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. Author manuscript; available in PMC: 2024 Apr 1.
Published in final edited form as: J Orthop Res. 2022 Jul 12;41(4):771–778. doi: 10.1002/jor.25413

Three-Dimensional MRI Analysis Shows Sex-Specific Patterns in Changes in Anterior Cruciate Ligament Cross-Sectional Area Along Its Length

Danilo Menghini 1,2, Shankar G Kaushal 1, Sean W Flannery 3, Kirsten Ecklund 4, Martha M Murray 1, Braden C Fleming 3, Ata M Kiapour 1
PMCID: PMC9825677  NIHMSID: NIHMS1821638  PMID: 35803594

Abstract

Smaller anterior cruciate ligament (ACL) size in females has been hypothesized to be a key contributor to a higher incidence of ACL tears in that population, as a lower cross-sectional area directly corresponds to a larger stress on the ligament for a given load. Prior studies have used a mid-length cross-sectional area measurement to quantify ACL size. In this study, we used magnetic resonance imaging (MRI) to quantify the CSA along the entire length of the intact ACL. We hypothesized that changes in the ACL cross-sectional area along its length would have different patterns in males and females. We also hypothesized that changes in ACL cross-sectional area along its length would be associated with body size or knee size with different associations in females and males. MR images of contralateral ACL-intact knees of 108 patients (62 females, 13–35 years) undergoing ACL surgery were used to measure the cross-sectional area along the ACL length, using a custom program. For both females and males, the largest cross-sectional area was located at 37%-39% of ACL length from the tibial insertion. Compared to females, males had a significantly larger cross-sectional area only within the distal 41% of the ACL (P<.001). ACL cross-sectional area was associated with patient height and weight in males (r>0.3; p<.05), whereas it was associated with intercondylar notch width in females (r>0.3; p<.05). These findings highlight the importance of standardizing the location of measurement of ACL cross-sectional area.

Keywords: ACL, Cross-Sectional Area, Sex Differences, Body Size, Knee Morphology

INTRODUCTION

Anterior cruciate ligament (ACL) injury rates have been extensively studied and found to be greater in females compared to males participating in the same activities.1–4 It is believed that these sex disparities are linked to several potential intrinsic and extrinsic factors.1,2,5,6 Among the potential intrinsic factors, intercondylar notch size, ligamentous laxity, anatomical alignment, femoral anteversion, genu valgum, hormonal differences and ACL morphology have been the focus of many research efforts.2,3,6–9 Predominant attention was given to the latter with several studies aimed at accurately measuring the ACL volume, cross-sectional area (CSA), and length, since these theoretically directly affect the ACL strength and subsequent risk of injury.2,3,7,8,10–18

Several studies, as listed in a recent systematic review,18 have shown smaller ACLs in females compared to males, across a number of parameters including ACL length, CSA, volume, and mass, using cadaveric and imaging based measurements.3,7,19–21 These sex-specific differences have been found to emerge in adolescence, with one recent study showing that sex differences in ACL CSA emerge as early as 11 years of age even after adjusting for body size 20 and another study showing sex differences in ACL CSA and ACL length emerging at 13 years of age.21 Moreover, a range of anthropometric measures (i.e. body weight, height and body mass index (BMI)), along with several anatomical features of the knee joint (i.e. bicondylar width and intercondylar notch size) have been shown to correlate to ACL CSA. 1–3,7,8 In particular, a narrower intercondylar notch has been associated with a smaller and thus more vulnerable ACL.3,7,22 Despite the indisputable sex differences in ACL size, there are inconsistencies in the reported dimensions and the magnitudes of these differences, as a result of variations in measurement techniques (i.e., cadaveric vs in vivo, differences in measurement techniques and measurement locations) used in these studies, as summarized by a recent systematic review.23 Such inconsistencies have also resulted in inconclusive results in the relationships between ACL size and measures of body size.1,7,24–26 A detailed three-dimensional analysis of ACL CSA along its entire length would address some of those inconsistencies. Such data would also help guide development of techniques to assess risk of ACL injury and to gauge the success of a surgical treatment to replicate native anatomy of an intact ACL.

