading led to a successful longterm reconstruction: no complications or reoperations, nor tumor recurrence during
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follow-up. In addition, osteo-fusion with the autologous bone was observed with an intense remodeling involving both MBA and VFA, which also led to the formation of
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cortical fronts between them. However, there were valgism of the femoral neck,
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decrease in bone density in the femoral head and neck, decrease in MBA cortical thickness, enlargement of the peroneal medullary canal in conjunction with decrease in
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peroneal bone density, formation of cortical rings between MBA and VFA (Taddei et al.,
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Experimental data
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2015) (Fig. 1).
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Lower-body CT scans and motion analysis data of five motor activities were acquired after 76 months of follow-up, when the patient was 15 years old, 48.5 kg and 170 cm (Fig. 1). Before CT scanning, the patient was instrumented with 22 reflective markers on pelvis and lower limbs according to an established protocol (Leardini et al., 2007), which were also visible on the CT images. The patient performed ten walking trials, three stair ascent, stair descent and chair rise/sit trials each, and four squat trials. An additional static posture was acquired in standing position. Stair ascent and descent were
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ACCEPTED MANUSCRIPT performed by using a four-step modular staircase, allowing measurement of also ground reaction forces on the second and third steps. Chair rise/sit was performed by using a swivel stool, with the feet separately over the two force platforms, as well as during squatting. Marker trajectories and ground reaction forces were collected using an 8-
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camera motion capture system (Vicon 612 Motion System, Oxford, UK) and two force
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platforms (Kistler, Winterthur, Switzerland), respectively. The local ethical committee
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approved all procedures, and the parents of the patient provided written informed
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consent for participation.
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Musculoskeletal model
A subject-specific musculoskeletal model of the lower limbs was created from CT by
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using a previously developed workflow (Valente et al., 2014) (Fig. 2). The model
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included nine rigid bodies (pelvis, thighs, shanks, tali, feet), articulated by 12 degrees of freedom (DOF) and actuated by 85 musculotendon units. Body volumes and inertial
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properties were derived from the CT images. Each hip was modeled as a 3-DOF ball-
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and-socket joint, each knee as a 1-DOF hinge joint, and each ankle as a 2-DOF universal joint including two non-intersecting hinges at the tibiotalar and subtalar joints
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(Valente et al., 2015). Body and joint coordinate systems were defined according to the recommendations of the International Society of Biomechanics (Wu et al., 2002). The number and paths of the musculotendon actuators were defined according to a generic model (Delp et al., 1990). Additional wrapping surfaces were included to represent the ankle capsule to prevent soleus, medial and lateral gastrocnemius from penetrating the tibia during dorsiflexion. According to the reconstruction surgery, the right vastus intermedius was not included in the model, and the origin of the right vastus lateralis 8
ACCEPTED MANUSCRIPT was moved distally. The maximum isometric force (Fmax) of each musculotendon unit (i) was calculated as follows (Valente et al., 2014):
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i
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Fmax i
Vol Vol ( PCSA)i l ( gen ) lMT l0 i ( gen ) 0 lMT
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where PCSA is the muscle physiological cross-sectional area, Vol is the muscle volume
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calculated from CT, l0 and lMT are the optimal fiber length (unknown) and the musculotendon length (calculated from CT) for the subject-specific model, respectively,
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( gen ) are the corresponding quantities for a generic model (Delp et al., 1990), l0( gen ) and lMT
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and σ is the maximum muscle tension set to 61 N/cm 2 according to Arnold et al (Arnold et al., 2010). The subject-specific musculoskeletal model was created in the OpenSim
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file format (Delp et al., 2007) using NMSBuilder (Valente et al., 2014). All motor activities
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were simulated using this musculoskeletal model and the motion analysis data to calculate joint angles, joint moments, muscle forces and activations, and joint contact
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forces, leveraging OpenSim. Joint angles describing the motion were calculated from
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the experimental marker trajectories through Inverse Kinematics, minimizing errors between the experimental marker positions and the corresponding markers on the model. Joint moments were calculated from the joint angles and the ground reaction forces through Inverse Dynamics. Muscle forces were calculated by decomposing the joint moments among musculotendon units through Static Optimization, minimizing the sum of muscle activations squared and neglecting the force-length-velocity relationships
9
ACCEPTED MANUSCRIPT of muscle (Anderson and Pandy, 2001). Joint contact forces were calculated from the instantaneous force equilibrium through Joint Reaction Analysis. Finite Element model
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FE models of both femurs were generated from CT by using a previously validated
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procedure (Schileo et al., 2014) (Fig. 2). Bone, plate and screws volumes obtained from
advancing
front
algorithm
(Hypermesh
v.10,
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image segmentation were meshed with 10-node tetrahedral elements using an Altair
Engineering
Inc.,
USA).
