Effects of Initial Graft Tension on Anterior Cruciate Ligament Reconstruction
Phase: NA
Conditions: Anterior Cruciate Ligament Rupture
Sponsor: Rhode Island Hospital

 
 
 
 
 
 
 
Initial Graft Tension and ACL Surgery 
 
PI: Braden C. Fleming, PhD 
 
Rhode Island Hospital 
Providence RI 02903 
 
 
ClinicalTrials.gov identifier: NCT00434837 
 
Updated: 09/10/2019 (after NIH funding received for 15-year follow-up; R01-AR074973) 

 
 
SPECIFIC AIMS 
 
The primary objective of this prospective, randomized, double-blinded, controlled study is to assess 
OA progression following ACL reconstruction (ACLR), and to determine how the initial tension applied 
to the graft at the time of surgery may influence disease progression.  ACLR is commonly performed to 
restore joint function and to decrease the risk of post-traumatic osteoarthritis (OA) in the ACL-deficient knee. 
However, clinical studies suggest that the outcome is highly variable, and that OA often progresses despite 
ACLR. The tension applied to the graft at the time of ACLR fixation (“initial graft tension”) affects knee 
kinematics and the distribution and magnitude of contact stress, which in turn, is thought to influence articular 
cartilage damage. The effects of low- and high-initial graft tensions on graft healing and articular cartilage 
degeneration following ACLR are unknown and are currently under investigation in this study. Over the past 
funding cycle, ACL-injured subjects (108 patients) and matched controls (60 subjects) were recruited and 
enrolled. Short-term (≤84 months) post-surgical evaluations have been performed. The objective of this update 
is to prospectively obtain valuable long-term (15 year) follow-ups on this captured patient/control population. 
We intend to follow these patients a minimum of 15 years. These long-term data will allow us to establish not 
only the incidence of OA after ACLR following an isolated ACL tear, but whether changing the initial graft 
tension can decrease this risk.  
 
This study is designed to compare two common initial graft tension protocols for ACLR that influence 
joint contact mechanics. The first treatment group consists of patients whose grafts were tensioned to 
restore the normal anterior-posterior displacement of the tibia relative to the femur (“AP laxity”) at the time of 
surgery (i.e. AP laxity equal to that of the contralateral normal knee; the “low-tension” treatment). The second 
treatment group consists of patients whose grafts were tensioned to over-constrain the joint (i.e. AP laxity 2mm 
less than that of the contralateral knee; the “high-tension” treatment). In the last funding cycle, we have shown 
that the initial joint contact conditions between these two groups are significantly different in cadavers 39, and 
that the associated laxity differences in patients are different in vivo. The two treatment groups are being 
compared to a third matched control group. Fifty-four subjects were enrolled into each group. With this update, 
they will be followed 180 months after surgery. We are planning to follow these patients for a minimum of 15 
years. Significant changes in cartilage integrity are expected within this long-term time frame in this patient 
population 26,35,50. 
 
Radiographic assessment of joint space narrowing is the only validated indicator of structural change 
used to evaluate OA progression in clinical studies, and it will continue to be the primary outcome 
measure of cartilage damage 67. MR images of the articular cartilage and associated knee joint structures will 
provide secondary structural biomarkers for the early detection of OA 31. MRI is being used to directly measure 
changes in cartilage thickness in the load bearing regions 11,12, while joint integrity will be assessed using the 
Whole Organ Magnetic Imaging Score (WORM score) 56. Using these imaging-based outcome measures, we 
will test the primary hypothesis: 
 
● Tibiofemoral joint space width (via radiography) and cartilage thickness (via MRI) in the reconstructed 
knees of the “high-tension” treatment group will be equal to that of the control group, while the joint 
space width and cartilage thickness in the “low-tension” treatment group will be significantly less than 
that of the control group 15 years after surgical reconstruction of the anterior cruciate ligament.  
 
Surgical outcome will also be assessed via: 1) patient-oriented outcome scores 59,76, 2) AP laxity (an 
indicator of graft integrity 6,44 and knee kinematics 23), 3) isokinetic strength (an indicator of dynamic 
knee function 16), and 4) clinical outcome scores 48,78. Analysis of primary and secondary outcomes will 
enable us to determine the long-term effects of initial graft tension on cartilage status and knee joint function, 
and to evaluate the relationships between longitudinal changes that occur in tibiofemoral (TF) joint space (x-
ray), cartilage thickness (MRI), general MRI scores (WORM score), knee laxity (KT-1000), strength (Biodex 
strength test, 1 legged hop test) and patient-oriented outcome scores (SF-36, Knee Osteoarthritis Outcome 
Score). In the past funding cycle, data were obtained from ACL-reconstructed patients pre-operatively, 
immediately post-operatively, and after 6, 12, 36, and 84 months of healing. From the control group data were 
obtained at the time of recruitment and at 12, 36, and 84 months. In this update, additional evaluations will be 
performed 144 and 180 months in the ACLR and control subjects, a time frame in which cartilage damage 
should become prevalent in the ACLR patient population. We intend to follow these patients for a minimum of 
15 years. 

 
 
RESEARCH DESIGN AND METHODS 
 
1. 
Overview of Research Design 
 
This investigation is designed as a prospective, randomized, double-blinded clinical study evaluating 
the effects of two different initial tension conditions applied to an ACL graft at the time of fixation on 
healing using biomechanical, clinical, and patient-oriented outcome measures. The primary outcome is 
evaluating the progression of OA via objective radiographic measurements of joint space narrowing. We are 
also assessing temporal changes in cartilage thickness, and the integrity of various knee joint structures using 
MRI. We will test the hypothesis that tibiofemoral (TF) joint space width (via radiography) and cartilage 
thickness (via MRI) in the reconstructed knees of the “high-tension” treatment group will be equal to that of the 
control group, while the joint space width and cartilage thickness in the “low-tension” treatment group will be 
significantly less than that of the control group 15 years after surgical reconstruction of the ACL. We intend to 
follow these patients for a minimum of 15 years. 
 
