Journal of Dental Research

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Numerical Simulation of Bone Regeneration in a Bone Chamber

L. Geris, K. Vandamme, I. Naert, J. Vander Sloten, J. Duyck and H. Van Oosterwyck J DENT RES 2009 88: 158 DOI: 10.1177/0022034508329603 The online version of this article can be found at: http://jdr.sagepub.com/content/88/2/158

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Statement of Correction Geris L, Vandamme K, Naert I, Vander Sloten J, Duyck J, Van Oosterwyck H. Numerical simulation of bone regeneration in a bone chamber. Journal of Dental Research. 2009:88(2):158-163 (DOI: 10.1177/0022034508329603) This PDF has been modified from its original publication. In the original version, 2 blocks of text were inadvertently switched. The text on the right-hand side of page 159 has been switched with the text on the left-hand side of page 160 to correct this error.

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RESEARCH REPORTS
Biomaterials & Bioengineering

L. Geris1,*,, K. Vandamme2,, I. Naert2, J. Vander Sloten1, J. Duyck2, and H. Van Oosterwyck1

1 Division of Biomechanics and Engineering Design, Department of Mechanical Engineering, K.U. Leuven, Celestijnenlaan 300CPB 2419, 3001 Leuven, Belgium; and 2Department of Prosthetic Dentistry/BIOMAT Research Cluster, School of Dentistry, Oral Pathology and Maxillofacial Surgery, Faculty of Medicine, K.U. Leuven, Kapucijnenvoer 7, 3000 Leuven, Belgium; authors contributing equally to this study; *corresponding author, Liesbet.geris@mech.kuleuven.be

Numerical Simulation of Bone Regeneration in a Bone Chamber

INTRODUCTION

J Dent Res 88(2):158-163, 2009

Abstract
While mathematical models are able to capture essential aspects of biological processes like fracture healing and distraction osteogenesis, their predictive capacity in peri-implant osteogenesis remains uninvestigated. We tested the hypothesis that a mechano-regulatory model has the potential to predict bone regeneration around implants. In an in vivo bone chamber set-up allowing for controlled implant loading (up to 90 m axial displacement), bone tissue formation was simulated and compared qualitatively and quantitatively with histology. Furthermore, the model was applied to simulate excessive loading conditions. Corres ponding to literature data, implant displacement magnitudes larger than 90 m predicted the formation of fibrous tissue encapsulation of the implant. In contradiction to findings in orthopedic implant osseointegration, implant displacement frequencies higher than 1 Hz did not favor the formation of peri-implant bone in the chamber. Additional bone chamber experiments are needed to test these numerical predictions.

KeY WorDs: tissue differentiation, bone chamber, numerical simulation, mechanobiology, finite element analysis.

DOI: 10.1177/0022034508329603 Received September 6, 2007; Last revision September 19, 2008; Accepted November 10, 2008 A supplemental appendix to this article is published electronically only at http://jdr.sagepub.com/supplemental.