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Inhomogeneous isotropic material properties were mapped from CT onto the mesh
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elements using the Bonemat algorithm (Taddei et al., 2007), which allows conversion of Hounsfield Units (HU) values of CT data into elastic modulus values for each mesh
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element (Schileo et al., 2008). Poisson’s ratio of 0.3 was assumed for all materials.
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Metal artifacts on CT images due to titanium alloy plate and screws were reduced before performing material mapping, by assigning a 1600 HU threshold to all values greater
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than 1600 HU, i.e. the maximum value detected in the cortical bone of the contralateral
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femur. The sets of loading for each motor activity applied to the femurs were selected from the trials presenting the highest peak in hip contact force. These sets of forces
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allowed representation of the maximum physiological loading conditions in the different motor activities. Muscle forces were applied on either origin/insertion or intermediate via points of the muscle paths, to account for the correct directions of the muscle forces. In the origin/insertion points, the forces were applied to the mesh node closest to the muscle attachment point. In the intermediate via points (i.e. gluteus maximus anterior, middle and posterior, iliacus, vastus lateralis, intermedius and medialis, gastrocnemius lateralis and medialis), the forces were applied to rigid beam elements (i.e. MPC184 10
ACCEPTED MANUSCRIPT element type in Ansys) that connected the origin/insertion on the femur to the consecutive intermediate via point. Force directions were defined as the vector connecting the application point belonging to the femur to the consecutive point in the muscle path belonging to the other body segment (i.e. pelvis or shank). The hip contact
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forces were applied on the center of the femoral head. The femurs were physiologically
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constrained by applying displacement constraints at three nodes on the femur to prevent
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rigid body motion (Speirs et al., 2007): a node placed on the intercondylar fossa was fully constrained, a node on the center of the femoral head was constrained in the
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antero-posterior and medio-lateral directions, and a third node on the lateral epicondyle
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was constrained in the antero-posterior direction. FE linear-elastic simulations were
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performed using Ansys (v. 14, Ansys Inc., USA).
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Biomechanical analyses
To analyze the internal loads during the different motor activities, joint contact forces
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and the most influential muscle forces (i.e. gluteus medius, iliacus, psoas, medial and
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lateral hamstrings, rectus femoris, vasti, gastrocnemius and soleus) were first expressed in percentage of motor activity cycle and normalized to the subject body-weight (BW).
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Then mean and maximum differences in joint contact forces between the operated and the contralateral limb over the activity cycles were calculated, and Wilcoxon signed rank tests (p < 0.01) were performed to evaluate significant differences. In addition, Pearson correlation coefficients (R) were calculated to quantify similarities in force patterns between limbs.
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ACCEPTED MANUSCRIPT The safety of the reconstruction and the bone mechanical competence in both femurs were evaluated in the loading configurations corresponding to the maximum peak of hip contact force among all trials for each motor activity. To evaluate the safety of the reconstruction, von Mises stress in the plate and screws and the principal tensile and
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compressive strain in the bone, excluding the region distal to the reconstruction (Fig. 2),
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were calculated, in the current configuration and in the configuration that simulated
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removal the three most proximal screws. Element-wise stresses and strains, calculated at the element centroid including the stress and strain distribution in the neighboring
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elements (ETABLE in Ansys), were considered in the analysis. The safety factor was
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determined as σlim/σmax for the plate and screws and εlim/εmax for the bone, where σlim is the fatigue limit of 240 MPa for titanium alloy in the most conservative condition
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(accounting for a stress concentration factor of 3.3)a, σmax is the maximum stress
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recorded in the femur, εlim is the limit strain of 1.04% compressive and 0.73% tensile (Bayraktar et al., 2004), εmax is the maximum strain recorded in the femur. To avoid
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boundary condition artifacts, the finite elements lying inside 10 mm spheres centered in
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the points of application of muscle forces and hip contact force were excluded from the calculations. To avoid metal artifacts, elements in contact with the metal components
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were also excluded.
