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Keywords:

  • OSTEOARTHRITIS;
  • SUBCHONDRAL BONE;
  • SYNCHROTRON RADIATION MICRO CT;
  • MICROSTRUCTURE;
  • DEGREE OF MINERALIZATION

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

We analyzed the microstructure and degree of mineralization of the subchondral trabecular bone in hip osteoarthritis (OA) using synchrotron radiation computed tomography (SRCT) to identify the relationship between bone structure and bone turnover. Subchondral bone samples were extracted from femoral heads of 10 terminal-staged hip OA patients. The SRCT scan was performed at 30 keV energy and 5.9 µm voxel size. Trabecular bone structure, bone cyst volume, and the degree of trabecular bone mineralization were measured, and correlations between bone structure and the degree of mineralization were analyzed. In addition, the trabecular bone was divided into the area immediately surrounding the bone cyst and the remaining area, and they were compared. The average cyst volume fraction in the whole region was 31.8%, and the bone volume fraction in the bone region was 55.6%. Cyst volume was the only structural parameter that had a significant correlation with the degree of mineralization. The degree of mineralization was diminished when the bone cyst was larger (r = −0.81, p = 0.004). The trabecular bone immediately surrounding the bone cyst had a lower degree of mineralization when compared with the remaining trabecular bone (p = 0.008). In the bone sclerosis of OA subchondral bone, there are many large and small bone cysts, which are expected to play a significant part in the high bone turnover of OA. © 2012 American Society for Bone and Mineral Research.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

Osteoarthritis (OA) is generally characterized by cartilage attrition and joint pain. Various structural changes, such as subchondral bone sclerosis and cyst formation, are thought to be related to the pathophysiology of OA. The subchondral trabecular bone has a shock-absorbing function that protects the articular cartilage. Subchondral bone sclerosis is therefore considered to cause a decreased ability to absorb shock and lead to cartilage damage.1 The presence of a subchondral bone cyst sometimes leads to bone collapse and subsequent joint deformity.

There is also an increased bone turnover in the osteoarthritic subchondral bone. Various cytokines are considered to be released from this high-turnover area and affect the onset and progression of OA.2, 3 High bone turnover and bone resorption have been observed in the early stages of OA in animal studies. Animal studies have also indicated that bone resorption inhibitors suppress OA progression.4, 5 Several bone turnover–inhibiting drugs, such as alendronate, risedronate, and calcitonin, have been proposed as candidates for OA treatment.6, 7 Therefore, it is important to understand subchondral bone turnover to analyze OA pathophysiology and develop appropriate therapies.

Synchrotron radiation computed tomography (SRCT) is a µCT using a synchrotron radiation X-ray and has high spatial resolution and high quantitative capability. SRCT can perform three-dimensional (3D) microstructure analysis and identify trabecular bone mineralization (Fig. 1).8, 9 The synchrotron radiation is generated by accelerating electrons to the speed of light and passing them through a magnetic field. It has the features of high intensity and is practically parallel and monochromatic. By using the synchrotron radiation X-ray for µCT, beam hardening artifact and noise, which certainly occur in conventional µCT, can be almost completely eliminated, and high quantitative performance can be obtained. When the SRCT is used for the bone analysis, we can visualize the trabecular structure to a very fine degree and identify the 3D distribution of trabecular mineralization.

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Figure 1. Three-dimensional SRCT images of trabecular bone: (A) binarized image and (B) color scale image of mineralization. High spatial resolution and high quantitative capability of SRCT allow 3D microstructure (A) and mineralization distribution (B) analysis of trabecular bone. In panel B, the purple region indicates a high degree of mineralization, and the central region of the trabecular bone appears highly mineralized.