The objective of the study was to systematically document the ACL CSA along the length of the ACL in a cohort of females and males with intact ACLs. We hypothesized that 1) ACL CSA varies along its length (ACL CSA profile) with different patterns in females and males, and 2) ACL CSA is influenced by measures of body size (i.e., height, weight, and BMI) and knee size (i.e., bicondylar width and intercondylar notch width) with different associations in females and males.

METHODS

Participants:

Patients who enrolled in the IRB and FDA approved BEAR I and II trials (Clinical Trials #: NCT02292004 & NCT02664545)27,28 with available contralateral intact ACL MR images were included in this study (n=108, 62 females, age: 13 – 35 years (19.7±5.5; mean ± SD)). Detailed baseline characteristics are included in the Supplementary Table S1. The intact status of the contralateral ACLs was confirmed by a board-certified musculoskeletal radiologist (KE). It is important to note that using the contralateral knees of ACL injured subjects. As mentioned in the limitations section below, this may have introduced bias as these subjects are more susceptible to injury and may have altered joint morphology and biomechanics.

Imaging Outcomes:

Knee images were acquired using the three-dimensional Constructive Interference in Steady State (CISS) sequence (TR/TE=14/7 msec, FA=35, 16cm FOV, 80x512x512 (slice x frequency x phase)) using a 3T scanner (Tim Trio, Siemens, Erlangen, Germany) and a 15-channel knee coil. To quantify the ACL CSA along its length, ACLs were manually segmented (Figure 1A) by an experienced investigator using a commercially available image processing software (Mimics; Materialise, Belgium). It has been previously shown that the inter- and intra-examiner reliability of the segmentation is excellent (ICC>0.9).16,29,30 A custom Matlab (MathWorks, Inc, Natick, MA) script was used to turn the reconstructed 3D model from the segmented ACL (Figure 1B) into a 3D point cloud (Figure 1C). Linear regression was used to approximate the ACL angle the coronal, which was then used to realign the ACL to be parallel to the sagittal plane (coronal elevation angle = 90 degrees). Linear regression was then used to approximate ACL longitudinal axis in the sagittal plane (Figure 1C). The ACL was then reoriented to be horizontal based on the slope of the fitted regression line (Figure 1D). To avoid CSA measurement errors associated with ACL curvature, ACL regional longitudinal axis was automatically determined for every 1 mm of ACL length. The ACL length was then normalized to 0-100% to accommodate comparisons between subjects (0% at the tibial insertion and 100% at the femoral insertion). ACL regional CSA was then calculated as the area of the cross-section perpendicular to the longitudinal axis at every 1% of the ACL length (Figure 1E). To double check the validity of measurements, the images representing the perpendicular slices along the ACL length (Figure 1E) were generated for each ACL and manually reviewed by a member of the team (D.M.) to assure consistency. MR images were also used to measure bicondylar width and intercondylar notch width using the techniques described previously.16,30 Briefly, intercondylar notch width was measured in coronal plane, parallel to a line along the most inferior aspects of the femoral condyles. The measurement was done at the middle of the ACL attachment. Bicondylar width of the femur was also measured at the level of the popliteal groove in the same coronal view (Figure 2).

Figure 1.

Figure 1.

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Measurement technique used to quantify the ACL CSA along its length. A) Manual ACL segmentation. B) 3D reconstructed ACL geometry. C) ACL point cloud in the original sagittal orientation. D) horizontally oriented ACL point cloud. E) Regional slices, perpendicular to ACL longitudinal axis (black line), used to measure ACL CSA along its length at 1% increments.

Figure 2.

Figure 2.

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Measurements of the bicondylar width (BCW) and intercondylar notch width (NW) from MRI in the coronal view.

