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The influence of cyclic compression and distraction on the healing of experimental tibial fractures
ELSEVIER
Journal of Orthopaedic Research
Journal of Orthopaedic Research 22 (2004) 709-715
www.elsevier.comllocate/orthres
The influence of cyclic compression and distraction on the healing of experimental tibia1 fractures R. Hente
B. Fiichtmeier ', U. Schlegel b, A. Ernstberger
a,
S.M. Perren
Abstract Interfragmentary displacement has a main effect on callus formation in fracture healing. To test whether compressive or distractive displacements have a more pronounced effect on new bone formation, a sheep osteotomy model was created whereby the gap tissue was subjected to constant bending displacement. A diaphyseal osteotomy with a gap of 2 mm was created in 18 sheep tibiae and stabilized with a special unilateral actuator-driven external fixator. Two experimental groups with six sheep each received either 10 or 1000 cycles evenly distributed over 24 h. The third group of six sheep served as a control group without actively induced displacement. The amount and direction of cyclic displacement was kept constant throughout the observation period, resulting in 50% compressive and 50'%)distractive displacement within the osteotomy gap. At sacrifice, six weeks after surgery, bending stiffness was measured and new bone formation was assessed radiologically and microradiographically. In all cycled groups, the amount of periosteal callus formation was up to 25 times greater on the compression compared to the distraction side (p < 0.001). The application of the higher number of daily cycles resulted in an up to 10-fold greater amount of periosteal new bone formation on the compression side ( p < 0.012), while the difference on the distraction side was not significant. Ten cycles applied a day were sufficient to create an abundant periosteal callus on the compression side. In the 1000 cycle group, bending stiffness revealed slightly lower values but the difference was not significant. Solid periosteal bridging of the gap was observed in two sheep in the control group, whereas bridging in the cycled groups was observed exclusively at the medullary side. In conclusion, cyclic compressive displacements were found to be superior over distractive displacements. A higher number of enforced and maintained compressive displacements enhanced periosteal callus formation but did not allow bony bridging of the gap. 0 2003 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved. Krjworcls: Interfragmentary micromotion: Fracture healing: Fracture biomechanics; Callus formation: Animal model
Introduction The concept of biological osteosynthesis with minimal vascular damage and relative stability of fixation at the fracture site was introduced in the last decade [8,11,22,26]. In general, elastic fixation systems like intramedullary nailing or transcutaneously implanted plates are used to stabilize the main fragments and to regain the anatomical axes of the joint [2,10,15,17]. Early, sufficient callus generation is required to regain stiffness and to prevent fatigue failure of the implants [11,22]. Often, free fragments were left untouched in order to prevent additional vascular damage [17]. The *Corresponding author. Tel.: +49-941-944-6805; fax: +49-941-9446806. E-niuil udciress: [email protected] (R. Hente).
elastic fixation results in interfragmentary displacements during functional loading. Therefore, bending displacement between the fragments occurs, resulting in cyclic distractive as well as compressive interfragmentary displacements. The mechanical environment, especially the amount of interfragmentary displacement, has a decisive effect on the amount of callus formation [ 19,23,24]. As far as compressive interfragmentary micromotion is concerned, it has been shown that active displacements applied daily can enhance fracture healing [4,9,27,29]. However, little experimental data is available on the effects of distractive cyclic displacements on fracture healing. Augat et al. [I] have found no significant enhancement of periosteal bone healing under cyclic distractive displacement. Furthermore, Matsushita and Kurokawa [18] did not find any difference in fracture healing when comparing cyclic compressive versus distractive
0736-02661$ - see front matter 0 2003 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved doi: 10.1016lj.orthres.2003.11.007
displacements. In all these and other [4] experimental models, the interfragmentary displacement was loadcontrolled. Therefore, the actively induced interfragmentary displacement diminished with time due to the increasing stiffness of the newly formed interfragmentary callus [5,20,29], resulting in changing mechanical conditions during the experiment. Hence, the interpretation of the main tissue response to compressive versus distractive displacements and frequency of cyclic displacement is uncertain. We tested the hypothesis that forced compressive displacement has a superior effect on callus formation in relation to distractive displacement. An animal model was designed using elastic external fixation where bending displacements were actively imposed and enforced over the whole observation period. Thus, a compressive and distractive displacement inside the same osteotomy gap was created.
Materials and methods Aiiimal
iiiotld
The effect of controlled interfragmentary bending displacement on osteotomy repair was investigated in sheep tibiae. The amount of displacement was enforced and maintained over the whole observation period of six weeks. An actuator-driven and instrumented unilateral external fixator achieved bending of the fracture with the fulcrum in the middle of the osteotomy gap (Fig. I). The actuator created a bending moment of 22.5 N i n to secure that displacement of the fragments was not overcome by soft tissue hardening. Each displacement started from the neutral position of a 2 mm parallel osteotomy gap so that the near side of the gap was widened to 3 inm and the far side of the gap was closed to 1 mm. Eighteen sheep were randomly assigned to three groups. The first group (C0) served as a control without active displacement. In the second group (CIO), 10 cycles. and
in the third group (CIOOO) 1000 cycles of interfragmentary displacement per day were enforced by the actuator. The cycles in each group were evenly distributed over 24 h. The pulse duration of one cycle was 0.8 s in all groups. At weekly intervals starting after operation, radiographs (55 kV. 16 mAs) at the neutral and at the peak position of one cycle were obtained using a guide to reproduce positioning.