urrent research in the field of (oral) implant osseointegration is predominantly of an experimental nature and investigates specific aspects of the osseointegration process, ranging from implant geometry over implant surface characteristics to the effect of (immediate) implant loading. Conflicting results with respect to the influence of mechanical loading on the osseointegration process (Isidor, 2006) stress the need for more accurate characterization and quantification of the experimental conditions in interpretation of the observations. Owing to the arduous nature of this experimental research, mathematical modeling of biological processes (Chaplain et al., 2006; Bertrand et al., 2007) as a parallel approach has been introduced in several biomedical domains (e.g., cancer research, drug development). Mathematical models allow investigators not only to optimize the experimental set-up, but also to test new hypotheses and to design optimal treatment strategies (Enderling et al., 2007), which can subsequently be verified experimentally. Several (types of) experimentally validated mathematical models have been developed to investigate the mechanoregulation of bone regeneration (Prendergast et al., 1997; Carter et al., 1998; Claes and Heigele, 1999) in fracture healing and distraction osteogenesis of long bones (Lacroix and Prendergast, 2002; Isaksson et al., 2006a,b). Based on previous studies (Isaksson et al., 2006a; Geris et al., 2008), the mechano-regulatory model developed by Prendergast et al. (1997) was applied in this study. For the experimental modeling of implant osseointegration, we have developed an in vivo bone harvest chamber model (Duyck et al., 2004) that combines a mechanically isolated environment with controlled implant loading and elimination of the site- and subject-variation from the results. An important target in prosthetic dentistry is the establishment of optimal implant osseointegration conditions and, more specifically, optimal mechanical loading conditions of implant and peri-implant tissue (for review, see Isidor, 2006; Avila et al., 2007; Esposito et al., 2007). This study aims to investigate the effects of various implant loading parameters, namely, implant displacement magnitude and frequency, using mathematical bone chamber models. It is hypothesized that a mathematical model is able to capture the peri-implant bone regeneration in the bone chamber and therefore can contribute to our quantitative understanding of the mechanoregulation of periimplant bone regeneration. Various bone chamber experiments with moderate loading conditions were simulated. After corroboration of the simulation results by comparison with experimental data, the model was applied to simulate excessive loading conditions that have either not yet been investigated (implant displacement frequencies above 1 Hz) or fall beyond the scope of the bone chamber (implant displacement magnitudes above 90 m).

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where an implant displacement of 30 m, 1 Hz, 400 cycles was applied 3x a wk for 9 wks, and to other conditions (Duyck et al., 2006), where implant displacements of 30, 60, and 90 m, 1 Hz, 800 cycles were applied twice a wk for 6 wks. For comparison with the histological findings, the value for the bone area fraction in the entire bone chamber for different histological sections (Fig. 1E) was calculated from the simulation results. In addition to the experimental conditions that were already tested in the bone chamber, additional loading conditions with higher loading frequencies (up to 20 Hz) and implant displacements (up to 500 m) were modeled.

MATERIALS & METHODS

Experimental Model
The rabbit tibial bone chamber (Duyck et al., 2004) consists primarily of dual-structure perforated hollow cylinders with a centrally positioned implant (Fig. 1A). Both cylinders have matching perforations, allowing for bone ingrowth into the bone chamber. The outer part osseointegrates in the tibia and remains there, while the inner part ( = 9 mm) can be removed after each experiment for assessment of the bone formation that has taken place inside the chamber. A titanium implant ( = 2 mm) with supportive bearing is located in its center and can be loaded in a defined and controlled manner by means of a loading device (Fig. 1B). In earlier studies, a positive correlation between controlled mechanical implant stimulation and periimplant bone formation was established for several experimental protocols (Duyck et al. 2006; Vandamme et al., 2007a,b,c, 2008; Geris et al., 2008).

RESULTS
The bone chamber was predicted to be filled with a mixture of bone and cartilage after a simulated period of 9 wks, both for the 3D (Fig. 3A) and 2D axisymmetric models (Fig. 3B). For the 3D model, good agreement was found between the measured and predicted bone area fraction values for all considered sections (Fig. 3A). For the 2D model, bone area fraction values agreed well for the bottom section S1 and top section S5 only. In the 2D axisymmetric model, varying the implant displacement magnitude from 30 up to 500 m showed a complete

