Vibratory Stimuli: A Novel Rehabilitation Method for Preventing Post-traumatic Knee Osteoarthritis
Phase: NA
Conditions: Knee Osteoarthritis
Sponsor: University of North Carolina, Chapel Hill

 
Vibratory Stimuli: A Novel Rehabilitation Method for Preventing Post-
Traumatic Knee Osteoarthritis 
 
 
 
NCT number: NCT02605876  
Document Date: 10/14/2019  
 

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PROTOCOL TEMPLATE: INTERVENTIONAL STUDY 
 
Complete Title: Vibratory Stimuli: A Novel Rehabilitation Method for Preventing Post-Traumatic Knee 
Osteoarthritis  
Short Title: Vibration and Knee Osteoarthritis 
Drug or Device Name(s): whole body vibration, local muscle vibration 
FDA IND/IDE (if applicable): IDE granted by UNC-Chapel Hill Biomechanical IRB (IRB# 15-0838) 
Sponsor: US Department of Defense 
Protocol Date: 5/18/2015 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
Table of Contents ...................................................................................................................... 2 
Abbreviations and Definitions of Terms .................................................................................... 3 
Protocol Synopsis ...................................................................................................................... 4 
1 
BACKGROUND  AND RATIONALE .......................................................................................................................... 6 
2 
STUDY OBJECTIVES ................................................................................................................................................ 9 
3 
INVESTIGATIONAL PLAN ....................................................................................................................................... 9 
4 
STUDY PROCEDURES ........................................................................................................................................... 10 
5 
STUDY EVALUATIONS AND MEASUREMENTS ................................................................................................... 13 
6 
STATISTICAL CONSIDERATIONS .......................................................................................................................... 14 
7 
STUDY INTERVENTION (DEVICE OR OTHER INTERVENTION) ............................................................................ 16 
8 
STUDY INTERVENTION ADMINISTRATION ......................................................................................................... 16 
9 
SAFETY MANAGEMENT ....................................................................................................................................... 17 
10  DATA COLLECTION AND MANAGEMENT ............................................................................................................ 18 
11 RECRUITMENT STRATEGY ................................................................................................................................... 18 
12 CONSENT PROCESS ............................................................................................................................................. 19 
13 PUBLICATION ....................................................................................................................................................... 13 
14 REFERENCES ........................................................................................................................................................ 13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
 
 
 
Abbreviation 
Definition 
ACL 
Anterior cruciate ligament 
ACLR 
Anterior cruciate ligament reconstruction 
CAR 
Central activation ratio 
HST 
Heelstrike transient 
LMV 
Local muscle vibration 
OA 
Osteoarthritis 
vGRF 
Vertical ground reaction force 
WBV 
Whole body vibration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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PROTOCOL SYNOPSIS 
 
Study Title 
Vibratory Stimuli: A Novel Rehabilitation Method for Preventing 
Post-Traumatic Knee Osteoarthritis  
Funder 
US Department of Defense 
Clinical Phase 
Phase II 
Study Rationale 
Anterior cruciate ligament injury and reconstruction surgery (ACLR) 
dramatically increase the risk of developing knee osteoarthritis (OA). 
Individuals with ACLR possess deficits in quadriceps muscle function 
and proprioception (joint position sense) that alter knee joint 
loading during tasks such as walking in manners that contribute to 
development of knee OA. Vibratory stimuli enhance quadriceps 
function and proprioception and may, therefore, reduce the risk of 
knee OA. The purposes of this study are to 1) evaluate and compare 
the effects of whole body vibration (WBV) and local muscle 
vibration (LMV) on quadriceps function, knee joint proprioception, 
and walking gait biomechanics in individuals with ACLR and 2) 
identify characteristics that determine the efficacy of WBV and LMV 
for improving quadriceps function, knee joint proprioception, and 
walking gait biomechanics in individuals with ACLR. 
Study Objective(s) 
Primary  
• 
To determine the effects of WBV and LMV on quadriceps 
function, proprioception, and gait biomechanics in individuals 
ACLR 
• 
To compare the effects of WBV and LMV on quadriceps 
function, proprioception, and gait biomechanics in individuals 
ACLR 
• 
To identify factors that predict the effects of LMV and WBV on 
quadriceps function, proprioception, and gait biomechanics in 
individuals ACLR 
Test Article(s) 
WBV or LMV delivered at a frequency of 30Hz and intensity of 2g 
Study Design 
 
This preclinical investigation will utilize a single-blind randomized 
controlled experimental design whereby 75 individuals with primary 
unilateral ACLR will be randomly assigned to WBV, LMV, and Control 
groups.  Stratified randomization into 3 groups of equal size (n = 25) 
will be performed using a computer generated randomization 
algorithm to ensure stratification with respect to age and time since 
ACLR. 
Subject Population 
key criteria for Inclusion 
and Exclusion: 
Inclusion Criteria 
1. Subjects age 18-35 

