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Research Papers

Local Changes to the Distal Femoral Growth Plate Following Injury in Mice

[+] Author and Article Information
Lauren M. Mangano Drenkard

Biomedical Engineering,
Boston University,
110 Cummington Mall,
Boston, MA 02215
e-mail: lmangano@bu.edu

Meghan E. Kupratis

Biomedical Engineering,
Boston University,
110 Cummington Mall,
Boston, MA 02215
e-mail: mkup@bu.edu

Katie Li

Biomedical Engineering,
Boston University,
110 Cummington Mall,
Boston, MA 02215
e-mail: kli430@bu.edu

Louis C. Gerstenfeld

Biochemistry,
Boston University School of Medicine,
72 East Concord Street,
Boston, MA 02118;
Orthopaedic Surgery,
Boston University School of Medicine,
72 East Concord Street,
Boston, MA 02118
e-mail: lgersten@bu.edu

Elise F. Morgan

Mem. ASME
Biomedical Engineering,
Boston University,
110 Cummington Mall,
Boston, MA 02215;
Mechanical Engineering,
Boston University,
110 Cummington Mall,
Boston, MA 02215;
Orthopaedic Surgery,
Boston University School of Medicine,
72 East Concord Street,
Boston, MA 02118
e-mail: efmorgan@bu.edu

1Corresponding author.

Manuscript received November 29, 2016; final manuscript received April 30, 2017; published online June 6, 2017. Assoc. Editor: Eric A Kennedy.

J Biomech Eng 139(7), 071010 (Jun 06, 2017) (9 pages) Paper No: BIO-16-1485; doi: 10.1115/1.4036686 History: Received November 29, 2016; Revised April 30, 2017

Injury to the growth plate is associated with growth disturbances, most notably premature cessation of growth. The goal of this study was to identify spatial changes in the structure and composition of the growth plate in response to injury to provide a foundation for developing therapies that minimize the consequences for skeletal development. We used contrast-enhanced microcomputed tomography (CECT) and histological analyses of a murine model of growth plate injury to quantify changes in the cartilaginous and osseous tissue of the growth plate. To distinguish between local and global changes, the growth plate was divided into regions of interest near to and far from the injury site. We noted increased thickness and CECT attenuation (a measure correlated with glycosaminoglycan (GAG) content) near the injury, and increased tissue mineral density (TMD) of bone bridges within the injury site, compared to outside the injury site and contralateral growth plates. Furthermore, we noted disruption of the normal zonal organization of the physis. The height of the hypertrophic zone was increased at the injury site, and the relative height of the proliferative zone was decreased across the entire injured growth plate. These results indicate that growth plate injury leads to localized disruption of cellular activity and of endochondral ossification. These local changes in tissue structure and composition may contribute to the observed retardation in femur growth. In particular, the changes in proliferative and hypertrophic zone heights seen following injury may impact growth and could be targeted when developing therapies for growth plate injury.

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Figures

Grahic Jump Location
Fig. 1

(a) Schematic of surgical model. (b) Length of the injured and uninjured (contralateral) femora, measured from the apex of the greater trochanter to apex of the left condyle: The height of each bar represents the group mean, and the error bars represent one standard deviation. *p < 0.01 over all time points.

Grahic Jump Location
Fig. 2

Local thickening of the injured growth plate: (a) Top: Sections of the growth plate stained with safranin O and fast green. Bottom: Matched CECT slices (cartilage is rendered according to the colorbar that shows attenuation in Hounsfield units (HU)). Arrows indicate the injury site. (b) Correlation of histologically and CECT-measured thickness of the growth plate (R2 = 0.94, p < 0.0001). Each point indicates the average thickness of one sample. (c) Maximum thickness projection maps of the growth plate. Arrows indicate the injury site. (d) Average thickness of the growth plate near to (within 0.5 mm) and far from the injury site and at matched locations in the contralateral growth plate. The height of each bar represents the group mean, and the error bars represent one standard deviation. *p < 0.0001 versus injured near (across all time points). The average thickness of the contralateral growth plate was 0.086 mm, 0.064 mm, and 0.042 mm at days 7, 21, and 42, respectively.

Grahic Jump Location
Fig. 3

CECT attenuation remains high at the injury site: (a) Maximum intensity projection maps of CECT attenuation in the growth plate. Arrows indicate the injury site. (b) Average CECT attenuation of the growth plate near to (within 0.5 mm) and far from the injury site and at matched locations in the contralateral growth plate. The height of each bar represents the group mean, and the error bars represent one standard deviation. *p < 0.0001 versus day 7, #p < 0.0001 versus day 21; p < 0.05, ††p < 0.005, and †††p < 0.0001 versus corresponding VOI in contralateral.

Grahic Jump Location
Fig. 4

Bone bridge formation. (a) Histological sections of injured growth plate. Arrows indicate disorganized chondrocyte columns. Asterisks indicate hypertrophic cells. (b) Sagittal μCT sections of the distal femora containing the injured growth plates shown in panel A. Arrows indicate bone bridges at the injury site. Circles indicate bone bridges outside the injury site. (c) Bone volume fraction (BV/TV) and tissue mineral density (TMD) of bone bridges within the growth plate. The height of each bar represents the group mean, and the error bars represent one standard deviation. *p < 0.01 and **p < 0.001. (d) Matched histological section and matched μCT section of the injury site at day-7 in a sample where the bone bridge has not yet formed. Arrows indicate the injury site. (e) Matched histological section and matched μCT section of the injury site at day-42 in a sample where the mineralized bone bridge is stained with safranin O. Arrows indicate the injury site. (f) Histology and matched CECT of a bone bridge formed outside the injury site and matched histological section and matched μCT section of bone bridges formed in the contralateral growth plate and outside the injury site. Stars indicate bone bridges.

Grahic Jump Location
Fig. 5

Zone heights. (a) Height of the resting, proliferative, and hypertrophic zones near to the injury site, far from the injury site, and in the contralateral growth plate. (b) Proportional height of the resting, proliferative, and hypertrophic zones near to the injury site, far from the injury site, and in the contralateral growth plate. In both plots, the height of each bar represents the group mean, and the error bars represent one standard deviation. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001.

Grahic Jump Location
Fig. 6

Collagen X immunostaining at day 21. (a) Injury site, (b) injured growth plate far from injury site, (c) contralateral growth plate. Arrow indicates the injury site. The scale bar applies to all three images.

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