Surgical outcome will also be assessed via: 1) patient-oriented outcome scores 59,76, 2) AP laxity (an 
indicator of graft integrity 6,44 and knee kinematics 23), 3) isokinetic strength (an indicator of dynamic 
knee function 16), and 4) clinical outcome scores 48,78. Analysis of primary and secondary outcomes will 
enable us to determine the long-term effects of initial graft tension on cartilage status and knee joint function, 
and to evaluate the relationships between the longitudinal changes that occur in TF joint space narrowing (x-
ray), cartilage thickness (MRI), general MRI scores (WORM score), knee laxity (KT-1000), thigh strength 
(Biodex strength test, 1 legged hop test) and patient-oriented outcome scores (SF-36, Knee Osteoarthritis 
Outcome Score). In the past funding cycle, data were obtained prospectively from ACLR patients and matched 
control subjects from the time of recruitment (pre-operative) through 84 months of healing. In this update, 
additional evaluations will be performed 144 and 180 months, a time frame in which cartilage damage should 
become more pronounced in this patient population. These analyses will shed light on potential factors that 
may play a role in the degenerative process and long-term outcome.  
 
2. 
Subjects 
 
108 ACL-injured patients, who required ACLR, were recruited during the first three years of the initial 
funding cycle. It was our intent to identify patients with isolated ACL injuries while minimizing confounding 
variables. To do this, all patients who came through the sports medicine clinics of University Orthopaedics Inc 
between 02/09/2004 and 02/08/2007 were considered for the study. All who met the pre-operative inclusion 
criteria and did not meet the exclusion criteria (Table 1) were asked to participate and provide their informed 
consent. Additional “intra-operative” inclusion/exclusion criteria were then evaluated at the time of surgery 
(Table 1). If the patient remained eligible, minimum likelihood allocation was used to randomly assign each 
subject to one of the two initial graft tension groups 1. Randomization was performed to achieve balance 
between the treatment groups for characteristics that would influence long-term outcome and cartilage health; 
age, gender, race, and activity level (Tegner score). The number of patients who injured their ACL and choose 
ACLR within the clinical practice was documented, and the reasons for excluding subjects were recorded.  
 
60 “matched” control subjects, who had no known history of knee injury or symptoms of arthritis, were 
recruited from the hospital campus, local colleges, and Providence community. They were selected to 
match the frequency of individuals by age (±5 years), gender, race, and activity level (Tegner score ± 1 point). 
The subjects’ knees were evaluated by clinical exam at a screening visit. Subjects were not included in the 
control group if they have a side-to-side difference in AP laxity greater than or equal to 2-mm (KT-1000), a 
Tegner activity score less than 5 69, or if they meet any of the other exclusion criteria (Table 1). It was our intent 
to establish a control group that matched the characteristics of the population at risk to ACL injury.  
 
 
3. 
Research Design 
 
This study is designed as a prospective, randomized, double-blinded controlled trial comparing the 
outcome of two different initial tension conditions applied to the ACL graft at the time of surgery, and 
to determine the relationship between factors that may predict who will be risk for OA. The project 
statistician and the operating surgeon initially knew a patient’s assignment at the time of surgery, however, the 

 
 
surgeon was not allowed to review the assignment once the surgery was completed, and the statistician was 
not allowed to review the assignments until after all the subjects were enrolled. The patient, the therapist 
performing the follow-up assessments, the AP laxity and isokinetic strength testing, the engineer performing 
the radiographic joint space width and cartilage thickness measurements, and the radiologist performing the 
WORM scoring will continue to be blinded from the subject’s group assignment throughout the study. An intent-
to-treat protocol is being utilized. All subjects randomized to each group are being followed, and all available 
data will be analyzed even if the graft fails, if the subject is unwilling to perform a particular follow-up test 
(missing data), or if a subject completely drops out of the study.  
 
Table 1. 
Inclusion/exclusion criteria for patient enrollment. 
 
Treatment Groups (Hi- and Lo-tension) 
Inclusion 
Criteria 
Male or female subjects between the ages of 15 and 50 years with unilateral ACL injury. 
Candidates for ACLR using bone-PT-bone or four-stranded hamstring tendon autograft. 
A Tegner activity score 69 ≥ 2. 
Minor tears of the menisci that require minimal treatment (<1/3). 
Exclusion 
Criteria 
An ACL tear occurring more than 12-months prior to the 1st office visit. 
Previous injury to either knee. 
Increased clinical laxity of the MCL, LCL, or PCL as compared to the control knee. 
Evidence of degenerative arthritis on radiographs. 
Women who are pregnant. 
Diseases that predispose a patient to articular cartilage damage. 
Moderate sized fissures or lesions in articular cartilage. 
Meniscal tears requiring partial meniscectomy involving more than 1/3 of meniscus. 
Control Group 
Inclusion 
Criteria 
Male or female subjects between the ages of 18 and 50 years. 
A Tegner activity score 69 ≥ 2. 
Exclusion 
Criteria 
Previous injury to either knee. 
Increased laxity of the MCL, LCL, or PCL compared to the control knee. 
Evidence of degenerative arthritis on radiographs 
Women who are pregnant. 
Diseases that predispose a patient to articular cartilage damage (e.g. rheumatoid 
arthritis, osteoporosis, metabolic diseases). 
 