Surgii,cil procrthrre and upplicarion o f rlie esternal,fi.~utor All protocols for the animal study were approved by the Swiss federal commission. The sheep (average weight 62 2 8 kg) were operated on the right tibia under sterile conditions using general anesthesia. The special external fixator was implanted along the anteromedial plane using a guide to reproduce the identical geometrical position and orientation of the pins. A skin incision of approximately 6 cm length was made over the medial aspect of the tibia near the fulcrum of bending and the soft tissues were dissected. The periosteum was carefully exposed and a circular incision was made through it. Using a guide, a transverse osteotomy was performed exactly between the inner pins under constant cooling using Ringer solution. The external fixator was then mounted close to the bone at a distance of 20 min. At the cnd of the operation, a patellar tendon-tenotomy was performed to prevent result of uncontrolled animal reaction. For the same purpose, the sheep were kept in single pens postoperatively and protected by a loosely adapted harness in which they could lay down to rest. To determine the axial stiffness, the external fixator was mounted on a freshly explanted, dissected and osteotomized sheep tibia, whereby the geometrical configuration of the system and the gap were reproduced. The construct was then placed in a material testing machine and a load of up to 300 N was applied to the proximal fragment along the long axis of the bone to calculate axial stiffness.
E v c i w hetitling stiffI7ms The bending stiffness of the operated tibia and of the intact contralateral tibia was measured in a non-destructive four-point-bending test using a mechanical testing machine (Instron 4200 Series, Instron, Canton, MA, USA). The ends of the tibiae were embedded in methylmethacrylate and mounted in metal tubes. A free bone length of 100 mni remained between both cylinders with the osteotomy gap centered. After applying a preload of 1 N, a non-destructive measurement of bending stiffness was performed. using a deflection rate of 2 mmlmin up to a maximum force of 60 N, equivalent to a bending moment of 1 .S N in. Each specimen was tested in both directions of the axis of the external fixator and perpendicular to it (anteromedial to posterolateral and anterolateral to posteromedial, respectively). For each orientation, the bending stiffness was calculated. The average value of the four tests was used for analysis. The contralateral non-operated control tibiae were prepared and measured in a similar manner to calculate relative stiffness.
Rurliogrtipliic eraluatioti
Fig. I . Diagram of the experimental setup. The movement of the fragments is created by the external fixator. The four bar linkage creates a bending movement with the center of rotation inside the gap. perpendicular to the longitudinal axis of the bone. Thus, compressive on the far side and distractive displacement on the near side of the external fixator is created. With every cycle, the gap is closed by 50% and opened by 50% in relation to the original gap width. The amount of interfragmentary displacement is maintained over the whole observation period of six weeks.
The amount of projected new periosteal callus formation was measured using a digital subtraction radiography technique. The standardized radiographs were digitized with a digital image analysis system (IMCO 1000, Kontron AG, Eching. Germany). For each sheep, the image of the postoperative radiograph was subtracted from the radiograph obtained after the sixth week to normalize individual variation and to focus on fracture repair differences during the test period. The circumference of the periosteal callus outside the original cortex was outlined and the lower threshold of grey-level manually set to mark all newly formed periosteal callus. The area of projected callus formation was then digitally marked and measured. Two regions of interest were established, one on the periosteal side near the external fixator, representing the distraction area. and the other on the opposite side, representing the compression area.
Microrrrdiiograpliic evulirrrtion After non-destructive mechanical testing, the central section was fixed in 4% formalin solution for 72 h, dehydrated and embedded in
methylmethacrylate. A longitudinal undecalcified section of 300 pm thickness was taken from the central part of the gap, while ensuring a parallel cut in the plane of the external fixator. The section was ground down to 100 pm thickness (Zeiss precision saw, Zeiss, Wetzlar, Germany) and high-resolution radiographs (AGFA DCfilm, 55 kV) were taken (Faxitron Model 43855A. Faxitron X-ray corporation, Illinois, USA). Thereafter, the radiographs were digitized using a transmitting light scanner (Epson 1680 Pro, Epson Incorporation. USA) with a resolution of 2400 dpi. The periosteal and endosteal new bone formation was determined by using a grey-level threshold to differentiate between new bone and background noise. Quantitative measurernents (Image-Pro Plus, Media Cybernatics Inc.. Silver Spring, MD, USA) in different areas were performed. The first area represented the far side (compression), the second area represented the near side outside the original cortex (distraction) and the third area represented intramedullary new hone formation between the original cortices. Qualitative evaluation of the microradiographic sections was carried out for the location and extent of the new bone formation. In the central microradiographic section of each sheep, bridging of the gap o n the near and the far sides, though separated into periosteal and endosteal bridging, was assessed as continuity of woven bone.
S/u/i.v/ku/unrrlj,.si.s Statistical differences between the groups were obtained by a oneway analysis of variance followed by the least-significant-difference method of multiple comparisons (one-way ANOVA, Tukey-test) to calculate the level of significance of the measured differences among the treatment groups. The maximum and minimum p-values are given whenever beveral groups were compared. If the p-value was more than 0.05, the specific p-value is only given if two groups were compared. Determination of statistically significant differences within specimens was done using a paired t-test. In all tests, the significance level was set to 0.05. All statistical evaluations were done with SPSS-Software (SPSS Inc.. Chicago, USA).
Results
CIinicul ohser v a t ion In all groups postoperative clinical recovery was uneventful. From the third week on, when healing of the tenotomy had advanced, the sheep started to put partial weight on the operated leg. One of the sheep from the 1000 cycle group had to be excluded from the experiment due to infection around the proximal pins with consequent complete pin loosening after three weeks. Mechunicul property o j the externulJixutor The in vitro testing of the external fixator showed a mean axial stiffness of 1666 ? 35 N/mm. Therefore, at a load of 400-600 N, equal to the weight of a sheep, and with every fully functional loading cycle a displacement could be estimated of between 0.22 and 0.38 mm (11% and 19%)of gap closure, respectively).