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2. Undergone primary unilateral ACLR within 6 months to 5 
years of participation 
3. Knee Injury and Osteoarthritis Outcome Score (KOOS) self-
report survey Pain subscale score > 53.1 and Symptom 
subscale score > 44.9 
4. Cleared by physician to resume physical activity, and 
currently physical active at least 20 minutes 3x per week 
5. Quadriceps central activation ratio < 95% 
Exclusion Criteria 
6. History of ACL graft rupture 
7. History of neurological disorder 
8. History of musculoskeletal injury to either leg within the 6 
months prior to participation 
9. Pregnant or planning to become pregnant 
Number Of Subjects  
75 
Study Duration 
Each subject’s participation will last approximately 3 hours and 45 
minutes over approximately 2 weeks. 
The entire study is expected to last 3 years. 
Study Phases 
Screening 
Study Treatment 
Follow-Up   
(1) Screening: screening for eligibility and obtaining consent and (2) 
Intervention: study intervention/experimental treatment.  Phase 2 
will involve 2 testing sessions separated by approximately 1 week.  
Efficacy Evaluations 
1. Gait biomechanics (vertical ground reaction force linear and 
instantaneous loading rates, peak internal knee extension 
moment, peak internal knee valgus moment) 
2. Somatosensory function (knee joint position sense error) 
3. Quadriceps function (isometric peak torque) 
Statistical And Analytic 
Plan 
Pre-Post change scores for each of the primary outcomes will be 
compared between groups via one-way ANCOVA 
DATA AND SAFETY 
MONITORING PLAN 
David Berkoff, MD from the UNC-Chapel Hill Department of 
Orthopaedics will serve as the Research Monitor for this 
investigation. The PI will provide the Research Monitor a summary 
report during each quarter of the funding period that details 
information detailing enrollment, verification of informed consent, 
and adverse event documentation.  The Research Monitor’s primary 
responsibilities relate to the proper conduct of the investigation and 
the welfare of the subjects who are involved.  As such, Dr. Berkoff 
will have the authority to suspend research associated with the 
project in the event of violations of study protocol. 
 

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1 
BACKGROUND AND RATIONALE 
1.1 
Introduction 
Osteoarthritis (OA) is the most common cause of medical discharge from military service during 
peacetime and the second most prevalent cause during armed conflict, ranking it as one of the largest 
military “force subtractors”.1  Traumatic knee injuries are of particular concern, as they almost 
universally result in post-traumatic OA in military personnel.2  Knee injuries comprise 19% of all injuries 
sustained during military training3 and 15% of all non-combat injuries during deployment.4  Additionally, 
knee injuries are the third most prevalent type of injury leading to battlefield evacuation, and Rivera et 
al.2 reported that 100% of knee injuries sustained during combat resulted in OA.   
Anterior cruciate ligament (ACL) injury dramatically increases the risk of developing knee OA.5  ACL 
injury also accelerates knee OA development, as radiographic evidence of OA has been identified as 
early as 5 years following injury.6  While surgical reconstruction (ACLR) is the standard of treatment and 
improves joint stability, ACLR does not reduce the risk of developing knee OA.7  Therefore, ACLR 
represents an ideal model for evaluating novel rehabilitation techniques for preventing development of 
post-traumatic knee OA.   
 
Impulsive/high rate joint loading contributes to the development of 
knee OA.8, 9  Quadriceps dysfunction/weakness is a highly common, 
lingering complication associated with ACLR and other traumatic knee 
injuries that is caused by a neuromuscular phenomenon known as 
arthrogenic muscle inhibition (AMI).10  Because the quadriceps 
functions as a shock absorber in the early stance phase during walking 
and running gait, quadriceps dysfunction results in impulsive loading 
of the knee joint as evidenced by higher loading rates.11, 12  Given the 
repetitive nature of gait and its integral role in human locomotion, 
this impulsive loading contributes to development of OA.8, 9  Recent 
evidence suggests that that quadriceps dysfunction associated with 
ACLR results in joint space narrowing, a radiographic indicator of knee OA.13  Individuals with traumatic 
knee injuries also display sensory/proprioceptive deficits14, 15 which magnify quadriceps dysfunction16 
and contribute to impulsive loading.17, 18  As such, treatments that improve quadriceps function and 
proprioception may reduce the risk of developing post-traumatic knee OA (Figure 1).   
 
1.2 
Name and Description of Investigational Product or Intervention  
Whole Body Vibration (Power Plate pro5) 
Local Muscle Vibration (prototype stimulator – IDE granted by UNC-Chapel Hill Biomedical Institutional 
Review Board) 
 
1.3 
Non-Clinical and Clinical Study Findings 
Quadriceps strengthening is an inherent component of rehabilitation of ACLR and other traumatic knee 
injuries, but is commonly ineffective due to the fact that the underlying neural deficiencies (i.e. AMI) are 
not addressed by conventional approaches.10, 19, 20  However, both direct (local muscle vibration - LMV) 
and indirect (whole body vibration - WBV) vibratory stimuli enhance quadriceps function in individuals 
with non-pathological knees,21-23 and may minimize the negative effects of AMI.  We demonstrated that 
LMV enhances quadriceps function in healthy individuals,23 and that both WBV and LMV produce 

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equivalent improvements in quadriceps function following experimental knee joint effusion (i.e. 
simulated knee trauma) in healthy individuals.24  Vibratory stimuli also improve proprioception,25, 26 and 
we demonstrated that improving knee proprioception decreases impulsive loading during walking gait in 
individuals diagnosed with knee OA.27, 28  These findings suggest that vibratory stimuli may improve 
quadriceps function, proprioception, and gait biomechanics (e.g. impulsive loading) following traumatic 
knee injuries, potentially reducing the risk of developing knee OA.   
 