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The degree of trabecular mineralization is related to the density of the mineral deposited in the collagen and is regarded as an index of bone turnover as well as a mechanical property of bone.8 Highly mineralized bone generally means that the bone is mature, with low bone turnover and hard material. Low bone mineralization indicates that the bone has high bone turnover and soft material. Therefore, SRCT is one of the few ways to perform 3D analysis of the trabecular bone microstructure and metabolism simultaneously. One previous study analyzed the subchondral bone of hip OA using SRCT. In that study, an increased trabecular thickness and a decreased degree of mineralization was observed in subchondral bone.10

We hypothesized that bone metabolism changes in OA subchondral bone are caused by bone structural changes such as trabecular bone thickening and bone cyst formation, and that subchondral bone turnover is correlated with subchondral bone structure. Resolution of clinical CT and magnetic resonance imaging (MRI) has improved significantly in recent years, and the subchondral bone structure of OA patients can now be analyzed more finely and quantitatively.11, 12 Evaluating these bone changes with clinical CT and MRI might be useful for understanding pathophysiology, prognosis prediction, treatment selection, and therapy evaluation.

Therefore, we analyzed the structure and the degree of mineralization in subchondral trabecular bone excised from hip OA patients using SRCT to identify the relationship between bone microstructure and bone turnover. The research questions were as follows: 1) What are the features of the trabecular structure and the degree of mineralization of the subchondral bone in hip OA patients? 2) Is there any relationship between the trabecular structure and the degree of mineralization? 3) How do the structural changes influence the degree of mineralization?

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

Subjects

The subjects were 10 hip OA patients who had undergone joint replacement at our hospital between 2006 and 2008 (mean age 72 ± 5 years, range 66 to 81 years, all female, terminal-staged OA). Inclusion criteria were females with the diagnosis of terminal-staged hip OA secondary to hip dysplasia. Men, patients with OA secondary to osteonecrosis, rheumatoid arthritis, or trauma, and patients who had hip osteotomy were excluded.

Ten subchondral bone samples were extracted from femoral heads obtained in joint replacement. Ten-millimeter-diameter bone columns were extracted with a coring reamer from the center of the cartilage loss and eburnation area, and formed into 10-mm-long sections (Fig. 2). The samples were stored frozen in sealed acrylic cases filled with saline.

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Figure 2. Subchondral bone columns 10 mm diameter by 10 mm long were extracted from the center of the cartilage loss and eburnation area of the femoral heads in terminal-staged hip OA patients (A, B). Measurements were taken of the trabecular bone (All-Tb: red + yellow region) and the bone cyst (blue) in the 8-mm-diameter and 8-mm-height columnar region. The trabecular bone was divided into the bone 0.5 mm surrounding the bone cyst (Cys-Tb: red region) and the remaining bone (Cen-Tb: yellow region) (C, D).

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The study protocol was approved by the ethics review board of our institute and complied with the Declaration of Helsinki of 1975, revised in 2000.

Imaging

SRCT scanning was performed at the beamline BL20B2 in the synchrotron radiation facility SPring-8 (Hyogo, Japan). A 30-keV energy X-ray and 4000 × 2624 charge-coupled device (CCD) camera were used. The voxel size was 5.9 µm. The samples were scanned inside the saline-filled acrylic cases. The samples were thawed gradually at room temperature and maintained at the same temperature during scanning. The samples were placed on the table, underwent a 1-second exposure, and were then rotated 0.1°; this process was repeated over 180° so that 1800 radiographic projections were performed. The scan time of each sample was approximately 2.5 hours. The raw data were reconstructed to tag image file format (TIFF) images.

Measurements

The bone cyst volume, microstructure, and the degree of mineralization of the trabecular bone was measured using bone microstructure measurement software TRI/3D-BON (Ratoc System Engineering, Tokyo, Japan). The measurement region was 8 mm in diameter and 8 mm in height in a columnar region located 1 mm beneath the joint surface in order to exclude small bone fragments that occurred while making bone samples (Fig. 2).

Only bone cysts greater than 1 mm in diameter were extracted by an automatic method, and their volumes were measured. The automatic method was performed using a dilation function of the software. To exclude small bone fragments in bone cysts, bones less than 150 µm in diameter were deleted (Fig. 3C). By dilating trabecular bone 0.5 mm from the surface, bone marrow spaces were closed and only bone cysts greater than 1 mm in diameter could remain (Fig. 3D). Then, by dilating the cysts 0.5 mm from the surface (Fig. 3E), only bone cysts over 1 mm in diameter could be extracted (Fig. 3F). The ratio of the bone cyst volume to the whole measurement region was defined as cyst volume fraction (Cyst/TV).