Ex vivo bending stiffness After six weeks, the mean value of absolute as well as relative bending stiffness revealed similar values with slightly lower values for the 1000 cycle group (absolute values: 124 k 75, 106 k 64 and 89 ? 40 N/mm; relative
250 0
200
0
0
150 -
E
E
2 700
-
50
-
04
0 Cycles
10 Cycles
1000 Cycles
Fig. 2. Boxplots of bending stiffness [Nlmm] of the different treatment groups at six weeks. With increasing numbers of cycles applied daily, bending slightly decreases without significant difference. Outer lines represent 75th percentile, inner line represents median value, and thick line represents mean value.
values: 24 k I3%, 25 ? 14% and 18 ? 8% for the CO, C 10 and ClOOO group, respectively; p > 0.59) (Fig. 2). Radiological eculuution In the radiological evaluation all tibiae showed secondary bone healing. The evaluation of the projected callus area showed significant differences between all groups in the amount of new bone formation on the compression side (Fig. 3). With a higher number of cyclic displacements applied daily, the amount of periosteal new bone formation on the compression side was significantly greater (0.001 < p < 0.012, Table 1). On the compression side the radiological area of periosteal new bone formation was more than 10 times higher in the 1000 cycle group compared with the control group ( p < 0.001, Table 1). However, the 10 cycle group showed half the amount of periosteal new bone forrnation when compared to the 1000 cycle group (p = 0.004). On the distraction side, the 10 and 1000 cycle group, on average, only showed a slight tendency to a more pronounced periosteal callus in relation to the control group (p = 0.10). Comparison of compression and distraction in each animal revealed significantly more periosteal new bone formation on the compression side, showing significant data in the cycled groups (p-values of CO = 0.039, C10 = 0.001 and ClOOO = 0.003, respectively). The mean ratio between compression and distraction was similar in all cycled groups. Callus production was about twenty five times higher on the compression side compared with the distraction side (Table 1). In the control group the distribution of callus development was not uniform, showing significantly more callus at the far cortex compared to the near cortex ( p = 0.039).
712
0 cycles
1000 cycles
10 cycles
Fig. 3. Typical radiographs from digital subtraction analysis and corresponding central microradiographic section of the tibiae. In all groups periosteal callus formation is significantly increased on the far side of the external fixator (right side of the bone), where compressive displacement was induced. Only a small amount of periosteal callus formation was observed on the distraction side. With a higher number of applied cycles, the amount of periosteal callus formation is increased, but bridging of the gap only occurs in the active groups on the medullary side. In the control group, the amount of periosteal callus formation was higher on the far side where the amount of interfragmentary displacement due to functional loading of the leg was higher.
Table 1 New bone formation as determined from radiographs and from central microradiographic sections at six weeks Number of cycles/day
Area ol' callus formation from digital subtraction analysis (mm')
Area of new bone formation from central microradiographic section ( m i d )
Near (distr.)
Near (distr.)
Far (compr.)'l
Sum'
Far (compr.)'
Medullary
30.5? 25.6 4.4 k 4.0 22.8 2 17.5 18.2 k 9.5 1.2 ? 1.8' 29.2 ? 23.8 77.3 ? 38.2 49.6 k 28.2 6.7 ? 6.0" I56.0? 43.3 169.4 f 46.9 8.7? 6.7d 1 2 . 8 f 14.0d 326.6 f 90.8 339.4 k 90.8 13.9f 15.0d 168.3? 73.2 57.9 k 54.0 Mean valueskSD; compr.: Compression side: distr.: Distraction side in the 10 and 1000 cycle groups. "Significant difference between all groups (0.001 < p < 0.012). 'Group C0 differ-s from group ClOOO ( p < 0.001), Group C10 differs from group Cl000 (JJ<0.026). c p = 0.039. Intraindividual significant differences between the Far (compression) and near (distraction) sides (0.001 < p < 0.01). 0 cycles IZ = 6 10 cycles n = 6 1000 cycles 11 = 5
Micro rudiogruph ic P uuluut ion
The radiological data was confirmed by the microradiographic evaluation, revealing higher mean values of periosteal new bone formation on the compression side, the higher the number of cyclic displacements applied (Table 1). Significant differences were found between the control group and the 1000 cycle group (p < 0.001) and between the 10 cycle and the 1000 cycle group (p = 0.01 1). On the distraction side, in all cycled groups new bone formation revealed small values without significant differences (Table 1). In the control group
Sumb 54.5 f 19.6 129.7 f 67.3 233.6k 79.7
(CO), only a small amount of periosteal bone formation was seen in 4 out of 6 sheep. Also, microradiographic comparison of the compression versus distraction side in each sheep revealed large differences in the amount of new bone formation. In all cycled groups, periosteal callus formation on the compression side was about 10 times as high as on the distraction side (p < 0.001, Fig. 3, Table 1). In the control group, a more pronounced callus was seen at the far cortex (p = 0.058). The amount of medullary new bone formation showed a tendency to a higher mean value in the cycled groups compared with the control
R. Hente et ul. I Joiirnul oJ Ortliopciedic Reseurcli 22 (2004) 709-715
713
Table 2 Evaluation of gap bridging from the central microradiographic sections Group with number of cycleslday
Near cortex (distraction)
Far cortex (compression)
Periosteal
Endosteal
Endosteal
Sum
Periosteal
0 cycles n = 6 0 4 4 2 10 10 cycles n = 6 0 1 4 0 5 1000 cycles n = 5 0 1 3 0 4 Qualitative evaluation of gap bridging at different locations is shown as determined from central microradiographic sections. Numbers represent counts of specimen regions revealing solid bridging of the individual location.
group but without significant differences (Table I , p = 0.16). Qualitative testing of gap bridging revealed that bridging most often occurred in the endosteal region with prevalence at the far cortex (Table 2, Fig. 3). In the cycled groups (C10 and ClOOO) the number of bridging areas on the endosteal side was lower compared with the control group. No sheep showed bridging of the periosteal side of the near cortex, but bridging was observed in 2 sheep of the 0 cycle control group at the far cortex.