Our preliminary data and findings reported by other researchers14, 25, 26, 29 support our hypothesis that 
vibratory stimuli may enhance rehabilitation of traumatic knee injuries.  These studies indicate that 
incorporation of vibratory stimuli into ACLR rehabilitation improves postural stability, quadriceps 
strength, and proprioception.14, 25, 26  Additionally, a recent animal model demonstrated that WBV 
minimized articular cartilage loss in rats with knee OA caused by ACL transection.29  However, the effects 
of vibratory stimuli on factors linked to the development of post-traumatic knee OA have yet to be 
investigated.   
 
Clinical application of WBV may be limited, as these devices require a fixed location, permit limited types 
of rehabilitation exercises due to the restricted space of the device (~5 ft2), and may be cost-prohibitive 
(as much as $10,000).  However, LMV can be integrated into a portable, cost-effective device (~$250) 
for use in a variety of rehabilitation tasks and settings.  LMV may also be more effective, as it is applied 
directly to the quadriceps, thus it is less susceptible to damping of the vibratory stimulus as it passes 
through the lower extremity such as occurs with WBV.30  However, it is unclear if WBV and LMV have 
similar effects on quadriceps function, proprioception, and gait biomechanics in individuals with 
traumatic knee injuries. 
The results of this investigation will provide “proof of concept” regarding the utility of WBV and LMV for 
prevention and management of knee OA, and will advance our understanding of the development and 
progression of this disease. Traditional rehabilitation and treatment methods have been only 
moderately effective due to the fact that AMI limits the efficacy of quadriceps strengthening by 
preventing adequate activation. Therefore, the results of this investigation may promote the 
development of improvements in patient care by supporting a shift in the treatment of knee pathologies 
(i.e. by demonstrating that AMI should be addressed before attempting to strengthen the quadriceps to 
enhance traditional rehabilitation). As knee OA adversely affects quality of life, the improved ability to 
treat and prevent knee OA resulting from this investigation would lead to improvements in quality of 
life. This information would also inform the development of a larger, long-term clinical trial to evaluate 
these effects on the long-term health and clinical outcomes in individuals who are afflicted with knee OA 
or are at heightened risk for development of post-traumatic knee OA. These outcomes would have a 
direct impact on the substantial burden of knee OA on the US health care system.  
 
Exercise in general, including rehabilitation exercise, carries the risk of injury, pain, and 
soreness/discomfort. However, the tasks subjects will be asked to perform in this investigation are 
common to activities of daily living and rehabilitative exercise (i.e. quadriceps contractions, squatting, 
and walking), and strength training, and do not present increased risk of adverse events compared to 
these same risks when these activities are performed outside the laboratory setting (i.e. rare). The risk 
of subjects experiencing mild discomfort for a brief period of time (less than 1 second) during the 
electrical stimulation used for the Quadriceps Function Assessment is very common. However, this 
discomfort will immediately cease, and subjects will be familiarized with the electrical stimulation before 

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the testing procedure begins. Exposure to vibration may infrequently cause itching in the lower 
extremity and dizziness, both of which typically subside within minutes following exposure. 
 
1.4 
Relevant Literature and Data 
We have conducted a series of investigations that support the rationale for the proposed investigation and 
demonstrate our ability to conduct the proposed RESEARCH STRATEGY.  Each study is described below.   
1. LMV enhances quadriceps function several minutes 
following application.  We evaluated the effects of LMV on 
quadriceps activity in healthy individuals with non-
pathological knees (n=22).23  Quadriceps activity 
(electromyographic amplitude) was measured during 
maximal isometric contractions prior to and immediately, 
5, 15, and 30 minutes following LMV or a Control 
condition (no vibration).  A custom-built device identical 
to what we have proposed was used to deliver the LMV 
stimulus. LMV enhanced quadriceps activity, and this 
effect persisted for several minutes following application (Figure 2).  These findings support our 
hypothesis that LMV enhances quadriceps function for a sustained period of time.  It is likely that these 
healthy individuals were subject to a “ceiling effect” regarding improvements in maximal quadriceps 
activity.  This suggests that LMV has a robust neuromuscular effect, thus we anticipate that individuals 
with knee pathologies who possess deficits in quadriceps function (e.g. ACLR) will realize larger 
improvements in quadriceps function compared to the healthy individuals in this preliminary study.     
 
2. WBV and LMV enhance quadriceps function similarly in individuals with simulated knee trauma. We 
evaluated the effects of WBV and LMV on quadriceps function in healthy individuals with simulated knee 
trauma (n=43).24  The underlying cause of quadriceps dysfunction, AMI,  is attributable to sensory 
information that signals pathology including pain, inflammation, swelling, and damage to 
mechanoreceptors.31  AMI can also be induced experimentally by injecting saline into the knee joint 
which mimics the effects of swelling/effusion.32  Quadriceps function was assessed via the central 
activation ratio (CAR).  CAR quantifies an individual’s ability to voluntarily activate a muscle, and is an 
indicator of AMI.  A detailed description of this method is provided in the RESEARCH STRATEGY below.  
Following pre-test measures, 60mL of saline was 
injected into the knee joint space to induce AMI. 
Subjects were then exposed to WBV, LMV, or no 
vibration (Control), and quadriceps function was 
reassessed post-intervention.  The interventions and 
methods for assessing quadriceps function utilized in 
this preliminary study are identical to those proposed 
in the RESEARCH STRATEGY.  CAR improved 
significantly with WBV (+8.3%) and LMV (+5.9%), but 
not in the Control group (+0.7%).  While both forms of 
vibration improved quadriceps function, this 
improvement did not differ between LMV and WBV.   
Additionally, subjects who experienced the greatest inhibitory effects of effusion displayed the greatest 
improvements in quadriceps function with vibratory stimuli. These findings support our hypothesis that 
WBV and LMV may enhance quadriceps function similarly in individuals with knee pathology.  We 