Numerical Study

For the computational models, both an axisymmetric (longitudinal section through the perforation) and a 3D finite element model of a cylindrical implant and the tissue inside the bone chamber were created. The 3D geometry and the applied boundary conditions are shown (Figs. 1C, 1D). Implant loading took place in an axial displacement controlled manner and was modeled by the imposition of displacement boundary conditions. The tissue was modeled to be connected to the implant and the bone surrounding the chamber, but not to the inner bone chamber walls and the apex of the implant. At the perforation sites, free fluid flow (pore pressure [p] = 0) was allowed. All tissues were modeled as biphasic materials. More information on the FE model can be found in the Appendix and Geris et al. (2008). The mechano-regulatory model used in this study, proposed by Prendergast et al. (1997), predicts tissue differentiation based on local mechanical stimuli (fluid flow and tissue distortional strain) and the presence of precursor cells capable of differentiation (Fig. 2). Tissue ingrowth into the chamber was modeled by means of the migration of precursor cells, originating from the marrow surrounding the bone chamber. After each simulated loading event (corresponding to the loading protocol of the experiments), the mechanical stimuli were calculated from the finite element analysis, and, based on the maximum stimulus values encou nt er ed during this loading event, a new tissue phenotype was predicted according to the mechano-regulatory model. Adaptation of the material properties took place based upon the predicted phenotype, the local loading history, and the local concentration Figure 1. Bone chamber composition, protocol, and models. (A) Schematic drawing of the bone of precursor cells. [Additional information chamber (above) and the loading device and implant site (below). 1, outer bone chamber; 2, inon the simulation protocol can be found in ner bone chamber; 3, area for bone regeneration; 4, Teflon bearing; 5, implant; 6, piezo stack; 7, the Appendix and Lacroix and Prendergast load cell; 8, bone chamber; 9, proximal tibia; and 10, clamping device. (B) Harvested inner bone (2002).] chamber with indication of the analyzed sections (S1 to S5). (C) 3D finite element model of the tissue The experimental conditions modeled inside the chamber. (D) The boundary conditions for the FE analyses (u, displacement; p, pressure). in this study correspond to those reported (E) Illustration of the histomorphometric measurement bone area fraction (BAF). Scale bar = 500 m. previously (Vandamme et al., 2007a), Stevenels blue and Von Giesons picrofuchsin staining.

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predicted with the 2D simulations. Therefore, although not capable of capturing the local tissue distribution, 2D simulations are a sufficientand computationally less demandingmeasure for assessing the global behavior of the bone chamber under various loading conditions as performed in this study. Excessive implant displacements, ranging from 150 m to 500 m depending on the implants design and surface characteristics, have been shown to inhibit successful osseo integration (Pilliar et al., 1986; Sballe et al., 1992). Since the loading device used in the bone chamber experiments was limited to a maximal implant displacement of 90 m, these excessive implant displacements could only be explored with mathematical models. Comparison of experimental and numerical results for various implant displacements within the range of the loading device showed a good agreement between the two. Furthermore, the Figure 2. Simulation scheme for tissue differentiation. Each iteration starts with the determination experimental study by Duyck et al. of the mechanical stimuli in an FE analysis. MATLAB (v 7.1, The Mathworks Inc., Natick, MA, USA) (2004) showed that although the determines new phenotypes based on mechanical stimuli and determines, after averaging (rule of mixtures) and smoothing, new material properties. amount of bone formation in the chamber increased for higher implant absence of bone-to-implant contact and the occurrence of a displacements, this was not the case for the bone formation at fibrous tissue layer for the higher implant displacement magnithe implant surface, which was also observed in the simulatudes (Fig. 3B). The thickness of the fibrous tissue layer was tion results. These qualitative and quantitative agreements predicted to increase from 250 m, for a 150-m implant disoffer a positive prospect for the results obtained by extrapoplacement, up to 1 mm, for a 500-m implant displacement. lation to higher implant displacements beyond the limits of There was good agreement between the measured and calcuthe loading device. An implant displacement of 150 m was lated values of bone area fraction for implant displacement predicted to lead to a fair amount of bone still present in the magnitudes of 30, 60, and 90 m (Fig. 3C). The application of bone chamber. However, bone-to-implant contact could no different implant loading frequencies, ranging from 1 up to 20 longer be observed. A 250-m-thick layer of fibrous tissue Hz, showed a bone chamber filled mainly with soft tissue and a formed immediately at the implant interface. This weak tisdecrease in bone-to-implant contact for the highest loading sue shielded the other tissues in the bone chamber from the frequencies (Fig. 3D). implant surface. This provided a mechanically stable environment at the periphery of the implant, which favored the formation of bone tissue. This is in contrast to the 30-m DISCUSSION implant displacement case, where immediate bone- (and carAlthough the 2D axisymmetric model has been shown to be tilage-) to-implant contact was established. These stiffer tisable to capture the global bone area fraction in the bone chamsues transmitted the load directly from the implant to the ber (Geris et al., 2008), only the 3D model correctly predicted surrounding tissues, instead of shielding them from being the spatial distribution of the bone in the chamber. This could loaded, as in the case of the weaker fibrous tissue. The presbe attributed to the correct representation of the geometry of ence of such a fibrous tissue layer in clinical practice would the perforations. In the simplified axisymmetric model, there constitute a failed implant due to a lack of osseointegration. was a 360o opening in the chamber, whereas, in reality, there Further increasing the implant displacement up to 500 m led were only 3 oval perforations at 120o from each other. In a to an increase in the thickness of the fibrous tissue layer longitudinal plane through the implant axis and the middle of encapsulating the implant. a perforation (i.e., corresponding to the plane of the 2D axiIn recent decades, many studies have investigated the effect symmetric model), the tissue distribution pattern predicted of high-frequency loading/high loading rate on bone regenerawith the 3D model was not substantially different from the one tion in fracture healing (Usui et al., 1989; Goodship et al.,