To compare the bone mechanical competence between limbs, the principal tensile and compressive strain distributions were evaluated in five transverse sections of the proximal reconstruction (Fig. 2). The analysis of results was then focused on the
a
http://www.matweb.com/
12
ACCEPTED MANUSCRIPT representative section at half implant, where higher stress and strain due to bending were expected, and on the corresponding section in the contralateral limb. Mean and maximum values of principal strains for all motor activities were calculated in the lateral and medial portions of the sections, to identify the clearest trends observable in a
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complex structural configuration including MBA and VFA. For the operated limb, the
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calculations were also performed after simulation of the screws-removal configuration. RESULTS
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Internal loads during motor activities
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Overall, there were differences in lower-limb joint contact forces between the operated
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and contralateral limb in all motor activities (Fig. 3, Table 1). The differences were less marked during walking, and were more marked during more demanding activities,
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particularly during double-support ones (i.e. chair rise/sit and squat). The loads were
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generally larger in the contralateral limb, with a peak difference of 3.4 BW at the knee during squat (Fig. 3, Table 1). This was mostly induced by a muscle compensation
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strategy from the vasti, gastrocnemius and hamstrings of the contralateral limb (Fig. 4).
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However, the hip loads were slightly larger in the operated limb during gait activities (i.e. walking, stair ascent and stair descent), as a result of different strategies of muscle coordination (Fig. 3, Table 1, Fig. S-1). Particularly, during stair descent, the gluteus medius, psoas and hamstrings exerted larger forces in the operated limb during stance, as well as gastrocnemius during early stance (Fig. 4), which led to also have a higher first peak in knee contact force in the operated limb. Although marked differences in joint
13
ACCEPTED MANUSCRIPT contact forces occurred, there were similarities in force patterns confirmed by the high correlation values (R) in almost all cases (Table 1). Safety of the reconstruction
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The reconstruction was mechanically safe, as safety factors in both the metal implant
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and bone were never below unity (Table 2). Overall, the most demanding activities were
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stair descent and walking. In the current configuration, the minimum bone safety factor (1.67) was found in the reconstruction, close to the MBA hole. However, most of the
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bone volume showed significantly larger safety factors, with levels of 3-5 at the proximal
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femur (Fig. 5). In the screws-removal configuration, safety was not threatened (Table 2). However, consistently with the increased load-sharing in the bone, there was a general
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decrease in the safety factor (Fig. 5), especially during stair descent, although the
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minimum values (1.61) did not change markedly.
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Comparison of bone mechanical competence between limbs
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The different motor activities resulted in different distributions of tensile and compressive strains in the selected femur sections (Figs. 6 and S-2). In the contralateral limb,
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assumed as physiological reference condition, the lateral aspect was mainly subjected to tensile strain in all motor activities, while the medial aspect to compressive strain (Fig. 6). In the operated limb in the current configuration, the lateral aspect was markedly shielded from tensile strain, to the extent that compressive strain was larger in all motor activities (Fig. 6). The tensile strain in the lateral aspect was always less than half of the corresponding values in the contralateral limb (Table 3). Conversely, the medial aspect was less shielded from compressive strain during gait activities (Fig. 6), where the ratio 14
ACCEPTED MANUSCRIPT of the compressive strain in the operated limb could even exceed 100% during stair descent (Table 3). However, the ratios were lower during double-support activities, where markedly lower loads were applied compared to the contralateral limb (see internal loads during motor activities). In the screws-removal configuration, all values of
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tensile and compressive strains increased compared to the current configuration (Fig.
IP
6). In gait activities, a contralateral-like strain configuration could be restored, as the
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tensile strain in the lateral aspect and the compressive strain in the medial aspect were close to the corresponding strains in the contralateral limb (Table 3). Particularly, in stair
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descent, the tensile strain markedly increased in the lateral side, whose mean value
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passed from 48% to 131%. Conversely, in double-support activities where markedly lower loads were applied, a contralateral-like strain configuration could not be restored
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(Fig. 6, Table 3).