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anticipate that individuals with “real” knee pathologies (as opposed to the acute, simulated trauma in 
this preliminary investigation) will realize substantially larger improvements in quadriceps function due 
to the chronic nature of their quadriceps dysfunction.     
   
3. Treatment modalities that improve proprioception may reduce impulsive loading.  We evaluated the 
effects of stochastic resonance electrical stimulation (SR) on proprioception and gait biomechanics in 
individuals with knee OA (n=52).27, 28  Impulsive loading was quantified from the loading rates of the 
peak vertical ground reaction force (vGRF) and heel 
strike transient (HST).  The HST is a rapid, transient 
rise in the vGRF which occurs shortly following ground 
contact during gait that is indicative of impulsive 
loading.11, 12  SR improved proprioception and altered 
gait biomechanics in manners that may slow knee OA 
progression.  Specifically, SR increased the knee 
flexion angle at ground contact, decreased 
quadriceps/hamstring coactivation, and decreased 
impulsive loading (Figure 4).  These findings 
demonstrate that modalities that improve 
proprioception potentially reduce impulsive loading.  
We anticipate that WBV and LMV will both improve 
proprioception in individuals who have undergone ACLR, thus altering gait biomechanics in manners 
that would reduce the risk of developing knee OA.     
 
2 
STUDY OBJECTIVE  
The long-term objective of this line of research is to improve rehabilitation of traumatic knee injuries and 
prevent post-traumatic knee OA.  The objectives of this proposal are to 1) determine the acute effects of 
WBV and LMV on quadriceps function, proprioception, and gait biomechanics in individuals who have 
experienced traumatic knee injury (ACLR); 2) compare the efficacy of LMV and WBV for these purposes; 
and 3) identify factors which predict the efficacy of these modalities.   
 
3 
INVESTIGATIONAL PLAN (brief overview) 
3.1 
Study Design 
This preclinical investigation will utilize a single-blind 
randomized controlled experimental design whereby 75 
individuals who have undergone ACLR will be randomly 
assigned to WBV, LMV, and Control groups (Figure 5).  This 
convenience sample will include individuals recruited from two 
local orthopaedic clinics (UNC Department of Orthopaedics 
and Triangle Orthopaedic Associates), local rehabilitation 
clinics, and the University population, as well as veterans 
recruited from the Veterans Affairs Medical Center in nearby 
Durham, NC.  Quadriceps function, proprioception, and 
walking gait biomechanics will be assessed prior to and 
following vibratory treatments (LMV or WBV) or a Control intervention.  The WBV and LMV groups will 

10 
 
receive a single session of vibratory stimuli which we previously demonstrated to enhance quadriceps 
function.23, 24  The Control group will perform identical procedures, but no vibratory stimulus will be 
applied.   
 
3.2 
Allocation to Treatment Groups and Blinding (if applicable) 
Stratified randomization into 3 groups of equal size (n = 25) will be performed using a computer 
generated randomization algorithm.  This algorithm will ensure stratification with respect to age and 
time since ACLR.   
 
3.3 
Study Duration, Enrollment and Number of Subjects 
We anticipate that the entire study will last approximately 3 years.  Each subject’s participation will last 
approximately 3 hours and 45 minutes over approximately 2 weeks. 
  
3.4 
Study Population 
We will recruit subjects who meet the following criteria:  
1) age 18-35 years  
2) undergone unilateral ACLR within 5 years prior to participation 
3) at least 6 months post-ACLR 
4) no history of ACL graft rupture or revision surgery 
5) no history of neurological disorder 
6) no history of injury to either leg within 6 months prior to participation (other than the initial ACLR) 
7) Knee Injury and Osteoarthritis Outcome Score (KOOS) self-report survey Pain subscale score > 53.1and 
Symptom subscale score > 44.9 
8) cleared by a physician for return to physical activity, and currently physically active, participating in at 
least 20 minutes of physical activity 3x per week.   
Age will be restricted to 18-35 years as this age group is at the greatest risk of ACL injury33 but is unlikely to 
possess idiopathic/non-traumatic knee OA.34  The post-ACLR interval (6 months-5 years) will ensure that 
subjects are outside the acute inflammatory phase and reduce the likelihood that they have already developed 
post-traumatic knee OA.  A history of graft rupture or bilateral ACLR may infer inadequate rehabilitation or 
flawed surgical procedures, and may alter the dependent variables.  Neurological disorders, acute orthopaedic 
injuries, and high-level pain and symptoms in the ACLR limb may also influence the dependent variables.  The 
criterion values for the KOOS subscale scores are based on reference values obtained from more than 4,000 
individuals 1 and 2 years post-ACLR.35  Lastly, sedentary individuals may develop knee OA via other mechanisms 
(e.g. compromised waste-nutrient exchange) rather than the hypothesized loading mechanisms. 
Though highly prevalent, not all individuals display quadriceps dysfunction following ACLR.10, 36-38  We 
hypothesize that individuals who do not display quadriceps dysfunction are less likely to develop post-traumatic 
knee OA, and would receive limited benefits from vibratory stimuli.  Self-report surveys, including the KOOS, will 
always be assessed first followed immediately by quadriceps function.  In the event that subjects do not possess 
quadriceps dysfunction (i.e. CAR < 95%),10, 38 they will be excluded from the investigation.  These procedures 
will ensure that we enroll the target population.   
 