Patients were included in the study if they were candidates for autogenous ACLR with either a bone-
patellar tendon-bone or a 4-stranded hamstring tendon graft. Due to the popularity of these graft types, 
both were included to extend the recruitment base. It should be noted that we initially proposed to include only 
bone-patellar tendon-bone grafts in the study. However, the recent surge in popularity of the hamstring tendon 
graft and the need to extend our recruitment based convinced us to include this procedure after eight months 
of recruiting candidates for patellar tendon autograft only. This was justified since recent biomechanical studies 
have shown that the structural properties of the patellar tendon autograft are equal to that of the 4-stranded 
hamstring tendon autograft 79. Likewise, the in-situ forces, the passive load-displacement response, and 
dynamic kinematics of reconstructed knees with patellar tendon and 4-stranded hamstring tendon grafts are 
equivalent 68,82. Recent prospective randomized clinical trials comparing these two graft types have shown that 
functional and patient-oriented outcomes are equivalent 2,3,19,33,34,41,42,49,62,64. Finally, the two graft tension 
procedures in this study produced the same AP laxity values between graft types. Other than graft type, all 
surgically related parameters were standardized across surgeons. The same surgical instrumentation within 
each graft type was used to ensure that intra-articular graft placement was similar between patients. “Aperture” 
fixation interference screws were used to standardize graft fixation. Another variable, which could possibly 
affect outcome, is the rehabilitation program prescribed following surgery 8. Recent data comparing commonly 
used rehabilitation protocols has shown that rehabilitation with either an “accelerated” or “non-accelerated” 
program would produce the same clinical, functional and patient oriented outcomes 5,8. Nonetheless, all 

 
 
subjects were required to follow the same “accelerated” rehabilitation program, which was geared to get 
patients back to sport within 6-months. 
 
4. 
Independent variable (Initial graft tension condition based on AP laxity) 
 
Two initial graft tension conditions are being compared; 1) a graft tension that restored the AP laxity of 
the ACLR knee to that of the contralateral ACL intact knee (the “low-tension” treatment), and 2) a graft 
tension that reduced the AP laxity by 2mm in comparison to the contralateral ACL-intact knee (the 
“high-tension” treatment) at the time of surgery. Thus, a graft tensioning protocol that is based on the AP 
laxity at the time of graft fixation (“laxity-based” approach) was selected for this study instead of a “tension-
based” approach 39. It has been shown that the graft tension immediately after fixation is dependent on the 
knee angle and magnitude of tension applied immediately prior to fixation and that an increase in graft tension 
reduces knee laxity 17,38,39,81. The laxity-based approach implies that the tension in the graft is adjusted to 
produce an AP laxity value that is equal to or less than that of the contralateral normal knee, depending on a 
subject’s group assignment. A tension-based approach (e.g. 20 N, 40 N, etc) was not used for this study 
because the amount of force required to restore AP laxity would be subject specific 15, and prone to other 
sources of error 40,75. Although a laxity-based tensioning approach may require a variety of tension levels to be 
applied across patients within a treatment group, the tension applied to the graft in an effort to recreate normal 
AP laxity would be less than that required to over-constrain the joint, hence the terminology of “low-tension” 
versus “high-tension”. It is known that AP laxity values are significantly less when the graft is tensioned at 30o 
in comparison to full extension (0o), thus it is easy to control AP laxity by tensioning the graft at different knee 
flexion angles. The two initial tension treatments were controlled as follows. For the “low-tension” treatment, 
the tension was applied to the graft with the knee at 0o flexion (full extension). After an initial tension level was 
selected, the knee was flexed to 20o and an AP laxity test was performed (using the KT-1000S). The tension 
was adjusted iteratively until the AP laxity of the ACLR knee matched that of the contralateral limb (± 1.0 mm). 
For the “high-tension” treatment, the tension was applied with the knee at 30o of flexion. The tension was 
adjusted until the AP laxity value at 20o of flexion is 2mm (±1.0 mm) less than the contralateral limb. The graft 
was then fixed with an interference screw, and the laxity value rechecked to ensure that the initial tension 
condition was maintained during fixation. The difference in knee flexion angle at which the tension was applied 
between the high-tension treatment as compared to the low-tension treatment assists in producing a lower AP 
laxity value at 20o. Thus, higher forces are produced in the graft across the full range of knee flexion angles 
17,38,81. Another advantage of using AP laxity at the time of graft fixation to control graft tension was that 
changes in AP laxity can be measured at the post-operative follow-up visits as well. It would not be possible to 
directly measure graft forces immediately after graft fixation and at the follow-up visits if a tension-based 
approach was utilized. In our pilot analysis we demonstrated that it is possible to restore normal laxity (at +/- 90 
N shear force) and to reduce AP laxity by at least 1.5mm (at ± 90 N shear force) compared to the normal side 
using these initial graft-tensioning protocols. For the patients enrolled in the current study, the mean (± 
standard deviation) laxity difference at 133 N (reconstructed knee – control knee) for the high-tension group 
was -2.1 (±0.69) and -0.3 (±1.29) mm for the high- and low-tension groups, respectively, with the “manual 
maximum” test 23. The required difference in AP laxity at the time of graft fixation between tensioning 
techniques (the independent variable) was achieved. 
 
5. 
Outcome Measures (dependent variables) 
 
In this comprehensive evaluation of the effects of initial graft tension on ACLR, five sets of outcomes 
are under examination: 1) Imaging assessment of OA progression; 2) Patient-oriented outcomes; 3) 
Knee kinematics; 4) Dynamic joint function; and 5) Clinical outcome. Within each category (Tables 2&3), 
at least one test will be performed. In those categories featuring two or more tests, the first will be considered 
the primary test of that category.  
 