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1998), bone adaptation in whole bones (Oxlund et al., 2003; Warden and Turner, 2004), and implant osseointegration (Usui et al., 1989; Rubin and McLeod, 1994; De Smet et al., 2007). No consensus has yet been reached on which frequency has an optimal effect on bone. An increased bone response (i.e., bone ingrowth into the porous coating of an implant) to 20 Hz has been reported (Rubin and McLeod, 1994), compared with 1 Hz loading. In those experiments, implants were loaded indirectly by the application of a bending load to the bone. In contrast, others investigated a cortical guinea pig model, where loading was directly applied to the implant, and found that a frequency of 3 Hz favored the osteogenic response over 30 Hz stimulation (De Smet et al., 2007). Since the bone chamber set-up is distinctly different from these experimental set-ups, in terms of both loading characteristics and initial biological environment, their results cannot be directly transferred to the implant osseointegration process in the bone chamber. The mathematical model was applied to test the effects of higher implant displacement frequencies in the bone chamber. These frequencies were predicted to lead to increased amounts Figure 3. Simulation results. (A) (left) Tissue distribution throughout the bone chamber, as predicted of soft tissue in the bone chamber and to by the tissue differentiation simulation for the 3D model after 9 wks of loading (30 m, 1 Hz, 400 a reduction in bone-to-implant contact. cycles, 3x/wk). The sections analyzed during the histology are indicated (S1-S5). (right) Comparison This is due to the poro-elastic nature of of the measured (mean SD; significant differences, p < 0.05, indicated by ; Vandamme et al., the tissues. For higher implant displace- 2007a) and predicted (with both 2D axisymmetric and 3D FE models) distribution of the bone area ment frequencies, higher pressure gra- fraction over the different sections. The numbers in parentheses are the numbers of animals used for dients are present, leading to higher each data block. (B) Simulation outcomes for different implant displacement magnitudes in the 2D axisymmetric model. (C) Comparison of the measured (mean SD; significant differences, p < 0.05, local fluid flow velocities, thereby indicated by ; Duyck et al., 2006) and predicted (in a 2D axisymmetric model) bone area fraction favoring the formation of soft tissue for different implant displacement magnitudes after 6 wks of loading (1 Hz, 800 cycles, 2x/wk). over bone. From these numerical exper- The numbers in parentheses are the numbers of animals used for each data block. (D) Simulation iments, it seems that lower implant outcomes for different implant displacement frequencies in the 2D axisymmetric model. loading frequencies in the bone chambiological factors by which the bone chamber environment difber favor osseointegration. Further experiments are required fers from fracture healing. The bone chamber provides a to verify the numerical predictions. mechanical environment that is much more isolated than the For an extensive discussion on the limitations of the experifracture callus, where a more continuous exposure to mechanimental set-up and the relation between the bone chamber and cal loading exists. Another explanation could be that the amount clinical practice, the reader is referred to Vandamme et al. of tissue damage induced during the installation of an inner bone (2007a,b,c). Limitations of the mathematical model used in this chamber is much lower than the amount of damage associated study are thoroughly discussed in Geris et al. (2008). One recurwith a fracture, possibly leading to a quite different inflammarent incongruity between the simulations and the experimental tory response and subsequent regeneration process (Barnes et observations is the prediction of cartilage formation in the bone al., 1999). Furthermore, the good vascularization of the bone chamber, whereas cartilage has never been observed experimenchamber may have favored direct bone formation over cartilage tally (Duyck et al., 2006, 2007; Vandamme et al., 2007a,b,c, formation (Street et al., 2002). Finally, it is likely that all of the 2008). The mechano-regulatory model has been corroborated biological factors that may have regulated tissue differentiation in most extensively by comparisons of simulation results to experthe bone chamber originated from the bone marrow as opposed to imental data from fracture healing studies. The absence of cartifracture healing, where the periosteum and the surrounding lage in the bone chamber may be related to mechanical and/or