Discussion The aim of our study was to test the different influences of the cyclic compressive and distractive displacements that were enforced and maintained. We selected 0, 10 and 1000 cycles a day, superimposed on a somewhat flexible fracture fixation. Fracture healing by callus formation normally happens when the periosteal callus becomes stiffer, reducing interfragmentary movement while the loading amplitude is kept constant. Therefore, the interfragmentary displacement depends on the changing stiffness of the interfragmentary tissue. To study the effect of a given amount of displacement, its amplitude was kept constant over the whole observation period. Therefore, the current model allows observation of the effect of displacement in early fracture repair but does not allow final bridging. This is important for the evaluation of bending stiffness which is expected to be lower in the cycled groups due to constant displacements. Due to the short period of one cycle (0.8 s), it can be assumed that the effective neutral position of the system is similar to the rest position. We keep in mind that in our model the same amount of displacement (1 mm) under opening and closure of the gap results in the same amount of engineering strain but is different to true strain. At 5Ooh gap displacement, the true strain on the distraction side would be about 0.4 and about 0.7 on the compression side. This results in a higher strain level on the compression side compared to the distraction side. Additionally, three-dimensional distribution of strain levels can be expected and may lead to severe local strain variations inside each given gap displacement [7].
Therefore, the effective local strain that acts at the cell level may not be determined [21] and the relative gap closure does not linearly represent the amount of strain level. The elastic behaviour of the external fixator with the asymmetric geometry has produced a higher interfragmentary compressive displacement on the far side of the cortex compared to the near side. The amount of displacement due to functional loading could be estimated by the free length of pin visible outside the external fixator. If a linear elastic bending pattern is assumed, the amount of displacement on the far cortex will be one half higher than on the near cortex. The mean displacement during functional loading was measured to be between 11% and 19%) of gap width. Therefore, the relative gap displacement during functional loading on the near cortex can be assumed to be between 8%)and 13%)and on the far cortex between 15'% and 25%. This may explain why callus formation was also observed in the control group. The distribution of the callus was asymmetrical showing more than five times the amount of callus formation on the far side. Bridging of the fracture was observed mainly in the control group, but only on the far side. The smaller amount of displacement below 13% on the near side seemed to have too small an effect to allow bridging of the gap. It has been proposed that fluid flow at the fracture gap may play an important role in fracture healing [14,25]. In our experimental setup, two effects of volume change can be assumed. At the times when no active cycles are applied, small cyclic compressive displacements occur in all groups during functional loading due to the deformability of the external fixator. This causes the osteotomy site contents to be flushed in and out of the osteotomy. However, during each active cycle, the volume of the interfragmentary space will not change significantly, but the fluid will be slewed from one side to the other. Therefore, not only volume changes, but also the reallocation of the fluid due to displacements seems to have an important effect on the amount of callus formation. A further factor that might have an effect on the superior amount of new bone formation may be the higher degree of soft tissue coverage of the tibia on the posterolateral side, as has been observed in other experiments [I ,4].
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The aspect of compression versus distraction side revealed a clear difference in the cycled groups, showing highly significant enhancement of new bone formation on the compression side. In the literature, few data about different effects relating to cyclic compression and distraction are available and the results are contradictory. Matsushita and Kurokawa [ 181 applied either distractive or compressive displacements in a rabbit osteotomy model with a 3 mm gap size and found the same enhancement in fracture healing for both application modes. However, the elastic external fixator with thin pins that they used may also have led to significant compressivc displacements during functional loading and may have had a superior effect compared to the actively applied distractive displacements. In contrast, Augat et al. [I] did not find enhanced fracture healing in a sheep osteotomy model with a gap size of 2 mm after applying 500 cycles a day of only distractive displacement of either 0.2 or 0.8 mm, respectively. They found only a small increase of periosteal callus formation with a larger displacement magnitude, but without statistical significance. This is similar to our results, showing a slightly increased callus formation with a higher number of distractive cycles. However, the effect of distractive displacements on periosteal bone formation can be somewhat neglected in comparison to the significant increase in bone formation on the compression side that was about ten times higher in all cycled groups. These results strongly support the theoretical considerations and experimental findings [3,6,9,16,28,29] that compressive cyclic displacement is one of the most important factor in the production of new bone. The bending stiffness at six weeks showed slightly lower values if 1000 cycles were applied. At first glance, these results seem to be contradictory to other experiments that have shown increasing fracture stiffness with active cyclic displacements of the fracture [9,12,13]. In contrast to these, the amplitude of cyclic displacement was kept constant in the present study. Thus, the natural fracture healing that relies on increasing callus stiffness and subsequent reduction of interfragmentary displacement was prevented [19]. The applied load of the pneumatic system was high enough to maintain constant displacement of the fragments. Hence, every cyclic displacement to the end position may have constantly damaged the fibrils inside the periosteal callus, resulting in repeated breakage of the structure that otherwise would have contributed to a higher amount of bending stiffness. In conclusion, maintained compressive displacement during the first six weeks produced a higher amount of new bone formation whereas distractive displacement did not revealed a significant increase of new bone formation. With a higher number of compressive cycles a higher amount of periosteal new bone formation was observed. Ten cycles a day were enough to produce a
distinct amount of periosteal callus. Under constant displacements of the fragments the incidence of bony bridging diminished and bending stiffness was lower. Repeatedly enforced interfragmentary displucements at constant amplitude up to the sixth week did not allow bony bridging but was chosen to study the effect of standardized displacement. If interfragmentary compressive displacement were too small as, for example, on the near side of the gap in our control group, induction of callus formation may be too small to induce sound bridging of the fracture gap.
Acknowledgements
This project was supported by the AO-Research Foundation, Switzerland. The authors are grateful to S. Tepic, PhD for his excellent engineering contribution, to D. Wahl for help in mechanical testing, and to R. Wieling for his assistance in surgery.