5.1. 
Imaging assessment of OA progression 
 
Joint Space Narrowing (radiography): Measurement of joint space narrowing via radiographs is the 
current validated standard for quantifying the progression of OA in clinical studies 67, and is serving as 
the primary imaging outcome measure 54. Joint space width measurements are obtained from radiographs 
based on the semi-flexed metatarsophalangeal (MTP) view as originally described Buckland-Wright 14. The 

 
 
subjects stand facing the x-ray cassette with their weight evenly distributed between both feet. A custom 
designed platform that helps standardize limb and body position is used 29,54. The first MTP joint of each foot is 
aligned with, and below, the front edge of the digital cassette. The subjects’ feet are then rotated 15° externally 
(determined by the angle of the 2nd ray with the A-P axis), while maintaining the correct orientation of the MTP 
joint relative to the film cassette. The subjects then flex their knees until their patellae contact the film cassette. 
With the subjects in position for the first time, outlines of their feet were drawn on a dedicated paper to produce 
a foot map that is then used when repositioning the subjects for the subsequent radiographs over the long-
term. Posterior-anterior radiographs are taken of each knee. Measurements of joint space width in the medial 
and lateral compartments are then performed on the digital radiographs. The midpoint technique, as described 
by Ravaud et al. 58, is used to determine the joint space with custom developed software 54. Vertical lines are 
drawn at the medial and lateral aspects of the medial and lateral tibial plateaus and through the respective 
apex of the tibial spine. A third vertical line is then drawn equidistant between the two lines describing each 
compartment. The measurement points are selected from the two bony intersections of the midpoint lines. 
Subjects are identified as having radiographic signs of OA if they exhibit a change in the medial or lateral 
compartments greater that 0.30mm over the study period 51. 
 
Table 2: 
Schedule of follow-up visits and outcome measures for the ACLR treatment groups: MRI = 
Cartilage volume 12,31, thickness 11,12 & WORM score 56; JSN = joint space narrowing 29,54; DRS = Daniel Rating 
Scale 26; KT-1000 = Passive AP laxity 23; IKS = isokinetic strength testing 16; 1-hop = one-leg hop test 78; KOOS 
= Knee Injury and Osteoarthritis Outcome Score 59; SF36 = Short form 36 76; IKDC = International Knee 
Documentation Committee Score 48; and MA = muscle atrophy. Shaded areas denote the assessments from 
the previous funding cycle. 
 
Outcome 
Category 
Pre-op 
0-mo 
post-
op 
6-mo 
post-
op 
12-mo 
post-
op 
36-mo 
post-op 
60-mo 
post-op 
84-mo 
post-op 
144-mo 
post-op 
180-mo 
post-op 
OA 
JSN/MRI; 
DRS 
 
 
JSN; 
 
JSN/MRI; 
DRS 
JSN/MRI; 
DRS 
JSN/MRI; 
DRS 
JSN/MRI; 
DRS 
JSN/MRI; 
DRS 
Pt-oriented  
Outcome 
KOOS; 
SF36 
 
KOOS; 
SF36 
KOOS; 
SF36 
KOOS; 
SF36 
KOOS; 
SF36 
KOOS; 
SF36 
KOOS; 
SF36 
KOOS; 
SF36 
Knee 
Kinematics 
KT-1000; 
 
KT-
1000; 
 
KT-
1000; 
 
KT-
1000; 
 
KT-1000; 
 
KT-1000; 
 
KT-1000; 
 
KT-1000; 
 
KT-1000; 
 
Dynamic     
Function 
IKS; 
1-hop 
 
 
IKS; 
1-hop 
IKS; 
1-hop 
IKS; 
1-hop 
IKS; 
1-hop 
1-hop 
1-hop 
Clinical 
Outcome 
IKDC; 
MA 
IKDC; 
MA 
IKDC; 
MA 
IKDC; 
MA 
IKDC; 
MA  
IKDC; 
MA  
IKDC; 
MA  
IKDC; 
MA  
IKDC; 
MA  
 
Table 3: Schedule of follow-up visits and outcome measures for the control (ACL-intact) group. Shaded areas 
denote the assessments from the previous funding cycle. 
 
Outcome 
Category 
0-mo 
12-mo 
follow-
up 
36-mo 
follow-
up 
60-mo 
follow-
up 
84-mo 
follow-
up 
144-mo 
follow-
up 
180-mo 
follow-
up 
OA  
JSN/MRI; 
DRS 
JSN; 
 
JSN/MRI; 
DRS 
JSN/MRI; 
DRS 
JSN/MRI; 
DRS 
JSN/MRI; 
DRS 
JSN/MRI; 
DRS 
Pt-oriented  
outcomes 
KOOS; 
SF36 
KOOS; 
SF36 
KOOS; 
SF36 
KOOS; 
SF36 
KOOS; 
SF36 
KOOS; 
SF36 
KOOS; 
SF36 
Knee 
Kinematics 
KT-1000; 
 
KT-1000; 
 
KT-1000; 
 
KT-1000; 
 
KT-1000; 
 
KT-1000; 
 
KT-1000; 
 
Dynamic     
function 
IKS; 
1-hop 
IKS; 
1-hop 
IKS; 
1-hop 
IKS; 
1-hop 
IKS; 
1-hop 
1-hop 
1-hop 
Clinical 
Outcome 
IKDC; 
MA 
IKDC; 
MA 
IKDC; 
MA 
IKDC; 
MA  
IKDC; 
MA  
IKDC; 
MA  
IKDC; 
MA  
 

 
 
Subjective grading (radiography): The overall condition of the joint via radiographs will be graded 
using the system developed by Daniel et al 26. Weightbearing A-P, lateral and tunnel radiographs of the 
knees are taken before surgery and at the final follow-up visit. A grade of 0 (normal) to 3 (severe) will be 
assigned to six different radiographic factors: osteophyte formation, subchondral sclerosis, femoral condyle 
flattening, subchondral cysts, ligament calcification, and joint space narrowing. Each factor will be subdivided 
within regions of the knee. For example, osteophytes will be graded according to size (0=no osteophyte; 1=1- 
to 3-mm; 2=4- to 6-mm, and 3=<6-mm) in eight different sites; the medial femoral and tibial condyles, the 
lateral tibial and femoral condyles, femoral notch, tibial spine, femoral aspect of the patellofemoral joint, and 
the patella. A total radiographic score of 83 is possible, which represents severe damage. A zero represents no 
damage. A radiologist (GAT), who is blinded to the subject number and the subject’s group assignment, 
evaluates all of the films. 
 