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DISCUSSION
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Biomechanical interpretations of bone adaptation in biological reconstructions following
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bone tumors would be crucial for clinicians, particularly if based on quantitative data, to plan for surgical treatments and rehabilitative programs, as well as for communication
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with the patients. The aim of this study was to analyze, by using a multiscale musculoskeletal and finite element model, the biomechanical adaptation of a femoral reconstruction after bone tumor resection, and to relate the bone adaptation observed to the mechanical stimulus induced by different motor activities. Our results indicate that the long-term adaptation resulted in strategies of muscle coordination that generally led to larger joint contact forces in the contralateral limb, particularly at the knee. We raise a concern for the future safety of the reconstructed bone assembly, as the combination of 15
ACCEPTED MANUSCRIPT lower internal loads and the presence of a stiff metal plate makes the bone share loadbearing with the metal implant to the extent that the ratio of physiological strain with respect to the intact contralateral bone is markedly low. This evidence possibly explains the bone adaptation during the follow-up analyzed, which shows a decrease in allograft
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cortical thickness, enlargement of the peroneal medullary canal and decrease in
IP
peroneal bone density. In the perspective of bone adaptation, the removal of the three
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most proximal screws would still preserve the safety of the reconstruction and would help restore a physiological configuration thanks to the increased mechanical stimulus in
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the bone.
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Comparing the differences in joint contact forces between the operated and contralateral
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limb, we found larger contralateral loading that was increasingly evident with more demanding motor activities (Figs. 3 and 4, Table 1). Hip contact forces in the three gait
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activities were instead larger in the operated limb, particularly during stair descent.
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During this activity, the patient seemed to have less control on the operated limb at heelstrike and in the single-support phase, in accordance also with larger knee loads in the
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first peak (Figs. 3 and 4, Table 1). When we applied these internal forces to the organ-
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level models of the femurs, we found a clearly polarized situation. In the representative section at mid-diaphysis, while the compressive strain in the medial aspect was not markedly different from that in the contralateral bone, the mean tensile strain in the lateral aspect (where the screws were implanted) was only the 17% of the corresponding contralateral value during walking, and even during stair descent where the applied forces were indeed larger, did not exceed 48% (Fig. 6, Table 3). This mechanical effect known as strain shielding, which typically occurs when stiff and more
16
ACCEPTED MANUSCRIPT flexible materials are combined, led to strain levels below the percentage of physiological strain deemed necessary for bone formation (Martelli et al., 2014a). The strain shielding in the lateral aspect was mildened in the simulated screws-removal configuration during gait activities, even peaking 131% during stair descent (Fig. 6,
T
Table 3). However, during double-support activities, the mean tensile strain was up to
IP
62%, which can be explained by markedly lower forces exerted on the operated femur.
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In this described scenario, which is likely to re-establish a mechanical environment compatible with bone homeostasis (Martelli et al., 2014a), the safety of the
US
reconstruction was not threatened, showing small changes with respect to the current
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configuration (Table 2, Fig. 5).
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This is the first study that predicted muscle and joint forces and stress and strain conditions during different motor activities of a long-term biological reconstruction
ED
through subject-specific multiscale modeling of the musculoskeletal system. Therefore,
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a direct comparison with previous studies was not possible. Muscle and joint forces during walking in a biological reconstruction following osteosarcoma were investigated
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previously (Taddei et al., 2012), showing peak joint forces comparable with the present
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findings but different strategies of muscle coordination due to the specificity of the case regarding surgical details, follow-up and motor function. Our findings of bone strains in the contralateral limb in all activities and in the screws-removal configuration of the operated limb in gait activities are consistent with previous computational (Duda et al., 1998; Martelli et al., 2014b) and experimental (Aamodt et al., 1997) studies showing the lateral aspect of the diaphysial femur subjected to tensile strain and the medial aspect to compressive strains in daily activities, and are also in a comparable range of strain level.
17
ACCEPTED MANUSCRIPT This agreement further confirms the hypothesis that the bone adaptation during followup was related to the effect of proximal screws and muscle loading, although we need to consider two aspects. First, the cited studies include subjects that are not age-matched with our case. However, reference data for bone strains in healthy children are lacking
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because of ethical reasons. Second, the contralateral limb in our case may not be
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equivalent to a healthy control, as a 15 cm part of the fibula was harvested from that
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limb. However, regarding bone structure, this generates a high adaptive effort in the tibia to replace the mechanical function of the fibula (Taddei et al., 2009), suggesting that the
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femoral structure is preserved. Regarding motor function, a recent gait study in adults
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warns about an average long-term gait morbidity after fibula harvesting (Feuvrier et al., 2016), but this seemed not the case in the subject studied, possibly thanks to his young
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age and the extensive rehabilitation performed.