Statistical Analysis:

ACL lengths were normalized as percentage (tibial insertion at 0% and femoral insertion at 100%) and used to report changes in ACL CSA at 1% length intervals (ACL CSA Profile). Mean and 95% confidence intervals (95% CI) were used to visualize changes in ACL CSA along its length. Repeated measure one-way analysis of variance (ANOVA) was used to test if the ACL CSA (dependent variable) is affected by the location (% length, independent variable). Statistical parametric mapping (SPM) with unpaired t-tests were used to compare changes in ACL CSA along its length between females and males or between age groups (13 – 17 years vs 18 – 35 years). SPM is based on random field theory, and has been extensively used in timeseries data in imaging and biomechanics.31–36 SPM takes into account both the magnitude and shape of the entire dataset and calculates a critical threshold for each test. The SPM output includes a graph displaying test statistics along the dataset (e.g., time series) highlighting shaded regions where the significant differences exist (where the test statistics exceed the threshold). For this study, the t-statistics was calculated between the sexes or age groups. Pearson correlation was further used to assess the correlations between regional ACL CSA and measures of body size (i.e., weight, height and BMI) and knee size (i.e., bicondylar width and notch width). Separate analyses were done for each sex. Benjamini-Hochberg correction was used to control the false discovery rate and minimize type-I error associated with multiple correlation testing. Pearson correlation coefficients (r) for significant correlations were then plotted along the normalized (%) ACL length. All P-values are two-sided, and the statistical significance was set at P <.05.

RESULTS

ACL CSA Profile:

The mean (95% CI) of the ACL CSA along the length of the ACL is shown in Figure 3A. The CSA patterns along the ACL length was significantly affected by the measurement location (F=45.8, P<.001) with the location of the peak CSA varying between 4% to 90% of ACL length (Supplementary Figure S1). On average (Figure 3A), moving proximally from the tibial insertion, there was a consistent increase in ACL CSA which reached its peak (44.7 mm2 ± 12.9 mm2) at 38% ± 21% of ACL length, followed by reduction in CSA until ACL femoral insertion.

Figure 3.

Figure 3.

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A) Changes in the ACL CSA along the ACL length for both females and males combined. B) Changes in the ACL CSA along the ACL length for females (red) and males (blue). C) SPM of the sex differences in the ACL CSA along the ACL length. The shaded area indicates regions with statistically significant difference in ACL CSA between females and males. Vertical axis is the t-statistics and critical thresholds are indicated with dotted lines.

Sex Differences in ACL CSA Profile:

Both female and male ACLs had heterogenous CSA profiles (Supplementary Figure S1) with ACL CSA significantly affected by the measurement location (F=24.3 (females), F=21.6 (males), P<.001). On average, both females and males followed the same pattern, with females ACLs having the highest mean CSA (41.5 mm2 ± 11.7 mm2) at 39% ± 21% (range 4% - 86%) of the length and males having the highest mean CSA (49.0 mm2 ± 13.0 mm2) at 37% ± 21% (range 6% - 90%) of ACL length (Figure 3B). Compared to females, males had a larger ACL CSA in the distal 41% of ACL length (P<.001; Figure 3C). There were no sex differences in the location of peak ACL CSA (P=.567).

Age Differences in ACL CSA Profile:

The ACL CSA profile for patients ages 13 – 17 years and 18 – 35 years for each sex are presented in Figures 4A and 4B. The individual CSA profiles across each age group within each sex, highlighting the heterogeneity of changes in ACL CSA along the length (10 < F < 15; P<.001), are presented in Supplementary Figure S2. On average, both age subgroups exhibited similar ACL CSA profiles. In females, patients 13 – 17 years of age (n=40) had the highest mean ACL CSA (40.4 mm2 ± 4.3 mm2) at 40% ± 20% (range 13% - 86%) of the ACL length, which was comparable to the highest ACL CSA of 43.5 mm2 ± 4.8 mm2 achieved at 37% ± 22% (range 4% - 84%) of ACL length in 18 – 35 years old female subjects (n=22; P=.574; Figure 4A). In males, patients aged 13 – 17 years of age (n=18) reached their peak ACL CSA (46.6 mm2 ± 5.3 mm2) at 36% ± 22% (range 6% - 76%) of the ACL length, which was comparable to the peak ACL CSA of 51.0 mm2 ± 5.5 mm2 achieved at 38% ± 21% (range 6% - 90%) of ACL length in 18 – 35 years old male subjects (n=28; P=.737; Figure 4B). There were no statistical differences in CSA profile (change in CSA along the length patterns) between the age groups within each sex (Figure 4C and 4D).