Table 4: 
The scanning sequences being utilized for the MRI examinations (3T). The protocol was designed 
to provide the data to perform cartilage thickness measurements and the WORM scores while 
limiting MRI time to 1 hour per visit. 
 
Sequence 
Outcome  
Sagittal T1-weighted water-excitation (WE) three-dimensional (3D) fast low-angle shot (WE-3D 
FLASH): 20/7.6 [TR msec/ TE msec]; 12° [flip angle]; 160 mm [field of view, FOV]; 1.5 mm/0 
[slice thickness/interslice gap]; 80 slices per slab; 130 hz/pixel [bandwidth, BW]; 512x512 
[matrix]; right/left [phase encoding axis]; one average of two excitations. This sequence will 
cover all articular cartilage plates in the knee. 
Volume; 
Thickness; 
WORM 
score 
Coronal Intermediate-weighted turbo-spin echo (TSE): 3850/29; 7 [echo train length]; 140 mm; 
3mm/0mm; 41 slices; 352 hz/pixel; 307x384; right/left; one average. 
WORM 
score 
Sagittal¥ T2*-weighted WE-3D double echo steady state (WE-3D DESS): 16.3/4.7; 25°; 140 mm; 
0.7mm/0mm; 185 hz/pixel; 307x384; anterior/posterior; one average. 
WORM 
score 
Sagittal Intermediate-weighted TSE with fat-saturation: 3200/30; 5 ETL; 160 mm; 3mm/0mm; 248 
hz/pixel; 313x448; superior/inferior; one average. 
WORM 
score 
¥From the sagittal T2*-weighted WE-3D FLASH sequence, additional MR images will be reconstructed in both the   
transverse axial and coronal planes. 
 
Cartilage Thickness (MRI): Magnetic resonance (MR) imaging of both knees will be performed on a 3T 
whole-body scanner (Siemens TIM Trio; Erlangen, Germany) using a commercially available circularly-
polarized knee surface coil to measure temporal changes in cartilage thickness 11,12. Scans were 
obtained at the time of recruitment and after 36 and 84 months of healing and will be taken at the 144- and 
180-month follow-up visits. The cartilage thickness calculations will be based on the sagittal water-excitation 
T1-weighted 3D FLASH sequence (Table 4). A trained technologist, under the direction of the radiologist, will 
perform manual segmentations on all slices (1.5mm) for each knee using Mimics software 11. MRI's will be 
segmented in pairs and blinded to sequence. Segmented slices will then be grouped to generate a 3-D mesh 
to represent the volumetric shape 11,12,65. Once segmented, the cartilage structure will be registered between 
the multiple scans of the same subject taken at 0, 36, 60 and 84 months, the change in the shape of the 
cartilage will be characterized, and the shape and its change will be averaged and normalized across subjects. 
The segmented cartilage will be considered as unorganized point clouds, and intra-subject registration will be 
based on closest point algorithm 20-22,53,60. This will enable alignment of the cartilage between time points (0, 
36, 60 and 84 months) with a point-wise description of change. We will then focus our thickness 
measurements to the cartilage regions of the tibiofemoral joint with the greatest load bearing requirements. A 
cylinder will be fit to the bone-cartilage interface of the femoral cartilage of the reconstructed images. The 
notch marking the junction between the TF and patellofemoral joints on the lateral condyle is easy to identify 
on the sagittal MR view. A line will then be drawn from the notch (0o) to the center of the cylinder 12. Each 
condyle of the TF joint will then be divided at 40o, 70o, 100o, and 130o from the notch point toward the posterior 
aspect of the condyles to create 6 patches of cartilage (3 medial, 3 lateral); the width of each patch will be 20% 
of the overall width of the femoral cartilage and centered about the midline of each condyle (Fig. 6). Two 
patches on the tibial cartilage (1 medial, 1 lateral) will also be defined by calculating the centroid of each 
compartment and the inertial axes of the medial compartment using MATLAB (The Mathworks, Inc., Natick, 
MA). The inertial axes will serve as a coordinate system, and the patch in each compartment will be defined as 
the area ±20% of the overall depth (A-P) and ±15% of the overall width (M-L) from the centroid 12. The average 
thickness of each patch will be calculated by the closest point. The cartilage volume will be quantified for the 

 
 
tibia and femur by the numerical integration of the number of voxels contained within the segmented regions 
for each bone 32. The cartilage volumes will be normalized by the surface area of underlying bone from the 
Time 0 data set (pre-operative visit) in order to increase the construct validity of the measurement 47. Subjects 
will be labeled as having OA if they exhibit a cartilage volume loss exceeding 2.5% per year over the study 
period. This value was selected because patients without OA have been shown to have changes of 0.5% per 
year while those with OA lose approximately 4-6% per year 43. Although the changes in the cartilage volume 
for the femur will be assessed, the focus will be on the volume changes of the tibial condyles where OA is 
easiest to detect 18, and most affected by ACL injury 36. Note: Due to problems with artifact, this outcome 
measure was discontinued. The other imaging outcome measures were performed as originally planned. 
 