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Journal of Orthopaedic Research
Journal of Orthopaedic Research 22 (2004) 709-715
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The influence of cyclic compression and distraction on the healing of experimental tibia1 fractures R. Hente
B. Fiichtmeier ', U. Schlegel b, A. Ernstberger
a,
S.M. Perren
Abstract Interfragmentary displacement has a main effect on callus formation in fracture healing. To test whether compressive or distractive displacements have a more pronounced effect on new bone formation, a sheep osteotomy model was created whereby the gap tissue was subjected to constant bending displacement. A diaphyseal osteotomy with a gap of 2 mm was created in 18 sheep tibiae and stabilized with a special unilateral actuator-driven external fixator. Two experimental groups with six sheep each received either 10 or 1000 cycles evenly distributed over 24 h. The third group of six sheep served as a control group without actively induced displacement. The amount and direction of cyclic displacement was kept constant throughout the observation period, resulting in 50% compressive and 50'%)distractive displacement within the osteotomy gap. At sacrifice, six weeks after surgery, bending stiffness was measured and new bone formation was assessed radiologically and microradiographically. In all cycled groups, the amount of periosteal callus formation was up to 25 times greater on the compression compared to the distraction side (p < 0.001). The application of the higher number of daily cycles resulted in an up to 10-fold greater amount of periosteal new bone formation on the compression side ( p < 0.012), while the difference on the distraction side was not significant. Ten cycles applied a day were sufficient to create an abundant periosteal callus on the compression side. In the 1000 cycle group, bending stiffness revealed slightly lower values but the difference was not significant. Solid periosteal bridging of the gap was observed in two sheep in the control group, whereas bridging in the cycled groups was observed exclusively at the medullary side. In conclusion, cyclic compressive displacements were found to be superior over distractive displacements. A higher number of enforced and maintained compressive displacements enhanced periosteal callus formation but did not allow bony bridging of the gap. 0 2003 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved. Krjworcls: Interfragmentary micromotion: Fracture healing: Fracture biomechanics; Callus formation: Animal model
Introduction The concept of biological osteosynthesis with minimal vascular damage and relative stability of fixation at the fracture site was introduced in the last decade [8,11,22,26]. In general, elastic fixation systems like intramedullary nailing or transcutaneously implanted plates are used to stabilize the main fragments and to regain the anatomical axes of the joint [2,10,15,17]. Early, sufficient callus generation is required to regain stiffness and to prevent fatigue failure of the implants [11,22]. Often, free fragments were left untouched in order to prevent additional vascular damage [17]. The *Corresponding author. Tel.: +49-941-944-6805; fax: +49-941-9446806. E-niuil udciress: [email protected] (R. Hente).
elastic fixation results in interfragmentary displacements during functional loading. Therefore, bending displacement between the fragments occurs, resulting in cyclic distractive as well as compressive interfragmentary displacements. The mechanical environment, especially the amount of interfragmentary displacement, has a decisive effect on the amount of callus formation [ 19,23,24]. As far as compressive interfragmentary micromotion is concerned, it has been shown that active displacements applied daily can enhance fracture healing [4,9,27,29]. However, little experimental data is available on the effects of distractive cyclic displacements on fracture healing. Augat et al. [I] have found no significant enhancement of periosteal bone healing under cyclic distractive displacement. Furthermore, Matsushita and Kurokawa [18] did not find any difference in fracture healing when comparing cyclic compressive versus distractive
0736-02661$ - see front matter 0 2003 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved doi: 10.1016lj.orthres.2003.11.007
displacements. In all these and other [4] experimental models, the interfragmentary displacement was loadcontrolled. Therefore, the actively induced interfragmentary displacement diminished with time due to the increasing stiffness of the newly formed interfragmentary callus [5,20,29], resulting in changing mechanical conditions during the experiment. Hence, the interpretation of the main tissue response to compressive versus distractive displacements and frequency of cyclic displacement is uncertain. We tested the hypothesis that forced compressive displacement has a superior effect on callus formation in relation to distractive displacement. An animal model was designed using elastic external fixation where bending displacements were actively imposed and enforced over the whole observation period. Thus, a compressive and distractive displacement inside the same osteotomy gap was created.
Materials and methods Aiiimal
iiiotld
The effect of controlled interfragmentary bending displacement on osteotomy repair was investigated in sheep tibiae. The amount of displacement was enforced and maintained over the whole observation period of six weeks. An actuator-driven and instrumented unilateral external fixator achieved bending of the fracture with the fulcrum in the middle of the osteotomy gap (Fig. I). The actuator created a bending moment of 22.5 N i n to secure that displacement of the fragments was not overcome by soft tissue hardening. Each displacement started from the neutral position of a 2 mm parallel osteotomy gap so that the near side of the gap was widened to 3 inm and the far side of the gap was closed to 1 mm. Eighteen sheep were randomly assigned to three groups. The first group (C0) served as a control without active displacement. In the second group (CIO), 10 cycles. and
in the third group (CIOOO) 1000 cycles of interfragmentary displacement per day were enforced by the actuator. The cycles in each group were evenly distributed over 24 h. The pulse duration of one cycle was 0.8 s in all groups. At weekly intervals starting after operation, radiographs (55 kV. 16 mAs) at the neutral and at the peak position of one cycle were obtained using a guide to reproduce positioning.