4 
STUDY PROCEDURES (what will be done)   

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Subjects will report to the UNC Neuromuscular Research Laboratory for three separate sessions. During 
Session 1, subjects will complete the approved informed consent document, as well as the Self-Report 
Surveys, Gait Biomechanics Assessment, and Quadriceps Function Assessment described below. These 
procedures will be used to determine if subjects meet the inclusion criteria, familiarize the subject with 
the testing procedures, and establish parameters necessary for the subsequent testing sessions to 
expedite data collection. Upon reporting to the laboratory for Session 2, subjects will perform a 5 
minute warm up on a stationary cycle ergometer at a self-selected pace to reduce the likelihood of 
injury. They will then be fitted with motion capture markers and electromyography (EMG) electrodes 
followed by the Gait Biomechanics and Quadriceps Function assessments. They will then perform the 
respective intervention to which they have been assigned, followed by post-test measures of the 
aforementioned assessments. Procedures for Session 3 will be identical with the exception that the 
Proprioception/Sensory Assessment described below will be performed prior to and following the 
interventions. Sessions 2 and 3 will be separated by 1-week washout periods, and the order of these 
sessions will be counterbalanced. 
 
4.1 
Screening/Baseline Visit procedures 
Gait Biomechanics Assessment 
Subjects will walk forward along a 6m (~20 ft) walkway at a comfortable, self-selected “fast” speed while 
biomechanical data are collected.27, 39, 40  At least 5 practice trials will be performed during the 
familiarization session (Session 1) to determine the average preferred speed and ensure subjects can 
consistently strike a force plate mounted in the walkway with the test limb without noticeably altering 
their gait (i.e. “aiming” for the force plate).  Gait speed will be monitored via an infrared timing system 
to ensure each trial is within ±10% of the preferred speed.  Kinematics (knee motion patterns), kinetics 
(knee joint moments and ground reaction forces) and lower extremity muscle activity (quadriceps and 
hamstrings EMG) will be sampled during each trial. Subjects will perform 5 valid trials from which gait 
biomechanical variables will be averaged for statistical analysis.  
 
EMG electrodes will be placed over the back (hamstrings muscles) and front (quadriceps muscles) of the 
thigh via adhesive interfaces.  Electrode placement sites will be shaved, lightly abraded, and cleansed 
with isopropyl alcohol to improve adhesion to the skin and signal quality.  Motion capture markers will 
be secured on the trunk and pelvis, and the thigh, shank, and foot segments via double-sided tape.  All 
measurement hardware will be further secured via hypoallergenic tape.     
 
Quadriceps Function Assessment 
Subjects will be seated on a device used to measure muscle strength called an isokinetic dynamometer.  
Straps will be used to secure the torso, thigh, and lower leg to the device with the knee in 60° of flexion.  
The moveable arm of the dynamometer will be fixed in place.  Two adhesive stimulating electrodes will 
be placed on the anterior thigh over the quadriceps muscle.  Subjects will be asked to contract the 
quadriceps maximally and as quickly as possible by “kicking out” against the dynamometer in response 
to a visual (light) stimulus while torque data are sampled.  An investigator will view the torque data in 
real time and apply an electrical stimulus to the quadriceps after the torque reaches a maximal plateau.  
This electrical stimulus will consist of a 10 pulse train, pulse duration of 0.6ms, delivered at a frequency 
of 100Hz, and an intensity of 125V.  The electrical stimulator will be isolated from fluctuations in 
building’s electrical power supply via a stimulus isolation unit.  These methods and stimulus 
characteristics replicate those of previous investigations conducted in healthy41-43 and pathological20, 44-

12 
 
46 populations, including the recent investigations conducted in our laboratories noted above.  
Quadriceps AMI will be quantified via peak torque (PT), rate of torque development (RTD), and the 
central activation ratio (CAR) during these maximal contractions.   Measuring the CAR involves applying 
an electrical stimulus to a maximally contracting muscle (superimposed burst) which activates all the 
muscle’s motor units.  The ratio of torque resulting from the superimposed burst to the maximal 
voluntary torque represents the level of inhibition.20  Subjects will perform at least 2 practice trials to 
become familiar and comfortable with these procedures.  Three trials will then be recorded from which 
PT, RTD, and CAR will be averaged for statistical analyses. 
 