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Figure 3. Steps of the bone cyst extraction. After the binarization (A, B), bones less than 150 µm in diameter were deleted to exclude small bone fragments in bone cysts (C). By dilating bone 0.5 mm from the surface, bone marrow spaces were closed and only bone cysts greater than 1 mm in diameter could remain (D). By dilating the cysts 0.5 mm from the surface, only bone cysts greater than 1 mm in diameter could be extracted (E, F).

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There were three regions of interest (ROI) of trabecular bone: all trabecular bone (All-Tb), the trabecular bone immediately surrounding the bone cyst (Cys-Tb), and the central trabecular bone (Cen-Tb) (Fig. 2). All-Tb is the region obtained by subtracting the cyst region from the whole measurement region. Cys-Tb is the region 0.5 mm from the surface of the cyst to the trabecular bone, which could be extracted automatically using the expanding function. Cen-Tb is the region obtained by subtracting the Cys-Tb region from the All-Tb region.

The images were binarized with a fixed threshold, and the trabecular structure parameters were measured in each region. The threshold between bone and background on a histogram was determined by discriminant analysis, and the mean threshold value for five arbitrary samples was set as a fixed threshold (570 mg/cm3).

The measurement parameters were bone volume fraction (BV/TV; %), specific bone surface (BS/BV; mm2/mm3), trabecular thickness (Tb.Th; µm), trabecular number (Tb.N; 1/mm), trabecular separation (Tb.Sp; µm), connectivity density (ConnD; 1/mm3), structure model index (SMI), trabecular bone pattern factor (TBPf), and degree of anisotropy (DA).13–17

ConnD is a parameter of trabecular connectivity, where a higher value means greater connectivity. SMI is an index evaluating whether trabecular bone is rod-like or plate-like; a small value means a more plate-like structure. TBPf is an index evaluating convex or concave structure; TBPf greater than 0 means a more convex structure, whereas TBPf less than 0 means a more concave structure. Consequently, TBPf can also evaluate rod-like, plate-like, or honeycomb-like structure; TBPf greater than 0 indicates a rod-like structure, TBPf equal to 0 indicates a plate-like structure, and TBPf less than 0 means indicates a honeycomb-like structure. DA is determined by the mean intercept length (MIL) method; a higher value indicates higher anisotropy.

The CT value (HU) was converted into bone mineral density (BMD; mg/cm3) using a calibration curve obtained from the BMD phantom, and the average degree of mineralization was measured in each region. BMD phantoms made of hydroxyapatite (φ6 × 1 mm, 200 to 800 mg/cm3, Kyoto Kagaku, Kyoto, Japan) were scanned under conditions identical to those during bone sample scanning (inside a saline-filled acrylic case).

The reproducibility of the measurement was evaluated by the intraclass correlation coefficient (ICC) of three measurements taken by three investigators from three randomly selected samples.

Statistical analysis

Statistical analysis was performed using SPSS version 16.0 (SPSS, Chicago, IL, USA). The correlations between the degree of mineralization and age, bone cyst volume, and trabecular structure parameters were analyzed by Pearson's correlation coefficient test. In addition, the trabecular structure parameters and the degree of mineralization at Cys-Tb and Cen-Tb were compared by ANOVA and the Bonferroni test. For all analyses, the level of statistical significance was established at p < 0.01.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

The mean ratio of the bone cyst volume in the whole region (Cyst/TV) was 31.8% (0% to 58.5%). The mean ratio of the bone volume in the whole trabecular bone region (BV/TV in All-Tb) was 55.6% (44.3% to 66.0%), and mean Tb.Th was 235.9 µm (197.5 to 253.6 µm). The mean degree of mineralization was 1004.4 mg/cm3 (945.7 to 1076.8 mg/cm3) (Table 1).