Whole Organ Magnetic Imaging Score (secondary MRI measure): The general status of the knee will be 
independently assessed by an expert musculoskeletal radiologist (G. Tung) and the PI using the semi-
quantitative WORM score 56,71,77. The scoring utilizes four MR sequences (Table 5). The images are scored 
with respect to 14 independent features 56. Cartilage signal and morphology (8-point scale), subarticular bone 
marrow abnormality (4-point scale), subarticular cysts (4-point scale), subarticular bone attrition (4-point scale), 
and marginal osteophytes (8-point scale) will be evaluated in 15 regions (2 in the patella, 6 in the femur, 7 in 
the tibia). The regions are subdivided by distinct anatomical landmarks as described by Peterfy 56. In addition, 
the menisci (5-points), cruciate and collateral ligaments (2-points each), synovitis (4-points), loose bodies (4-
points), and periarticular cysts (3-points) are scored. A total of 332 points per knee is possible. WORM scores 
are calculated for each feature in each compartment and for all features combined. The musculoskeletal 
radiologist assessing the WORM scores has the expertise in doing so for ACL injured patients 28,73,74. 
 
5.2. 
Patient-reported outcomes 
 
The Knee Injury and Osteoarthritis Outcome Score (KOOS) and the Medical Outcomes Study Short 
Form-36 (SF-36) will be used to assess patient-oriented outcomes. The KOOS addresses knee 
performance and was designed and validated to monitor changes in outcome and the progression of OA 
following ligament and meniscal injuries 59. The KOOS is a self-administered questionnaire that evaluates 
treatment outcomes within 5-categories: 1) pain, 2) symptoms, 3) activities of daily living, 4) sports and 
recreation function, and 5) knee related quality of life. All questions within each category are scored on a 5-
point scale. The scores within each category are added to produce a scoring profile (on a scale of 100 for each 
of the five categories) that can be followed over time. A 15-point decrease in the KOOS is equivalent to the 
difference between a “mild” and “moderate” deficit 59. Although all five scores are evaluated, those that are 
most sensitive to change after ACLR are the KOOS-quality of life and the KOOS-sports 59. These are expected 
to provide the greatest insight into the patient-oriented outcome of our patients. The SF-36 is a validated, self-
administered instrument that is commonly used to monitor general health and to evaluate treatment effects in 
clinical studies 76. It assesses physical function, role limitations due to physical health issues, bodily pain, 
vitality, social functioning, mental health, and reported health transition. 
 
 
5.3. 
Knee kinematics 
 
A-P laxity: Passive laxity measurements 24,27, that are obtained with the leg muscles relaxed, are an important 
outcome since they assess ligamentous and capsular function, are predictive of the graft material properties 
6,44, and correlate with radiographic change in ACL-deficient knees 26. The KT-1000 is the most reliable of the 
commercially available knee laxity measurement devices 37,66, and is used by the clinical coordinator to 
document A-P laxity. For this study, A-P laxity is defined as the amount of A-P directed translation of the tibia 
(relative to the femur) between the shear load limits of -90 N (posterior) and 133 N (anterior). A-P laxity 
(instead of anterior laxity) was selected since variability is reduced when sagittal plane laxity is referenced to a 
posterior shear load rather than zero load 23,37. 
 
5.4. 
Dynamic joint function 
 
Isokinetic strength testing is performed to assess the strength of the quadriceps muscles. Isokinetic 
strength of the quadriceps has been shown to be a predictor of the peak external flexion moments that is 
produced during jogging (r2 = 0.83) 16,55. The clinical coordinator administers the tests using the Biodex System 
3 (Biodex Medical Systems, Inc. Shirley NY) located in our research facility. The subjects are positioned on the 

 
 
device with its axis of rotation aligned with the transepicondylar axis of the femoral condyles. The subjects 
perform the tests at 60o/sec 16. Averaging the peak torques of five repetitions and normalizing these values with 
respect to bodyweight and height quantifies peak quadriceps strength. Both knees are tested. Note: The 
isokinetic testing system failed after the 84-month follow-ups were completed. The system was not replaced 
and thus will not be used for the 12 and 15-year follow-up assessments.  
 
One-leg hop test is also performed to assess function 61,78. The subject performs the one-leg hop test for 
distance independently on each leg. Three trials for each are recorded and averaged. The difference in 
distance between the reconstructed and the normal knee is calculated. 
 
5.5. 
Clinical outcome 
 
Clinical outcome will be assessed using the International Knee Documentation Committee (IKDC) knee 
rating scale 23,48. The IKDC rating has been validated for ACLR 48. The IKDC scores evaluate four categories: 
1) the patient’s subjective assessment of function, 2) symptoms, 3) range of knee motion, and 4) clinical 
examination. The IKDC score rates knees as normal, nearly normal, abnormal, and severely abnormal, which 
can be transformed to an ordinal scale of 1 (normal) to 4 (severely abnormal). The final IKDC rating is then 
based on the score of the worst category 48. In addition, height, weight, body mass index, thigh circumference 
(6cm above joint line) and the number of recurrent injury episodes is recorded. A sports medicine physician 
and a physical therapist will continue to independently perform all of the pre- and post-operative clinical 
examinations. 
 
6. 
Controlled Variables 
 
Investigators have shown that the initial graft tension level required to restore normal knee laxity is 
specific to the graft material, cross-sectional area of the graft, and the free length of the graft between 
fixation sites 15, and these were controlled in this study. Initially, subjects undergoing ACL reconstruction 
using a bone-patellar tendon-bone autograft were recruited to control the variability due to graft type. However, 
there has been a recent surge in the popularity of the 4-stranded hamstring tendon graft. Thus, we elected to 
recruit patients who were candidates for ACL reconstruction with 4-stranded hamstring autografts to increase 
our population base. This was justified because recent biomechanical studies have demonstrated that the 
structural properties of the patellar tendon autograft are equal to that of the 4-stranded hamstring tendon 
autograft 79. Likewise, the in-situ forces, the passive load-displacement response, and dynamic kinematics of 
reconstructed knees with patellar tendon and 4-stranded hamstring tendon grafts are similar 68,82.  Finally, 
recent prospective randomized clinical trials have shown that functional outcome following ACL reconstruction 
with 4-stranded hamstring or patellar tendon autografts are equivalent 2,3,19,33,34,41,42,49,57,62,64.  
 