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tissues also play an important role. Bone-marrow-derived cells have been observed to differentiate into osteoblasts during fracture repair (Taguchi et al., 2005). Adding biological regulators and regulatory mechanisms (e.g., growth factors, angiogenesis) to the mechano-regulatory model will allow these hypotheses to be investigated and may further enhance the models predictive capacities and its relevance to clinical practice. The configuration of the bone chamber and loading device allows for investigation of the effect of axial loading on periimplant bone formation exclusively. Non-axial implant loading is known to generate a distinct distribution of stress/strain in the surrounding tissues compared with axial loading, resulting in a different remodeling response (Barbier and Schepers, 1997; Barbier et al., 1998; Duyck et al., 2000) and significantly more initial bone loss compared with axial loading (Wyatt and Zarb, 2002). Whether the positive correlation between controlled axial implant loading and peri-implant bone formation (Duyck et al., 2006; Vandamme et al., 2007a,b,c, 2008; Geris et al., 2008) also applies to non-axial loading needs further investigation. The hypothesis that the mechano-regulatory model (Prendergast et al., 1997) is able to capture peri-implant bone regeneration for various loading conditions was confirmed. The model was able to predict essential aspects of peri-implant tissue formation inside an in vivo bone chamber, such as the amount of bone and the spatial distribution thereof. Subsequently, the model was applied to simulate extreme loading conditions. High implant displacement magnitudes, beyond the bone chambers capacity, were predicted to generate substantial soft-tissue encapsulation of the implant, corresponding to what has been reported in the literature. Numerical simulations further predict that higher implant displacement frequencies, unlike what has been suggested in the literature, do not have a beneficial effect on implant osseointegration in the bone chamber. These predictions need to be confirmed by additional bone chamber experiments.

ACKNOWLEDGMENTS
This study is supported by the Research Council K.U. Leuven (OT/02/50) and the Research Foundation Flanders (FWO Vlaanderen) (O6260). LG and JD are post-doctoral research fellows of the Research Foundation Flanders. KV is a postdoctoral research fellow of the Research Fund K.U. Leuven. This paper is based on (parts of) the theses submitted (by both K. Vandamme and L. Geris) to the graduate faculty of the K.U. Leuven, in partial fulfillment of the requirements for the PhD degree.

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ERRATUM
In the February issue of the article entitled Numerical Simulation of Bone Regeneration in a Bone Chamber, by L. Geris, K. Vandamme, I. Naert, J. Vander Sloten, J. Duyck, and H. Van Oosterwyck (J Dent Res 88:158-163, 2009), two blocks of text were inadvertently switched at printing. The text on the righthand side of page 159 should be switched with the text on the left-hand side of page 160. The online version of this paper has been corrected. The Publisher regrets this error.

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