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The analysis of the fate of such femoral reconstructions was limited to a single, although
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exemplary, case. As similar bone adaptive mechanisms were shown (Ceruso et al., 2008; Manfrini et al., 2004), and still occur, applying the computational modeling
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workflow to other cases would provide general conclusions about potential revision
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surgery, suggestions about different solutions in plate and screws to be used, and support in the development of physical therapy protocols. Although musculoskeletal and FE models involve unavoidable simplifications and assumptions, we included the strengths of the subject-specific nature of the musculoskeletal modeling, whose robustness has been recently tested with good results (Valente et al., 2014), and the extensive experimental and clinical validation performed on the FE models of bone strength (Falcinelli et al., 2014; Schileo et al., 2014). In addition, the adoption of elastic
18
ACCEPTED MANUSCRIPT limits for bone tissue that were derived from bone samples of adults or elderly may be challenged. This choice was however corroborated by the few data available on children, showing substantial invariance of bone elastic limit strain (Currey, 2004; Öhman et al., 2011).
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Our findings demonstrated a close interaction between the predicted internal loads
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during motor activities and the bone mechanical competence when providing a biomechanical interpretation of the long-term adaptation of biological reconstructions.
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We confirm such a surgical approach as a valuable solution for limb-salvage surgery, as we observed that the vascularized autograft contributes to bone union when there is
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mechanical stimulus. However, there is a caveat concerning the long-term evolution, as
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stiff metal implants can have a negative influence on the bone mechanical stimulus. We can also speculate that the parallel bone assembly could be a valuable alternative to the
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concentric assembly in femoral reconstructions, to improve mechanical stimulus that
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would avoid autograft resorption by promoting its enlargement instead. A favorable sideconsequence would be to avoid holes in the allograft, which hosted the minimum safety
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factor in our analysis. To evaluate the efficacy of the present computational modeling
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workflow as a clinical decision-making tool, research trials should be performed that apply the proposed analysis at different timepoints of the follow-up to a population of biological reconstructions. This would eventually allow to establish which diagnostic tools and biomechanical indicators are relevant in the clinical practice. In summary, our study provided a biomechanical interpretation of the bone adaptation of a femoral reconstruction after bone tumor using a vascularized fibula autograft inlaid in a massive bone allograft. The novelty of our study resided in the multiscale approach in 19
ACCEPTED MANUSCRIPT subject-specific computational modeling applied to orthopedic oncology. Our results demonstrated a relationship between bone adaptation and in-vivo mechanical stimulus, suggesting that bone resorption is related to load-sharing with the metal implant and to the internal forces exerted during movement. In the long-term evolution of these bone
T
reconstructions, the mechanical stimulus should be promoted to avoid possible safety
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threatening of the bone assembly, by planning for additional surgical treatment, new
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designs of metal implants and physical therapy aimed at specific muscle strengthening.
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ACKNOWLEDGEMENTS
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This study was supported by the project “Biological bone reconstruction in children skeleton after sarcoma resection. Validation of the technique through CT scan analysis
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and histological evaluation of the retrieved cases” (RF-2010-2321501), funded by the
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CONFLICT OF INTEREST
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Italian Ministry of Health.
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The authors do not have any financial or personal relationships with other people or
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Leardini, A., Sawacha, Z., Paolini, G., Ingrosso, S., Nativo, R., Benedetti, M.G., 2007. A
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diaphyseal resection for lower extremity bony malignancy. J. Surg. Oncol. 102, 368–374.
Manfrini, M., Vanel, D., De Paolis, M., Malaguti, C., Innocenti, M., Ceruso, M., Capanna, R., Mercuri, M., 2004. Imaging of vascularized fibula autograft placed inside a massive allograft in reconstruction of lower limb bone tumors. Am. J. Roentgenol. 182, 963–970.