Surgii,cil procrthrre and upplicarion o f rlie esternal,fi.~utor All protocols for the animal study were approved by the Swiss federal commission. The sheep (average weight 62 2 8 kg) were operated on the right tibia under sterile conditions using general anesthesia. The special external fixator was implanted along the anteromedial plane using a guide to reproduce the identical geometrical position and orientation of the pins. A skin incision of approximately 6 cm length was made over the medial aspect of the tibia near the fulcrum of bending and the soft tissues were dissected. The periosteum was carefully exposed and a circular incision was made through it. Using a guide, a transverse osteotomy was performed exactly between the inner pins under constant cooling using Ringer solution. The external fixator was then mounted close to the bone at a distance of 20 min. At the cnd of the operation, a patellar tendon-tenotomy was performed to prevent result of uncontrolled animal reaction. For the same purpose, the sheep were kept in single pens postoperatively and protected by a loosely adapted harness in which they could lay down to rest. To determine the axial stiffness, the external fixator was mounted on a freshly explanted, dissected and osteotomized sheep tibia, whereby the geometrical configuration of the system and the gap were reproduced. The construct was then placed in a material testing machine and a load of up to 300 N was applied to the proximal fragment along the long axis of the bone to calculate axial stiffness.
E v c i w hetitling stiffI7ms The bending stiffness of the operated tibia and of the intact contralateral tibia was measured in a non-destructive four-point-bending test using a mechanical testing machine (Instron 4200 Series, Instron, Canton, MA, USA). The ends of the tibiae were embedded in methylmethacrylate and mounted in metal tubes. A free bone length of 100 mni remained between both cylinders with the osteotomy gap centered. After applying a preload of 1 N, a non-destructive measurement of bending stiffness was performed. using a deflection rate of 2 mmlmin up to a maximum force of 60 N, equivalent to a bending moment of 1 .S N in. Each specimen was tested in both directions of the axis of the external fixator and perpendicular to it (anteromedial to posterolateral and anterolateral to posteromedial, respectively). For each orientation, the bending stiffness was calculated. The average value of the four tests was used for analysis. The contralateral non-operated control tibiae were prepared and measured in a similar manner to calculate relative stiffness.
Rurliogrtipliic eraluatioti
Fig. I . Diagram of the experimental setup. The movement of the fragments is created by the external fixator. The four bar linkage creates a bending movement with the center of rotation inside the gap. perpendicular to the longitudinal axis of the bone. Thus, compressive on the far side and distractive displacement on the near side of the external fixator is created. With every cycle, the gap is closed by 50% and opened by 50% in relation to the original gap width. The amount of interfragmentary displacement is maintained over the whole observation period of six weeks.
The amount of projected new periosteal callus formation was measured using a digital subtraction radiography technique. The standardized radiographs were digitized with a digital image analysis system (IMCO 1000, Kontron AG, Eching. Germany). For each sheep, the image of the postoperative radiograph was subtracted from the radiograph obtained after the sixth week to normalize individual variation and to focus on fracture repair differences during the test period. The circumference of the periosteal callus outside the original cortex was outlined and the lower threshold of grey-level manually set to mark all newly formed periosteal callus. The area of projected callus formation was then digitally marked and measured. Two regions of interest were established, one on the periosteal side near the external fixator, representing the distraction area. and the other on the opposite side, representing the compression area.
Microrrrdiiograpliic evulirrrtion After non-destructive mechanical testing, the central section was fixed in 4% formalin solution for 72 h, dehydrated and embedded in
methylmethacrylate. A longitudinal undecalcified section of 300 pm thickness was taken from the central part of the gap, while ensuring a parallel cut in the plane of the external fixator. The section was ground down to 100 pm thickness (Zeiss precision saw, Zeiss, Wetzlar, Germany) and high-resolution radiographs (AGFA DCfilm, 55 kV) were taken (Faxitron Model 43855A. Faxitron X-ray corporation, Illinois, USA). Thereafter, the radiographs were digitized using a transmitting light scanner (Epson 1680 Pro, Epson Incorporation. USA) with a resolution of 2400 dpi. The periosteal and endosteal new bone formation was determined by using a grey-level threshold to differentiate between new bone and background noise. Quantitative measurernents (Image-Pro Plus, Media Cybernatics Inc.. Silver Spring, MD, USA) in different areas were performed. The first area represented the far side (compression), the second area represented the near side outside the original cortex (distraction) and the third area represented intramedullary new hone formation between the original cortices. Qualitative evaluation of the microradiographic sections was carried out for the location and extent of the new bone formation. In the central microradiographic section of each sheep, bridging of the gap o n the near and the far sides, though separated into periosteal and endosteal bridging, was assessed as continuity of woven bone.
S/u/i.v/ku/unrrlj,.si.s Statistical differences between the groups were obtained by a oneway analysis of variance followed by the least-significant-difference method of multiple comparisons (one-way ANOVA, Tukey-test) to calculate the level of significance of the measured differences among the treatment groups. The maximum and minimum p-values are given whenever beveral groups were compared. If the p-value was more than 0.05, the specific p-value is only given if two groups were compared. Determination of statistically significant differences within specimens was done using a paired t-test. In all tests, the significance level was set to 0.05. All statistical evaluations were done with SPSS-Software (SPSS Inc.. Chicago, USA).
Results
CIinicul ohser v a t ion In all groups postoperative clinical recovery was uneventful. From the third week on, when healing of the tenotomy had advanced, the sheep started to put partial weight on the operated leg. One of the sheep from the 1000 cycle group had to be excluded from the experiment due to infection around the proximal pins with consequent complete pin loosening after three weeks. Mechunicul property o j the externulJixutor The in vitro testing of the external fixator showed a mean axial stiffness of 1666 ? 35 N/mm. Therefore, at a load of 400-600 N, equal to the weight of a sheep, and with every fully functional loading cycle a displacement could be estimated of between 0.22 and 0.38 mm (11% and 19%)of gap closure, respectively).