The intra-articular position of the graft has been shown to affect the graft forces post-operatively, and 
was standardized in this study 10,17,25,38,46. A 2 mm deviation in femoral graft placement has been shown to 
have a pronounced effect on the graft elongation pattern 45. A graft that is placed to far anterior on the femur 
will cause it to get tight in flexion and slack in extension. Likewise, a graft that is placed in the “over-the-top” 
position will get tight in extension and slack in flexion. Thus, intra-articular graft position may influence the 
healing response 9,70. However, all the surgeons utilized the same drill guide system and anatomical landmarks 
to standardize graft position across subjects. Although variation may still exist, we have previously shown that 
they are equally distributed within each treatment group 9.  
 
Another standardized variable, which could possibly affect outcome, is the rehabilitation program 
prescribed following surgery 8. Recent data comparing commonly used rehabilitation protocols suggest 
otherwise. We have shown that rehabilitation with either an “accelerated” or “non-accelerated” program 
produces the same outcome with respect to AP knee laxity, clinical assessment, patient satisfaction, functional 
performance, strength, and proprioception 5,8. In the current study, all subjects were required to follow the 
“accelerated” rehabilitation program. They received supervised post-operative physical therapy for a minimum 
of 16 weeks. Because the patients were randomly assigned to each treatment group, we feel that any deviation 
from the rehabilitation program (either produced by the patient’s inability to keep up with the program, or the 
patient’s unwillingness to follow the prescribed rehabilitation) was equally distributed between the two groups.  
 

 
 
7. 
Protocol Summary 
 
When a subject (either surgical or control) consents to continue their participation in the study, 144- 
and 180-month follow-up assessments will be performed. All patients have been previously enrolled into 
the study. However, the lay summary consent forms were based on an 84-month follow-up. Therefore, the 
subjects will need to be re-consented in order to participate in the extended study. The clinical coordinator will 
consent the patients after contacting them via mail with a phone call follow-up. Within the initial contact letter, a 
card will be provided so that the subject can let us know if they do not want us to contact them by phone.  
 
The clinical examinations will occur at the sports medicine clinic of University Orthopaedics Inc. At the 
first visit (144 month), the subject will meet with the clinical coordinator to finalize the consent forms. Once the 
subject has granted informed consent, an X-ray technician will acquire the radiographs for the joint space width 
measurements. These will be obtained under the direction of the clinical coordinator who will make sure all the 
necessary steps required to reposition the patient relative to the x-ray system are taken. A research physical 
therapist will independently perform the clinical exam (IKDC). At this time, the clinical coordinator will 
administer the questionnaires (SF-36; KOOS; Tegner), the A-P laxity exam (KT-1000) and the functional 
assessment (One-leg hop). The clinical coordinator will also schedule the MRI examination, which will be 
performed at another site.  
 
The MRIs will be performed at the MRI Research Facility at Brown University under the guidance of a 
certified MR technician. The scans (Table 4) will be performed using the TIMS Trio scanner. The scans will 
be WORM scored by a board-certified radiologist with expertise in musculoskeletal MR.  
 
All subjects will be contacted by the clnical coordinator via phone each year that a visit is not 
scheduled. The primary reason for this will be to keep all of the subjects engaged in the study. 
 
8. 
Statistical analyses 
 
Treatment Comparisons - Primary Outcome Measure: Repeated measures analysis of variance will be 
used to evaluate differences among treatment groups with respect to temporal changes in joint space width 
(i.e. joint space narrowing). The statistical model will include fixed factors representing treatment group (“low-
tension”, “high-tension” and “control”), limb (operative vs. contra-lateral or two controls), location (medial vs. 
lateral), time (baseline, 12-, 36-, 60-, and 84-month), and their interactions. If significant interactions are 
detected, simple effects will be compared using the Student-Newman-Keuls procedure based on the 
appropriate error terms 80. Because one of the repeated factors (i.e. time) is quantitative, orthogonal polynomial 
will be used to partition the time effect into its individual quantitative components (i.e. linear and quadratic). The 
significance of these orthogonal contrasts will be used to evaluate the linearity (or non-linearity) of the temporal 
trend associated with degeneration. Analyses will be performed using SAS, PROC MIXED 52 that allows for 
covariance structures other than compound symmetry (e.g. unstructured, autoregressive, spatial power law). It 
is expected that the variability across subjects may increase across time due to only a subset of individuals 
exhibiting degeneration, which would violate the standard homogeneity of variance assumptions. The normality 
assumption will be examined based on residuals using normal probability plots and the Wilk-Shapiro test. If 
necessary, data will be transformed prior to analysis in order to satisfy the distributional assumptions.  
 
Treatment Comparisons - Secondary Outcome Measures: Repeated measures analyses of variance will 
also be used to test for differences in secondary outcome measures corresponding to knee kinematics, 
dynamic function, patient reported outcomes, and clinical outcomes. For measures that are performed on each 
limb (e.g. A-P laxity), the statistical model will include fixed factors representing treatment group, limb, and 
time, along with their interactions. Repeated measures analyses on secondary outcome that are not limb-
specific (e.g. KOOS and SF36) will include only treatment, time, and their interaction as factors. Post hoc 
analyses involving tests of simple effects and orthogonal polynomials will be similar to methodology previously 
described for joint space width. Because specific secondary outcome measures are assessed more frequently 
in the two experimental arms than in the control group (Tables 2&3), direct post hoc comparisons involving the 
two tension groups and examination of temporal trend in these group will utilize the additional assessments. 
 