Figure 4.

Figure 4.

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A) Changes in the ACL CSA along the ACL length in 13-17 years vs 18 – 35 years females. B) Changes in the ACL CSA along the ACL length in 13-17 years vs 18 – 35 years males. C) SPM of the age-differences in ACL CSA along the ACL length in females. Vertical axis is the t-statistics and critical thresholds are indicated with dotted lines. D) SPM of the age differences in ACL CSA along the ACL length in males. Vertical axis is the t-statistics and critical thresholds are indicated with dotted lines.

ACL CSA Correlations to Body Size:

There were no associations between ACL CSA, along its entire length, and any measure of the body size (i.e., height, weight, and BMI) in females. In males, the ACL CSA within the proximal 70% of the length (30 – 100%) was significantly associated with height (Figure 5A). Also, ACL CSA within 18 – 93% of the ACL length was associated with weight, in male subjects (Figure 5B). Similar to females, there were no significant correlations between ACL CSA, along its entire length, and BMI in male subjects.

Figure 5.

Figure 5.

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Significant correlations between ACL CSA and A) height and B) weight along the ACL length for males (blue). Pearson correlation coefficient has only been shown for adjusted significant (P<0.05) correlations. Shaded area indicates 95% confidence intervals for the Pearson correlation coefficients.

ACL CSA Correlations to Knee and Notch Size:

In females, there were no associations between ACL CSA, along its entire length, and bicondylar width. However, ACL CSA in females was significantly correlated to notch width along the entire ACL length except for 55 – 69% of length (Figure 6). There were no significant associations between ACL CSA, along its entire length, and bicondylar width or notch width in males.

Figure 6.

Figure 6.

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Significant correlations between ACL CSA and intercondylar notch width (NW) along the ACL length for females. Pearson correlation coefficient has only been shown for adjusted significant (P<0.05) correlations. Shaded area indicates 95% confidence intervals for the Pearson correlation coefficients.

DISCUSSION

The current findings suggest that the ACL CSA is heterogeneous along its length with location of the peak ACL CSA varying across the entire length of the ACL averaging at 38% of the length from tibial insertion. While females and males had similar ACL CSA profile along the ACL length, males had a significantly larger ACL CSA within the distal third of the ACL, supporting our first hypothesis. Finally, there were significant correlations between ACL CSA and body size (height and weight) in males, and notch size in females, supporting our second hypothesis.

The quantified regional ACL CSA values in the current study are within the range of reported values for females (24 – 58 mm2) and males (33 – 83 mm2) as outlined in a recent systematic review.18 However, our results go beyond previous reports, mapping how ACL CSA changes along its length, highlighting the importance of the location in consistent evaluation of ACL CSA. In an MRI study of 27 subjects, Thein et al. estimated the ACL CSA at three discrete locations corresponding to 25%, 50% and 75% of the ACL length from its tibial insertion and reported that the CSA was smallest at 50%.10 While our findings of the differences in ACL CSA along the length are in agreement with those observations, our analysis shows a sharp increase in ACL CSA from tibial insertion to ~30% of length followed by a slow steady decrease in ACL CSA towards the femoral origin. A similar finding persists in the separate analyses for females vs males, and for adolescent vs young adult subjects.