Ex vivo bending stiffness After six weeks, the mean value of absolute as well as relative bending stiffness revealed similar values with slightly lower values for the 1000 cycle group (absolute values: 124 k 75, 106 k 64 and 89 ? 40 N/mm; relative
250 0
200
0
0
150 -
E
E
2 700
-
50
-
04
0 Cycles
10 Cycles
1000 Cycles
Fig. 2. Boxplots of bending stiffness [Nlmm] of the different treatment groups at six weeks. With increasing numbers of cycles applied daily, bending slightly decreases without significant difference. Outer lines represent 75th percentile, inner line represents median value, and thick line represents mean value.
values: 24 k I3%, 25 ? 14% and 18 ? 8% for the CO, C 10 and ClOOO group, respectively; p > 0.59) (Fig. 2). Radiological eculuution In the radiological evaluation all tibiae showed secondary bone healing. The evaluation of the projected callus area showed significant differences between all groups in the amount of new bone formation on the compression side (Fig. 3). With a higher number of cyclic displacements applied daily, the amount of periosteal new bone formation on the compression side was significantly greater (0.001 < p < 0.012, Table 1). On the compression side the radiological area of periosteal new bone formation was more than 10 times higher in the 1000 cycle group compared with the control group ( p < 0.001, Table 1). However, the 10 cycle group showed half the amount of periosteal new bone forrnation when compared to the 1000 cycle group (p = 0.004). On the distraction side, the 10 and 1000 cycle group, on average, only showed a slight tendency to a more pronounced periosteal callus in relation to the control group (p = 0.10). Comparison of compression and distraction in each animal revealed significantly more periosteal new bone formation on the compression side, showing significant data in the cycled groups (p-values of CO = 0.039, C10 = 0.001 and ClOOO = 0.003, respectively). The mean ratio between compression and distraction was similar in all cycled groups. Callus production was about twenty five times higher on the compression side compared with the distraction side (Table 1). In the control group the distribution of callus development was not uniform, showing significantly more callus at the far cortex compared to the near cortex ( p = 0.039).
712
0 cycles
1000 cycles
10 cycles
Fig. 3. Typical radiographs from digital subtraction analysis and corresponding central microradiographic section of the tibiae. In all groups periosteal callus formation is significantly increased on the far side of the external fixator (right side of the bone), where compressive displacement was induced. Only a small amount of periosteal callus formation was observed on the distraction side. With a higher number of applied cycles, the amount of periosteal callus formation is increased, but bridging of the gap only occurs in the active groups on the medullary side. In the control group, the amount of periosteal callus formation was higher on the far side where the amount of interfragmentary displacement due to functional loading of the leg was higher.
Table 1 New bone formation as determined from radiographs and from central microradiographic sections at six weeks Number of cycles/day
Area ol' callus formation from digital subtraction analysis (mm')
Area of new bone formation from central microradiographic section ( m i d )
Near (distr.)
Near (distr.)
Far (compr.)'l
Sum'
Far (compr.)'
Medullary
30.5? 25.6 4.4 k 4.0 22.8 2 17.5 18.2 k 9.5 1.2 ? 1.8' 29.2 ? 23.8 77.3 ? 38.2 49.6 k 28.2 6.7 ? 6.0" I56.0? 43.3 169.4 f 46.9 8.7? 6.7d 1 2 . 8 f 14.0d 326.6 f 90.8 339.4 k 90.8 13.9f 15.0d 168.3? 73.2 57.9 k 54.0 Mean valueskSD; compr.: Compression side: distr.: Distraction side in the 10 and 1000 cycle groups. "Significant difference between all groups (0.001 < p < 0.012). 'Group C0 differ-s from group ClOOO ( p < 0.001), Group C10 differs from group Cl000 (JJ<0.026). c p = 0.039. Intraindividual significant differences between the Far (compression) and near (distraction) sides (0.001 < p < 0.01). 0 cycles IZ = 6 10 cycles n = 6 1000 cycles 11 = 5
Micro rudiogruph ic P uuluut ion
The radiological data was confirmed by the microradiographic evaluation, revealing higher mean values of periosteal new bone formation on the compression side, the higher the number of cyclic displacements applied (Table 1). Significant differences were found between the control group and the 1000 cycle group (p < 0.001) and between the 10 cycle and the 1000 cycle group (p = 0.01 1). On the distraction side, in all cycled groups new bone formation revealed small values without significant differences (Table 1). In the control group
Sumb 54.5 f 19.6 129.7 f 67.3 233.6k 79.7
(CO), only a small amount of periosteal bone formation was seen in 4 out of 6 sheep. Also, microradiographic comparison of the compression versus distraction side in each sheep revealed large differences in the amount of new bone formation. In all cycled groups, periosteal callus formation on the compression side was about 10 times as high as on the distraction side (p < 0.001, Fig. 3, Table 1). In the control group, a more pronounced callus was seen at the far cortex (p = 0.058). The amount of medullary new bone formation showed a tendency to a higher mean value in the cycled groups compared with the control
R. Hente et ul. I Joiirnul oJ Ortliopciedic Reseurcli 22 (2004) 709-715
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Table 2 Evaluation of gap bridging from the central microradiographic sections Group with number of cycleslday
Near cortex (distraction)
Far cortex (compression)
Periosteal
Endosteal
Endosteal
Sum
Periosteal
0 cycles n = 6 0 4 4 2 10 10 cycles n = 6 0 1 4 0 5 1000 cycles n = 5 0 1 3 0 4 Qualitative evaluation of gap bridging at different locations is shown as determined from central microradiographic sections. Numbers represent counts of specimen regions revealing solid bridging of the individual location.
group but without significant differences (Table I , p = 0.16). Qualitative testing of gap bridging revealed that bridging most often occurred in the endosteal region with prevalence at the far cortex (Table 2, Fig. 3). In the cycled groups (C10 and ClOOO) the number of bridging areas on the endosteal side was lower compared with the control group. No sheep showed bridging of the periosteal side of the near cortex, but bridging was observed in 2 sheep of the 0 cycle control group at the far cortex.