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ACCEPTED MANUSCRIPT Martelli, S., Kersh, M.E., Schache, A.G., Pandy, M.G., 2014a. Strain energy in the femoral
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Öhman, C., Baleani, M., Pani, C., Taddei, F., Alberghini, M., Viceconti, M., Manfrini, M.,
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Bielack, S. (Eds.), Pediatric and Adolescent Osteosarcoma. Springer US, Boston, MA, pp. 421–436. Pandy, M.G., Andriacchi, T.P., 2010. Muscle and Joint Function in Human Locomotion. Annu. Rev. Biomed. Eng. 12, 401–433.
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ACCEPTED MANUSCRIPT Rabitsch, K., Maurer-Ertl, W., Pirker-Frühauf, U., Wibmer, C., Leithner, A., 2013. Intercalary Reconstructions with Vascularised Fibula and Allograft after Tumour Resection in the Lower Limb. Sarcoma 2013, 1–8. Schileo, E., Balistreri, L., Grassi, L., Cristofolini, L., Taddei, F., 2014. To what extent can
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linear finite element models of human femora predict failure under stance and fall
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Viceconti, M., 2008. An accurate estimation of bone density improves the
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accuracy of subject-specific finite element models. J. Biomech. 41, 2483–2491.
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Speirs, A.D., Heller, M.O., Duda, G.N., Taylor, W.R., 2007. Physiologically based
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boundary conditions in finite element modelling. J. Biomech. 40, 2318–2323. Taddei, F., Balestri, M., Rimondi, E., Viceconti, M., Manfrini, M., 2004. Tibia adaptation
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Taddei, F., Martelli, S., Valente, G., Leardini, A., Benedetti, M.G., Manfrini, M., Viceconti, M., 2012. Femoral loads during gait in a patient with massive skeletal reconstruction. Clin. Biomech. 27, 273–280. Taddei, F., Schileo, E., Helgason, B., Cristofolini, L., Viceconti, M., 2007. The material mapping strategy influences the accuracy of CT-based finite element models of bones: An evaluation against experimental measurements. Med. Eng. Phys. 29, 973–979. 26
ACCEPTED MANUSCRIPT Taddei, F., Valente, G., Piroddi, S., Schileo, E., Pitto, L., Leardini, A., Roncari, A., Leardini, A., Manfrini, M., 2015. Extreme, biomechanically-explained remodelling of biological femoral reconstructions in pediatric oncology, in: Bone Abstracts. Presented at the 7th International Conference on Children’s Bone Health,
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Bioscientifica, Salzburg, Austria, p. P158.
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Taddei, F., Viceconti, M., Manfrini, M., Toni, A., 2003. Mechanical strength of a femoral reconstruction in paediatric oncology: a finite element study. Proc. Inst. Mech.
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Vahdati, A., Walscharts, S., Jonkers, I., Garcia-Aznar, J.M., Vander Sloten, J., van Lenthe, G.H., 2014. Role of subject-specific musculoskeletal loading on the
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Biomed. Mater. 30, 244–252.
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prediction of bone density distribution in the proximal femur. J. Mech. Behav.
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Valente, G., Pitto, L., Stagni, R., Taddei, F., 2015. Effect of lower-limb joint models on subject-specific musculoskeletal models and simulations of daily motor activities.
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Valente, G., Pitto, L., Testi, D., Seth, A., Delp, S.L., Stagni, R., Viceconti, M., Taddei, F., 2014. Are Subject-Specific Musculoskeletal Models Robust to the Uncertainties in Parameter Identification? PLoS ONE 9, e112625. van der Ploeg, B., Tarala, M., Homminga, J., Janssen, D., Buma, P., Verdonschot, N., 2012. Toward a more realistic prediction of peri-prosthetic micromotions. J. Orthop. Res. 30, 1147–1154.
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ACCEPTED MANUSCRIPT Wu, G., Siegler, S., Allard, P., Kirtley, C., Leardini, A., Rosenbaum, D., Whittle, M., D’Lima, D.D., Cristofolini, L., Witte, H., Schmid, O., Stokes, I., 2002. ISB recommendation on definitions of joint coordinate system of various joints for the reporting of human joint motion--part I: ankle, hip, and spine. International Society
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FIGURE LEGENDS
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Figure 1. Details of the surgical technique and the experimental data used in this study.
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Left panel: particulars of the biological reconstruction from the CT after surgery, including the section at half implant. Right panel: lower-body CT and motion analysis
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data after 76 months of follow-up used to create the multiscale body-organ models.