Despite similar overall patterns in how ACL CSA changes along the length in females and males, our data suggest smaller ACLs in females, but only along the distal 41% of the ACL. These observations are in line with prior reports of overall sex differences in ACL size,1,2,7,12,18,20 but suggest that these sex differences are location specific. Considering that a smaller CSA is associated with higher local stress distributions and potentially higher risk of injury,8,37 the observed sex differences in the distal 41% of the ACL may be a more specific contributor to higher risk of ACL injuries in females, compared to overall ACL CSA measurements. This region of observed sex differences partially overlaps with the midsubstance of the ACL, where majority of ACL tears have been reported.38,39 However, the sex-based difference in the distal region found here may not be entirely explanatory of the differing tear rates between sexes. Additional intrinsic factors (e.g., tissue quality, hormonal differences, morphological differences of surrounding structures such as tibial slope), are contributors to existing sex differences in ACL tear. Still, future studies are essential to investigate potential sex differences in ACL tear location and whether those correspond to the observed sex differences in ACL CSA within the distal 41% of the ACL

Interestingly, females and males had different overall associations between ACL CSA and measures of body size and notch size. After adjusting for multiple testing, ACL CSA in males was only associated with height and weight, while ACL CSA in females was only associated to notch width. Moreover, there were no associations between ACL CSA and BMI or bicondylar width (knee size). In males, the associations between ACL CSA and body size were spread along the proximal 70 - 80% of the ACL. In general, highest correlations between ACL CSA and height or weight were observed at the middle portion of the ACL (~50% of the length). While the ACL CSA in females did not correlate to global measures of body size, they showed significant correlations to intercondylar notch width. Interestingly the highest correlation coefficient to intercondylar notch width was observed at the location of the largest ACL CSA (35% of length from tibial insertion). These sex specific patterns shed light on some of the existing discrepancies in the associations between ACL CSA and measures of body size and knee size.1,7,24–26,40,41 In particular, looking at these associations at along the entire length of the ACL with proper statistical adjustment for multiple associations done in the study suggest that the most reproducible associations to ACL CSA are height, weight and intercondylar notch width. Most importantly, the current observations suggest that ACL CSA is primarily correlated to global measures of body size (i.e. height and weight) in males, whereas in females, it is mainly correlated to local measures of knee (i.e. notch width). This information also highlights the importance of proper selection of surrogate measures for ACL or graft size for each sex and to properly select co-variates to adjust for variations in body size, when investigating risk factors for ACL injuries.

There are several limitations for this study to consider. First, the data were collected from the contralateral intact ACL of patients with unilateral ACL injury, which may have introduced bias to the findings as these patients may be more susceptible to ACL injury. Despite the relevance of this cohort to ACL injury risk, additional analyses on the ACLs of patients without any ACL injury history may yield different findings. It is possible that the ACLs of the ACL injured patients be on average smaller with different ACL CSA profile compared to those without ACL injuries, which may have been a contributing factor to their ACL injury. The lack of non-ACL injury cases may limit the generalizability of the current findings. Second, the measurements were done at full extension, consistent with knee positioning during the MRI. How the current observations would change with knee flexion requires further investigation.

In conclusion, the current study provides new information on continuous changes in ACL CSA along its length in a cohort of adolescents and young adults. These results highlight the importance of the distal third of the ACL which contains the region with highest CSA and exhibit the spectrum with greatest sex differences in ACL CSA. Moreover, the results suggest sex differences in how the ACL CSA can be influenced by body or knee morphology, with female ACLs primarily influenced by local measures of knee size while male ACLs are influenced by global measures of body size. The overall findings emphasize the need to consider the location of the measurement when studying ACL CSA in the context of injury risk assessment and during surgical treatment to ensure an anatomically relevant reconstruction in each sex.