Proprioception/Somatosensory Assessment 
Proprioceptive/Somatosensory function will be assessed via a partial weight-bearing joint repositioning 
task.28, 47  Subjects will be positioned supine on a sliding platform that will be reclined 75° relative to the 
vertical (Figure 5, Appendix A).  This platform will permit unrestricted knee motion, but will control 
extraneous factors that influence joint position sense assessment during weight-bearing such as 
postural sway and trunk position.  Subjects will be blindfolded, and each trial will begin with the knee in 
full extension, and subjects will flex the knee to a prescribed angle (reference angle) by sliding the 
platform downward.  This angle will be maintained for 5s after which the subject will return to full knee 
extension, and will then attempt to replicate the reference angle.  The absolute difference between the 
reference angle and the reproduced angle will be calculated and averaged across 5 trials for statistical 
analyses.  Knee joint angles will be assessed via an electrogoniometer placed over the knee and secured 
using hypoallergenic double-sided tape.    
 
We will also measure vibratory perception threshold (VPT), a more clinically feasible assessment of 
somatosensory function.  Deficits in VPT have been identified in individuals with knee pathologies and 
are associated with impulsive loading during gait.18, 48  VPT is measured using a device called a 
biothesiometer which vibrates at varying amplitudes that are controlled by the investigator.  VPT will be 
assessed by placing the biothesiometer on bony prominences at the medial and lateral femoral 
epicondyles, medial (tibial) and lateral (fibular) malleoli, and 1st metatarsophalangeal joint.18, 48  The 
amplitude of the vibration will be increased gradually, and subjects will verbally indicate the point at 
which they consciously perceive the vibratory stimulus, and the corresponding amplitude will be 
recorded as VPT.  Three trials will be performed at each site and averaged for statistical analysis.     
 
Self-Report Surveys  
The International Knee Documentation Committee Subjective Knee Form (IKDC), Knee Injury and 
Osteoarthritis Outcome Score (KOOS), and Tegner Activity Scale self-report surveys will be used to 
document subjects’ knee trauma history, current symptoms, and functional ability.  The IKDC and KOOS 
have been demonstrated as valid indicators of knee function and clinical outcomes in individuals with 
knee pathologies,49, 50 while the Tegner scale is a valid indicator of physical activity level in these 
individuals.51  These surveys will be administered electronically via Qualtrics.   
 
4.2 
Intervention/Treatment procedures  
Vibratory Interventions 
All interventions will be performed with subject standing on a WBV device in approximately 40° of knee 
flexion, but the WBV device will only be “on” for the WBV group.  Subjects assigned to the WBV group 
will receive a vibratory stimulus (30Hz, 2g) applied for 1 minute.  This exposure will be repeated 6 times 
with 2 minutes of rest between exposures.  Subjects in the LMV group will receive an identical stimulus 
(30Hz, 2g) via a custom-built vibrator secured over the distal anterior thigh.  We have previously 

13 
 
demonstrated that these interventions enhance quadriceps activity.  Subjects in the Control group will 
perform these exact same procedures with the exception that no vibratory stimulus will be applied.  All 
interventions will be conducted by a graduate research assistant, and the PI will blinded to group 
assignment.   
 
4.3 
Follow- up procedures (by visits) 
None 
 
4.4 
Unscheduled visits 
None 
 
4.5 
Subject Completion/ Withdrawal procedures 
Subject participation in the study will be complete when he/she has completed Session 3.  Subjects will 
receive prorated monetary compensation at this time. 
 
4.6 
Screen failure procedures 
All subjects will provide informed consent prior to engaging in the screening procedures.  Potential 
subjects who complete the screening session but do not meet the inclusion criteria will be thanked for 
their time and excluded from further participation. 
 
5 
STUDY EVALUATIONS AND MEASUREMENTS (how measurements will be made)   
See 4.1 Screening/Baseline Visit procedures 
 
5.1 
Safety Evaluations 
All data will be deidentified. Subjects will be identified only by a subject ID# to which their personal 
information will not be linked. Deidentified data files (e.g. gait biomechanics data trials) will be stored 
and backed up in numerous password-protected locations including computers in the Neuromuscular 
Research Laboratory, external hard drives, and the UNC-CH Research Computing Mass Storage System.  
 
David Berkoff, MD from the UNC-Chapel Hill Department of Orthopaedics will serve as the Research 
Monitor for this investigation. Dr. Berkoff possesses both the research ethics and medical expertise 
necessary to carry out this role. The PI will provide the Research Monitor a summary report during each 
quarter of the funding period detailing the information that is necessary for Dr. Berkoff to perform his 
duties. These duties will include ensuring subjects meet the enrollment criteria, verifying the informed 
consent process for each subject, and monitoring adverse events. A detailed description of the Research 
Monitor's duties and authorities (i.e. conditions under which the Research Monitor can suspend 
research activities) has been uploaded in IRBIS.  
 
Prior to analysis, the data will be screened for outliers (values more than 3 sd beyond the mean) and 
evaluated for normality via the Shaprio-Wilk test, visual inspection of the histograms, and evaluation of 
the ratios of the skewness and kurtosis statistics to their standard errors to ensure quality.  
 

14 
 
The 5-minute warm-up prior to testing is designed to reduce the risk of muscle soreness and/or injury 
during testing. The electrical stimulator used for the Quadriceps Function Assessment will always be 
connected to a stimulus isolation unit to ensure that the subject is isolated from fluctuations in the 
building's power supply. Any safety concerns (i.e. musculoskeletal injury) would likely be recognized 
immediately during testing, but subjects will be instructed via the informed consent document that they 
should inform UNC Student Health Services or their personal physician in the event that they experience 
lingering issues after leaving the laboratory.  
 