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Bottom panel: 8 CT follow-up of the representative section at half implant showing bone
Figure 2. Workflow for the present subject-specific body-organ modeling and simulation. Left panel: creation of the body-level musculoskeletal model from CT using NMSBuilder(Valente et al., 2014), and simulations of the five motor activities using OpenSim(Delp et al., 2007) to calculate the internal loads (muscle forces and joint contact forces). Right panel: creation of the organ-level finite element models of both femurs, application of the loads from the musculoskeletal model and the physiological
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ACCEPTED MANUSCRIPT constraints(Speirs et al., 2007); linear-elastic simulation using Ansys to evaluate the safety of the reconstruction (excluding the region distal to the reconstruction) and compare the femurs in the current and screws-removal configurations in five transverse sections of the proximal reconstruction (with particular focus on the representative
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Figure 3. Joint contact forces in the operated and contralateral limbs during the different motor activities, expressed in body-weight (BW) as mean and standard deviation among
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Figure 4. The most influential muscle forces in the operated and contralateral limbs during stair descent (left panel) and squat (right panel), expressed in body-weight (BW)
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Figure 5. Safety factor distribution in the operated femur during walking (top panel) and stair descent (bottom panel), in the current configuration (left panel) and in the screws-
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removal configuration (right panel).
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Figure 6. Comparison of the bone mechanical competence of the selected section between the operated and contralateral limbs at the peak hip contact forces of the different motor activities, in the current real configuration and in the simulated configuration of possible removal of the three most proximal screws. Tensile (ε1) and compressive (ε3) strain distributions are presented, with the corresponding mean and maximum values in the lateral and medial aspect of the section. Principal strain
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Figure S-2. Tensile (ε1) and compressive (ε3) strain distributions in the additional
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selected sections of the operated limb at the peak hip contact forces of the different
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motor activities, in the current real configuration and in the simulated configuration of
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ACCEPTED MANUSCRIPT Table 1. Differences in joint contact forces between the operated and contralateral limb during the different motor activities. Mean and maximum differences over the motor activity cycle are reported in body-weight (BW). Significant differences (Wilcoxon signed rank tests, p < 0.01) are
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-0.29
-0.23
Mean Diff (BW)
1.07
-2.28
-0.67
Max Diff (BW)
0.77
0.92
0.83
0.95
R
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-0.24
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Mean Diff (BW)
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Max Diff (BW)
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0.81
0.65
0.69
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R
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-0.50
-0.69
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Mean Diff (BW)
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Max Diff (BW)
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ACCEPTED MANUSCRIPT Table 2. Safety factors of the metal implant (σlim/σmax, where σlim is the fatigue limit) and the operated femur bone (εlim/εmax, where εlim is the elastic limit) in the current configuration and in the simulated configuration of removal of the three most proximal
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2.19
Bone
1.67
Configuration
Screws-Removal
Bone
1.89
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Ascent 1.91
Stair
Chair
Descent
Rise/Sit
Squat
1.46
1.83
1.62
2.27
1.71
1.91
2.69
2.44
1.61
1.86
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Table 3. Mean and maximum ratio (%) of the strains in the operated limb with respect to the corresponding strains in the contralateral limb, calculated at the peak hip contact forces of the different motor activities in the lateral and medial aspect of the selected
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Principal Strains: Operated vs Contralateral Limb Current Configuration
Screws-Removal Configuration
Medial Slice
Lateral Slice
Medial Slice
Tensile
Compressive
Tensile
Compressive
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Mean
17%
79%
88%
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Max
18%
61%
135%
106%
Mean
22%
76%
60%
94%
Max
27%
70%
136%
108%
Mean
48%
118%
131%
149%
Max
34%
116%
186%
174%
Mean
40%
40%
50%
51%
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Stair Descent
Chair Rise/Sit
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Max
48%
70%
62%
92%
Mean
39%
57%
62%
74%
Max
42%
85%
84%
123%
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HIGHLIGHTS
Long-term biomechanical adaptation of a femoral reconstruction after bone tumor
Muscle coordination depends on motor activity and leads to larger joint loads in
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Load-sharing with the metal implant leads to markedly low ratio of physiological
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contralateral limb
strain
Bone resorption is related to load-sharing and to internal forces during movement
Mechanical stimulus should be improved though surgery modifications and
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specific physical therapy
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