Table 1. Bone Cyst Volume, Microstructural Parameters, and the Degree of Mineralization in All-Tb Region
 Cyst volume (mm3)Cyst/TV (%)BV/TV (%)BS/BV (1/mm)Tb.Th (µm)Tb.N (1/mm)Tb.Sp (µm)ConnD (1/mm3)SMITBPf (1/mm)DAMineralization (mg/cm3)
  1. All-Tb = all trabecular bone (Cys-Tb + Cen-Tb); Cyst/TV = cyst volume fraction, BV/TV = bone volume fraction; BS/BV = specific bone surface; Tb.Th = trabecular thickness; Tb.N = trabecular number; Tb.Sp = trabecular separation; ConnD = connectivity density; SMI = structure model index; TBPf = trabecular bone pattern factor; DA = degree of anisotropy; mineralization = degree of mineralization.

Average127.931.855.68.9235.91.08268.010.87−0.99−3.691.721004.4
SD98.924.67.11.020.00.0774.92.800.851.110.1746.7
Minimum0.00.044.37.2197.50.98185.16.47−2.39−5.271.45945.7
Maximum235.058.566.010.1253.61.22404.715.010.34−2.081.931076.8

The structural parameter that had significant correlation with the degree of mineralization was bone cyst volume; as the bone cyst became larger, the degree of mineralization was lower (r = −0.81, p = 0.004) (Table 2).

Table 2. Correlation Between Degree of Mineralization and Age, Cyst Volume, and Microstructural Parameters in All-Tb Region
 AgeCyst volumeBV/TVBS/BVTb.ThTb.NTb.SpConnDSMITBPfDA
  • All-Tb = all trabecular bone (Cys-Tb + Cen-Tb); BV/TV = bone volume fraction; BS/BV = specific bone surface; Tb.Th = trabecular thickness; Tb.N = trabecular number; Tb.Sp = trabecular separation; ConnD = connectivity density; SMI = structure model index; TBPf = trabecular bone pattern factor; DA = degree of anisotropy.

  • *

    p < 0.01, Pearson's correlation test.

r0.34−0.81−0.10−0.490.15−0.450.30−0.52−0.49−0.02−0.44
p0.330.004*0.780.150.680.200.400.120.150.950.20

When trabecular structure and degree of mineralization at Cys-Tb were compared with Cen-Tb, BS/BV at Cys-Tb was larger than Cen-Tb (p = 0.011), Tb.Sp was smaller (p = 0.008), ConnD was larger (p = 0.008), and the degree of mineralization was lower (p = 0.008) (Table 3).

Table 3. Comparison of Structural Parameters and Degree of Mineralization Between Cys-Tb and Cen-Tb Regions
 BV/TV (%)BS/BV (1/mm)Tb.Th (µm)Tb.N (1/mm)Tb.Sp (µm)ConnD (1/mm3)SMITBPf (1/mm)DAMineralization (mg/cm3)
  • Cys-Tb = trabecular bone around bone cyst; Cen-Tb = central trabecular bone; BV/TV = bone volume fraction; BS/BV = specific bone surface; Tb.Th = trabecular thickness; Tb.N = trabecular number; Tb.Sp = trabecular separation; ConnD = connectivity density; SMI = structure model index; TBPf = trabecular bone pattern factor; DA = degree of anisotropy; mineralization = degree of mineralization.

  • Values are average and standard deviation.

  • *

    p < 0.01, Wilcoxon signed-rank test.