Supplementary Material

1

ACKNOWLEDGEMENTS:

We would like to acknowledge the significant contributions of the BEAR clinical trial team including Bethany Trainor, Benedikt Proffen, MD, Nicholas Sant, BS, Gabriela Portilla, BA, Ryan Sanborn, BA, Christina Freiberger, BS, Rachael Henderson, BS, Yi-Meng Yen, MD/PhD, Dennis Kramer, MD, Lyle Micheli, MD. We would also like to acknowledge the contributions of our medical safety monitoring team of Joseph DeAngelis, Peter Nigrovic, and Carolyn Hettrich, our data monitors Maggie Malsch, Meghan Fitzgerald, and Erica Denhoff, as well as the clinical care team for the trial patients, including Kathryn Ackerman, Alyssa Aguiar, Judd Allen, Michael Beasley, Jennifer Beck, Dennis Borg, Jeff Brodeur, Stephanie Burgess, Melissa Christino, Sarah Collins, Gianmichel Corrado, Sara Carpenito, Corey Dawkins, Pierre D’Hemecourt, Jon Ferguson, Michele Flannery, Casey Gavin, Ellen Geminiani, Stacey Gigante, Annie Griffin, Emily Hanson, Elspeth Hart, Jackie Hastings, Pamela Horne-Goffigan, Christine Gonzalez, Meghan Keating, Elizabeth KillKelly, Elizabeth Kramer, Pamela Lang, Hayley Lough, Chaimae Martin, Michael McClincy, William Meehan, Ariana Moccia, Jen Morse, Mariah Mullen, Stacey Murphy, Emily Niu, Michael O’Brien, Nikolas Paschos, Katrina Plavetsky, Bridget Quinn, Shannon Savage, Edward Schleyer, Benjamin Shore, Cynthia Stein, Andrea Stracciolini, Dai Sugimoto, Dylan Taylor, Ashleigh Thorogood, Kevin Wenner, Brianna Quintiliani, and Natasha Trentacosta. We would also like to thank the perioperative and operating room staff and the members of the Department of Anesthesia who were extremely helpful in developing the perioperative and intraoperative protocols. We would also like to acknowledge the efforts of other scaffold manufacturing team members, including Gabe Perrone, Gordon Roberts, Doris Peterkin, and Jakob Sieker. We are also grateful for the study design guidance provided by the Division of Orthopedic Devices at the Center for Devices and Radiological Health at the U.S. Food and Drug Administration under the guidance of Laurence Coyne and Mark Melkerson, particularly the efforts of Casey Hanley, Peter Hudson, Jemin Dedania, Pooja Panigrahi, and Neil Barkin. Lastly, we would like to acknowledge funding support from the Translational Research Program at Boston Children’s Hospital, the Children’s Hospital Orthopaedic Surgery Foundation, the Children’s Hospital Sports Medicine Foundation and the National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases through grant numbers R01-AR065462 and R01-AR056834. This research was also conducted with support from the Football Players Health Study at Harvard University. The Football Players Health Study is funded by a grant from the National Football League Players Association. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Medical School, Harvard University or its affiliated academic health care centers, the National Football League Players Association, Boston Children’s Hospital or the National Institutes of Health. We are also especially grateful to the patients and their families who participated in this study, their willingness to participate in research that may help others in the future inspires all of us.

Disclosures:

This study received funding support from the Translational Research Program at Boston Children’s Hospital, the Children’s Hospital Orthopaedic Surgery Foundation, the Children’s Hospital Sports Medicine Foundation, Boston Children’s Hospital Faculty Council, the Football Players Health Study at Harvard University, and the National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases through grants R01-AR065462 and R01-AR056834. M.M.M. is a founder, paid consultant, and equity holder in Miach Orthopaedics, Inc, which was formed to work on upscaling production of the BEAR scaffold. M.M.M. maintained a conflict-of-interest management plan that was approved by Boston Children’s Hospital and Harvard Medical School during the conduct of the trial, with oversight by both conflict-of-interest committees and the institutional review board of Boston Children’s Hospital, as well as the US Food and Drug Administration. B.C.F. is an assistant editor for The American Journal of Sports Medicine, the spouse of M.M.M. with the inherently same conflicts. A.M.K. is a paid consultant for Miach Orthopaedics, Inc, maintained a conflict-of-interest management plan that was approved by Boston Children’s Hospital and Harvard Medical School during the conduct of the trial, with oversight by both conflict-of-interest committees and the institutional review board of Boston Children’s Hospital.

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