 
 
Relationship between A-P Laxity and Progression of OA: The longitudinal relationship between A-P laxity 
and progression of OA as measured by joint space narrowing (both radiographically and using MRI) will be 
examined in the context of hierarchical linear modeling 13, also known as random coefficient modeling. Using 
data obtained from the experimental subjects, SAS PROC MIXED will be employed to examine the association 
between individual subjects' changes in A-P laxity with their changes in joint space width (radiography) or 
cartilage thickness (MRI). This will be accomplished by considering A-P laxity as a covariate (predictor) that 
would potentially change over time with joint space width and cartilage thickness being considered as the 
dependent measures. Individual subjects are modeled based on unique intercepts and slopes corresponding to 
time and the covariate. Across subject factors such as tension group, gender, graft type, and age will also be 
considered. A similar analysis will be performed to establish the relationship between isokinetic strength, 
KOOS, functional testing and OA progression. 
 
Missing Visits and Subject Loss to Follow-up: Unlike traditional software used for repeated measures 
analyses (e.g. SAS PROC GLM and BMDP -2V), PROC MIXED appropriately handles incomplete data due to 
missed visits without completely excluding subjects from the analysis. The pattern of missing data is assumed 
to be random, which in-practice, is likely to be violated to some degree. We will test for differences in the rate 
of missed visits across treatment groups and across time using categorical repeated measures (SAS, PROC 
CATMOD). The proportion of subjects that are loss to follow-up will be compared across treatment and control 
arms using a chi square test.  Though we are finding that missed visits are infrequent and most likely equally 
distributed across treatment groups, we will examine whether specific baseline characteristics that may be 
predictive of outcome are also associated with missed visits using logistic regression. We recruited 54 subjects 
per group in an effort to have 46 assessable subjects per group at the three-year follow-up visit based on the 
estimated 15% dropout rate. We have more than met this goal (3% drop out in our treatment groups and 15% 
drop out in our control group at 3 years. For the proposed 180-month follow-up, we expect that we will have at 
least 35 patients/subjects in each group (20% drop out rate of subjects currently enrolled).  
 
Justification of Sample Size based on Primary Outcome Measure: The estimated sample size of 35 
assessable subjects per group through the 84-month study period will result in having sufficient power (1-
β=0.80 using α=.05) to detect a mean difference between groups of 0.25 mm in joint space narrowing over the 
84-month study period. This estimated difference is based on the following rationale. Previous studies have 
shown that patients with primary OA exhibit an estimated 0.3-mm change in joint space width per year 51,63. 
Since we will be studying patients at the time of OA onset, we will assume that patients who undergo initial 
changes will exhibit an average joint space narrowing of 0.1 mm per year, or a total of approximately 0.6 mm 
over the 84 months. This estimate was conservatively adjusted based on the study by Johma et al, who found 
that only 50% of the subjects that undergo ACL reconstruction after injury exhibit early degenerative changes 
following surgery 50. After taking into account that only a subset of subjects randomized may exhibit OA, the 
resulting mean difference is decreased to be 0.25-0.30 mm over the 84-month study period. An additional 
consequence of only a subset of the patients that are randomized exhibiting degeneration is an increase in the 
variability encountered across subjects with respect to joint space narrowing. The variability estimate used in 
our computations (σ∆=0.35 mm) resulted from increasing the estimate derived from the literature for a group of 
subjects with OA in order to reflect our expected mixture of two subsets of subjects. Based on each subset 
having σ∆=0.20, with 50% of the patients exhibiting narrowing a total of 0.6 mm and 50% showing no 
degeneration, the resulting overall estimated σ∆=0.35. Assuming joint space width at baseline is approximately 
4.5 mm 30, this detectable mean difference (0.25 mm) represents an approximate 5% change between the 
treatment groups in the mean rate of degeneration. We recruited 54 subjects per group in an effort to have 46 
assessable subjects per group at the three-year follow-up visit based on the estimated 15% dropout rate 4,7. 
We have more than met this goal (3% drop out in our treatment groups and 15% drop out in our control group 
at 3 years). For the proposed 180-month follow-up we expect that we will have at least 35 patients/subjects in 
each group (20% drop out rate of subjects currently enrolled).  
 
Power for Secondary Outcome Measures: Having determined the number of subjects needed to have 
sufficient power to detect expected differences in joint space narrowing, we computed the magnitude of the 
detectable difference for the main secondary outcome measures.  These estimates are based on our previous 
data and values found in the literature. When the estimates were based on cross-sectional data from the 
literature (i.e. isokinetic strength), moderate correlation across time was assumed (r=0.50). The following mean 
differences correspond to the estimated power=0.80 and α=.05 with the proposed sample sizes: A-P laxity = 

 
 
1.25 mm (a 16% change relative to the normal A-P laxity value 72); isokinetic knee strength = 18.5 Nm (a 12% 
change relative to normal, a “mild” deficit 16); KOOS- QOL score = 10.5 (a 10% change relative to full scale, 
considered less than a mild deficit 59); KOOS-sports score = 10.1 (a 10% change relative to full scale, 
considered less than a mild deficit 59), and IKDC score =.50 (a 12% change relative to normal 48). 
 
Note (9/29/2017): The 7 year data were completed and published in the American Journal of Sports Medicine 
in January 2016 (http://www.ncbi.nlm.nih.gov/pubmed/27159308). The study was extended to 12 and 15 years 
and the data collection for these time points is currently underway. 
 
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