Discussion The aim of our study was to test the different influences of the cyclic compressive and distractive displacements that were enforced and maintained. We selected 0, 10 and 1000 cycles a day, superimposed on a somewhat flexible fracture fixation. Fracture healing by callus formation normally happens when the periosteal callus becomes stiffer, reducing interfragmentary movement while the loading amplitude is kept constant. Therefore, the interfragmentary displacement depends on the changing stiffness of the interfragmentary tissue. To study the effect of a given amount of displacement, its amplitude was kept constant over the whole observation period. Therefore, the current model allows observation of the effect of displacement in early fracture repair but does not allow final bridging. This is important for the evaluation of bending stiffness which is expected to be lower in the cycled groups due to constant displacements. Due to the short period of one cycle (0.8 s), it can be assumed that the effective neutral position of the system is similar to the rest position. We keep in mind that in our model the same amount of displacement (1 mm) under opening and closure of the gap results in the same amount of engineering strain but is different to true strain. At 5Ooh gap displacement, the true strain on the distraction side would be about 0.4 and about 0.7 on the compression side. This results in a higher strain level on the compression side compared to the distraction side. Additionally, three-dimensional distribution of strain levels can be expected and may lead to severe local strain variations inside each given gap displacement [7].
Therefore, the effective local strain that acts at the cell level may not be determined [21] and the relative gap closure does not linearly represent the amount of strain level. The elastic behaviour of the external fixator with the asymmetric geometry has produced a higher interfragmentary compressive displacement on the far side of the cortex compared to the near side. The amount of displacement due to functional loading could be estimated by the free length of pin visible outside the external fixator. If a linear elastic bending pattern is assumed, the amount of displacement on the far cortex will be one half higher than on the near cortex. The mean displacement during functional loading was measured to be between 11% and 19%) of gap width. Therefore, the relative gap displacement during functional loading on the near cortex can be assumed to be between 8%)and 13%)and on the far cortex between 15'% and 25%. This may explain why callus formation was also observed in the control group. The distribution of the callus was asymmetrical showing more than five times the amount of callus formation on the far side. Bridging of the fracture was observed mainly in the control group, but only on the far side. The smaller amount of displacement below 13% on the near side seemed to have too small an effect to allow bridging of the gap. It has been proposed that fluid flow at the fracture gap may play an important role in fracture healing [14,25]. In our experimental setup, two effects of volume change can be assumed. At the times when no active cycles are applied, small cyclic compressive displacements occur in all groups during functional loading due to the deformability of the external fixator. This causes the osteotomy site contents to be flushed in and out of the osteotomy. However, during each active cycle, the volume of the interfragmentary space will not change significantly, but the fluid will be slewed from one side to the other. Therefore, not only volume changes, but also the reallocation of the fluid due to displacements seems to have an important effect on the amount of callus formation. A further factor that might have an effect on the superior amount of new bone formation may be the higher degree of soft tissue coverage of the tibia on the posterolateral side, as has been observed in other experiments [I ,4].
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The aspect of compression versus distraction side revealed a clear difference in the cycled groups, showing highly significant enhancement of new bone formation on the compression side. In the literature, few data about different effects relating to cyclic compression and distraction are available and the results are contradictory. Matsushita and Kurokawa [ 181 applied either distractive or compressive displacements in a rabbit osteotomy model with a 3 mm gap size and found the same enhancement in fracture healing for both application modes. However, the elastic external fixator with thin pins that they used may also have led to significant compressivc displacements during functional loading and may have had a superior effect compared to the actively applied distractive displacements. In contrast, Augat et al. [I] did not find enhanced fracture healing in a sheep osteotomy model with a gap size of 2 mm after applying 500 cycles a day of only distractive displacement of either 0.2 or 0.8 mm, respectively. They found only a small increase of periosteal callus formation with a larger displacement magnitude, but without statistical significance. This is similar to our results, showing a slightly increased callus formation with a higher number of distractive cycles. However, the effect of distractive displacements on periosteal bone formation can be somewhat neglected in comparison to the significant increase in bone formation on the compression side that was about ten times higher in all cycled groups. These results strongly support the theoretical considerations and experimental findings [3,6,9,16,28,29] that compressive cyclic displacement is one of the most important factor in the production of new bone. The bending stiffness at six weeks showed slightly lower values if 1000 cycles were applied. At first glance, these results seem to be contradictory to other experiments that have shown increasing fracture stiffness with active cyclic displacements of the fracture [9,12,13]. In contrast to these, the amplitude of cyclic displacement was kept constant in the present study. Thus, the natural fracture healing that relies on increasing callus stiffness and subsequent reduction of interfragmentary displacement was prevented [19]. The applied load of the pneumatic system was high enough to maintain constant displacement of the fragments. Hence, every cyclic displacement to the end position may have constantly damaged the fibrils inside the periosteal callus, resulting in repeated breakage of the structure that otherwise would have contributed to a higher amount of bending stiffness. In conclusion, maintained compressive displacement during the first six weeks produced a higher amount of new bone formation whereas distractive displacement did not revealed a significant increase of new bone formation. With a higher number of compressive cycles a higher amount of periosteal new bone formation was observed. Ten cycles a day were enough to produce a
distinct amount of periosteal callus. Under constant displacements of the fragments the incidence of bony bridging diminished and bending stiffness was lower. Repeatedly enforced interfragmentary displucements at constant amplitude up to the sixth week did not allow bony bridging but was chosen to study the effect of standardized displacement. If interfragmentary compressive displacement were too small as, for example, on the near side of the gap in our control group, induction of callus formation may be too small to induce sound bridging of the fracture gap.
Acknowledgements
This project was supported by the AO-Research Foundation, Switzerland. The authors are grateful to S. Tepic, PhD for his excellent engineering contribution, to D. Wahl for help in mechanical testing, and to R. Wieling for his assistance in surgery.
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