All members of the research team involved with data collection are certified in CPR and First Aid. These 
individuals will monitor subjects for adverse events during testing, and will refer any individuals who 
experience adverse events to the Stallings-Evans Sports Medicine Center (located in the building 
adjacent to Fetzer Hall where the Neuromuscular Research Laboratory is located), UNC Student Health 
Services, or Emergency Medical Services depending on the nature and severity of the adverse event. 
 
6 
STATISTICAL CONSIDERATION    
  
6.1 
Primary Endpoint 
This pre-clinical trial will evaluate the acute effects of the interventions, thus the immediate post-test 
assessment will serve as the primary endpoint.  
6.2 
Statistical Methods 
 
Specific Aim 1: To determine the effects of WBV and LMV on quadriceps function, proprioception, and gait 
biomechanics in individuals with ACLR.   
Analyses for Aim 1 will be performed using pre-post change scores for quadriceps function, 
proprioception, and gait biomechanics as dependent variables in separate statistical models.  Mean 
change scores will be compared across groups (WBV, LMV, and Control) via one-way analysis of 
covariance (ANCOVA).  Dunnett’s procedure will be used to evaluate each the least-squares means for 
each of the intervention arms (WBV and LMV) versus control in a relatively powerful manner while 
controlling the overall significance level at two-sided 0.05.  The corresponding pre-test values for each 
dependent variable will be managed as a covariate in these models to increase precision of the 
treatment effects, as well as to account any random imbalances among the groups with respect to these 
pre-scores.  Other covariates would include variables with random imbalances across the groups 
measured at the pre-test.  
 
The number of individuals who display HST prior to and following the intervention (or control) will be 
compared via McNemar’s test.  This analysis produces a χ2 statistic for paired samples (i.e., the 
proportion with HST at pre-test vs. post-test, separately for each group).     
 
Specific Aim 2: To compare the effects of WBV and LMV on quadriceps function, proprioception, and gait 
biomechanics in individuals with ACLR.   
Aim 2 will be evaluated using the statistical models described above for Aim 1, but with focus on the 
statistical contrast of WBV versus LMV.  Specifically, the pre-post change scores for each dependent 

15 
 
variable, adjusted for covariates, will be tested for the pairwise comparison of WBV versus LMV at the 
two-sided 0.05 significance level. 
 
Specific Aim 3: To identify factors that predict the effects of LMV and WBV on quadriceps function, 
proprioception, and gait biomechanics in individuals with ACLR.   
Aim 3 will be evaluated using multiple regression models.  Pre-post change scores for each dependent 
variable will be included only for the WBV and LMV groups.  We will then calculate simple correlations 
between these change scores and the pre-test values separately for quadriceps function, proprioception, 
and the KOOS.  We hypothesize that individuals with greater quadriceps dysfunction and proprioceptive 
deficits combined with lower KOOS scores (i.e. greater pain, symptoms, etc.) will display greater 
improvements. Separately for each dependent variable, these variables will then be placed into a 
stepwise multiple regression model (starting with a forward selection step).  In this way, the variable with 
the strongest relationship with the change score will be entered first, followed by the next strongest 
(after adjusting for the first), etc.    The model selection will stop when no additional variables are 
identified to enter to leave the model at the 0.10 significance level.  This less conservative significance 
level is selected to cast a wide net to include relevant candidate terms.  Next, we will examine each of 
these terms, one-at-a-time, as an independent variable in another regression model where the change 
score is the dependent variable; an indicator term for the intervention (WBV vs. LMV) will also be 
included as an explanatory variable, as well as the interaction between the intervention indicator and the 
candidate term.  The initial focus will be on the significance of the interaction term, as this will determine 
whether the effect of the candidate term is homogeneous (reflected by non-significance of the 
interaction at the 0.05 level) across the interventions, or not.  If the test is non-significant, the interaction 
term will be removed and the model refitted; the candidate term is then assessed from this model 
regarding its ability to predict the homogeneous effect of LMV and WBV on the corresponding 
dependent variable.  If the interaction test is instead statistically significant, then the interaction term is 
retained in the model, and statistical contrasts will be constructed to estimate and test the separate 
effects of the candidate term by intervention group. 
 
6.3 
Sample Size and Power 
Quadriceps function is the primary outcome for this investigation, as it is the critical factor in controlling 
impulsive knee joint loading linked to development of post-traumatic knee OA.  We conducted a priori 
power analyses52 using data from our preliminary investigation involving these same vibratory stimuli 
following experimental knee joint effusion.53  Pre-post change scores were calculated as described above 
in the statistical methods for Specific Aim 1, and effect size indices were calculated for one-way ANCOVA 
using pre-test scores as the covariate.  These analyses indicate that a sample of 45-63 subjects (15-21 per 
group) would provide statistical power of 0.80 for α = 0.05 to identify significant overall ANCOVA models 
for CAR (f = 0.48) and peak torque (f = 0.41), where f is the effect size calculated as the square root of the 
ratio of the between-group sum of squares and the error sum of squares.  Further, these preliminary 
data generated the pairwise effect sizes presented in the table below calculated using the following 
equation: 
 
 Effect Size= 
[∆WBV (or ∆LMV ) - ∆Control]
Pooled Standard Deviation       
 
 
 