Cys-Tb56.8 ± 4.312.0 ± 1.4213.2 ± 18.01.11 ± 0.22172.5 ± 21.015.1 ± 2.60.89 ± 0.55−3.31 ± 0.951.78 ± 0.20961.8 ± 37.7
Cen-Tb55.6 ± 8.79.5 ± 1.5231.8 ± 23.01.03 ± 0.09275.9 ± 82.49.9 ± 2.8−0.33 ± 1.19−3.60 ± 1.421.63 ± 0.181022.6 ± 40.4
p0.590.0110.170.370.008*0.008*0.0660.770.110.008*

The intraobserver and interobserver correlation coefficients were 1.00 and 1.00, respectively, for Cyst/TV; 0.99 and 0.99, respectively, for BV/TV; 0.97 and 0.99, respectively, for BS/BV; 1.00 and 0.99, respectively, for Tb.Th; 0.95 and 0.97, respectively, for Tb.N; 0.98 and 0.99, respectively, for Tb.Sp; 0.99 and 1.00, respectively, for ConnD; 0.99 and 0.99, respectively, for SMI; 0.89 and 0.92, respectively, for TBPf; 1.00 and 0.99, respectively, for DA; and 0.99 and 1.00, respectively, for degree of mineralization.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

This is the second study to analyze the subchondral bone of OA patients using SRCT and the first study to clarify the relationship between the degree of mineralization and microstructure of the OA subchondral bone.

In this study, we analyzed subchondral trabecular bone extracted from the center of cartilage loss area of the femoral head in terminal-staged hip OA patients.

Mean bone volume fraction in the whole trabecular bone region (BV/TV in All-Tb) was 56%, and mean cyst volume fraction in the whole region (Cyst/TV) was 32% (Table 1). This indicates that subchondral bone of hip OA has a quite nonuniform structure composed of bone sclerosis and bone cysts. In the trabecular bone region, as previous studies reported, increased Tb.Th and increased BV/TV were observed, which are thought to be formed by long-term mechanical stress and following bone formation (Fig. 4). In the trabecular bone around the bone cyst, interruption and holes were observed, indicating that these trabeculae are in the process of bone resorption (Fig. 4).

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Figure 4. Three-dimensional images of subchondral trabecular bone and subchondral bone cyst of hip OA. Subchondral bone cysts (blue) occupied a mean of 32% of the whole region (A). Interruptions and holes were observed in the trabecular bone around the bone cyst (B).

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Bone cysts were found to occupy a remarkable 30% of the subchondral bone under the cartilage loss and eburnation area (Fig. 4). This may indicate that there are many large and small bone cysts present in the subchondral bone of OA, which may be difficult to detect by plain radiograph and may greatly influence the etiology of OA.

Chappard and colleagues scanned subchondral bone of hip OA patients using SRCT and compared subchondral bone under the cartilage loss area and cartilage intact area. They reported that subchondral bone under the cartilage loss area had increased Tb.Th, increased BV/TV, and decreased degree of mineralization. These results are compatible with our findings.10

The only structural parameter significantly related to the degree of mineralization was the bone cyst volume; the degree of mineralization decreased as bone cyst volume increased (Table 2). This means that the decreased degree of subchondral bone mineralization in OA was influenced by bone cyst formation. Bone resorption resulting from cyst formation might cause this decreased degree of mineralization. Although it was possible that trabecular bone thickening with new bone formation also might cause a decreased degree of mineralization, trabecular bone thickness and bone volume fraction were not related to the degree of mineralization. This may be because all patients studied were terminally staged OA and a substantial time had passed since the bone formation and trabecular bone thickening had occurred.

Trabecular bone was divided into the trabecular bone immediately surrounding the bone cyst and the remaining area. A comparison revealed that the degree of mineralization around the bone cyst was lower than in the other areas (Table 3; Fig. 5). This indicates that the main region of the decreased degree of mineralization of subchondral bone of OA was immediately surrounding the bone cyst, and the trabecular bone turnover was increased at this site as well. It is estimated that in the process of bone cyst formation, bone metabolism such as bone resorption and bone formation was increased around the bone cyst, and low trabecular mineralization occurred. It is also possible that high bone turnover and a low mineralization region appeared in the subchondral bone, and a bone cyst replaced that region.

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Figure 5. Three-dimensional color images of subchondral trabecular bone mineralization of hip OA. The purple region indicates highly mineralized bone. White lines mean border between Cys-Tb and Cen-Tb. The degree of mineralization around the bone cyst is low, suggesting that bone turnover is increased in this region.

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The pathophysiology of the subchondral bone cyst in OA is still unknown, and two hypotheses have been proposed.18 The “synovial fluid intrusion theory”19 states that, because of the cartilage injury and resulting breakage of the barrier between the cartilage and subchondral bone, synovial fluid intrudes into the bone marrow of the subchondral bone and forms the subchondral bone cyst. The “bone contusion theory”20 states that the bone contusion at the subchondral bone causes bone necrosis, which is absorbed and replaced by the subchondral bone cyst. A recent prospective MRI study indicated that areas of bone marrow edema-like lesions changed to subchondral cyst-like lesions in knee OA patients. This study indicated that there was a profound relationship between bone contusion and subchondral bone cysts.21 However, our study was not designed to prove either hypothesis, and further studies are needed in this area.

Histologically, the existence of osteoclasts, activated osteoblasts, osteoid, and new bone formation is present surrounding the subchondral bone cyst in OA.22, 23 The osteoclasts remove the mineral from the collagen first (decalcification) and then remove the collagen. Therefore, the low bone mineralization levels observed in this study might be bone in the process of the decalcification or new bone at the early stage of mineralization.

The microstructure of the trabecular bone around the cyst also showed an increased BS/BV, decreased Tb.Sp, and increased connectivity density (Table 3). This might be because the bone resorption around the bone cyst made small holes through the trabecular bone (Fig. 4), resulting in a more porous structure, increased bone surface area, and decreased trabecular separation. Regarding the connectivity density, which is defined as “Conn.D = number of holes/total volume,” based on a concept that higher connectivity bone has more holes in its structure, the bone resorption around the cyst also might produce increased connectivity density.

One of the limitations of this study is the small number of the subjects. Because of the restricted scan opportunities and the long scan time, scanning many samples by SRCT is generally difficult. The previous study by Chappard and colleagues investigated 6 hip OA patients.10 More studies are needed in the future. In addition, all the bone samples in this study were terminal-staged OA, and we could not study early-staged OA or normal controls. It is generally difficult to obtain bone samples from early-staged OA patients and normal subjects. The only conclusion that can be made based on this study is that the factor most closely related to decreased degree of mineralization of subchondral bone in terminal-staged OA is bone cysts, and other factors may play important roles at other stages of OA. Studies using OA animal models might reveal other factors. Moreover, in the current study, all the bone samples were extracted from just the center of the cartilage loss area of the femoral head; however, bone cyst formation occurs at various regions in various sizes, and bone cyst volume might differ depending on the region of extraction.

There was a possibility that the effects of bone cysts were underestimated in this study because bone cysts less than 1 mm in diameter were excluded. We only included bone cysts greater than 1 mm in diameter because it is difficult to precisely differentiate between small bone cysts and bone marrow space. Thus, the present results are applicable only to bone cysts greater than 1 mm in diameter. Also, it is possible that dividing ROI into Cys-Tb and Cen-Tb affected bone microstructure values. In Tables 1 and 3, Tb.Th after ROI division (213.2 and 231.8 µm) were smaller than those before division (235.9 µm), which might have occurred because trabecular bones were divided into two ROIs inside the bone, resulting in thinner bones.

In conclusion, at the subchondral bone region under the cartilage loss area in terminal-staged hip OA, bone cysts occupied 32% of the whole volume. The degree of trabecular bone mineralization decreased as the bone cyst became larger, and the degree of mineralization around the bone cyst was lower than that in other areas of the sample. In the subchondral bone of OA, bone sclerosis contains many large and small bone cysts, which are related to high bone turnover.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

The authors thank Kentaro Uesugi and Naoto Yagi (SPring-8, Japan Synchrotron Radiation Research Institute, Hyogo, Japan) for SRCT imaging. This research was partially supported by a Grant-in-Aid for Scientific Research for Young Researchers (B) by the Japan Society for the Promotion of Science (JSPS).

Authors' roles: KC: design, collection and analysis of data, and drafting of the article. NN, SK, NO, and KT: design and collection and analysis of data. MO: collection of data and revision of the article. MI: design, collection and analysis of data, and revision of the article.

References

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  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References
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