 

16 
 
 
 
Effect Sizes for Post Hoc Group Comparisons of Pre-Post Change Scores  
Quadriceps Function Variable 
WBV vs. Control 
LMV vs. Control  
LMV vs. WBV 
CAR 
 
Peak Torque 
0.84 
 
0.98 
0.78 
 
0.70 
0.36 
 
0.35 
 
Statistical power for the effect sizes given in Table 2 was calculated for one-tailed independent t-tests.  
These estimates indicate that a sample of 39-78 subjects (13-26 per group) would provide statistical 
power of 0.80 for α = 0.05 to evaluate pairwise comparisons between the Control group and each 
vibratory intervention (i.e. Aim 1).  In contrast, 194 subjects (97 per group) would be necessary to 
provide adequate power to identify the relatively small effect sizes for comparing the two vibratory 
interventions (i.e. Aim 2).  The associated mean differences in CAR between WBV and Control and 
between LMV and Control were 8.26% and 5.86%, respectively, while the difference between LMV and 
WBV was only 0.68%.  Similarly, the associated mean differences in peak torque between WBV and 
Control and between LMV and Control were 0.29 N/kg and 0.20 N/kg respectively, while the difference 
between LMV and WBV was only 0.04 N/kg.  These data suggest that the small mean differences in the 
dependent variables between WBV and LMV, even when powered sufficiently, are not likely clinically or 
physiologically relevant.  Therefore, we will recruit a sample of 75 individuals (25 per group) to address 
the proposed specific aims.  This sample size will provide adequate power to demonstrate similar 
improvements in quadriceps function with WBV and LMV.   
 
7 
STUDY INTERVENTION (drug, device or other intervention details) 
7.1 
Whole Body Vibration 
Whole body vibration will be delivered in this investigation via a commercially available device (Power 
Plate pro5).  This device oscillates in the vertical dimension at a frequency of 30 Hz and acceleration of 
2g. 
  
7.2 
Local Muscle Vibration 
The local muscle vibration stimulator to be used in this investigation is a custom-built prototype 
developed in collaboration with the Department of Industrial and Systems Engineering at North Carolina 
State University as part of a collaborative grant to be used explicitly for the purposes of the proposed 
study.   As of 5/13/2015, this device has been used to enhance muscle function via the exact intervention 
proposed for this study in more than 100 subjects in multiple previously approved studies with no 
adverse events.  Furthermore, 25 of these subjects had undergone ACL reconstruction surgery and met 
the inclusion criteria for the proposed investigation.  
 
This stimulator consists of a single-axis electromagnetic oscillator mounted on a plastic frame. The plastic 
frame was produced via 3D printing such that its under surface is curved to accommodate the shape of 
the anterior thigh. The electromagnetic oscillator consists of a standard audio speaker that is coupled 
with a frequency generator through an amplifier that causes it to vibrate in the anterior-posterior 
direction (i.e. into the quadriceps muscle). This vibratory stimulus is similar to the mechanics of a reflex 
hammer when evaluating the tendon-tap/knee-jerk reflex clinically in that it creates rapid changes in 
quadriceps length, thus exciting the muscle via the muscle spindle system. Vibration frequency is held 

17 
 
constant at 30Hz as determined by the frequency generator in the controller unit, and the acceleration is 
constrained to 2g via feedback provided to the controller unit from an accelerometer mounted on the 
oscillator. 
 
8 
STUDY INTERVENTION ADMINISTRATION(if applicable)  
This preclinical investigation will utilize a single-blind randomized controlled experimental design 
whereby 75 individuals with primary unilateral ACLR will be randomly assigned to WBV, LMV, and Control 
groups.  Stratified randomization into 3 groups of equal size (n = 25) will be performed using a computer 
generated randomization algorithm to ensure stratification with respect to age and time since ACLR.  All 
individuals involved with data collection and analysis will be blinded to group allocation. 
 
9 
SAFETY MANAGEMENT 
Research Monitor Responsibilities and Authorities  
David Berkoff, MD from the UNC-Chapel Hill Department of Orthopaedics will serve as the Research 
Monitor for this investigation. Dr. Berkoff possesses both the research ethics and medical expertise 
necessary to carry out this role. The PI will provide the Research Monitor a summary report during each 
quarter of the funding period that details information necessary for him to perform the following 
responsibilities:  
 
1. Enrollment data  
a. # of subjects (total and per group)  
i. The Research Monitor will be unblinded to group, but the PI and all research team members 
involved with data collection will remain blinded.  
ii. Groups will be identified by number only (e.g. Group 1 = Control, etc.) in reports generated 
by the PI, and the Research Monitor will be provided a key to decode group membership by the 
unblinded research assistants who are delivering the interventions.  
iii. The Research Monitor will evaluate enrollment data to ensure the enrollment rate is 
consistent with the project timeline (i.e. 30 subjects per year for Years 1 and 2; 15 for Year 3).  
 
b. The Research Monitor will verify subjects meet the enrollment criteria  
i. Relevant data regarding the inclusion/exclusion criteria (e.g. age, KOOS scores, CAR, time 
since ACL reconstruction surgery, etc.) will be entered in an electronic data management 
system (Epi Info, Centers of Disease Control and Prevention). This system is capable of 
generating spreadsheets for data organization. These spreadsheets will be provided to the 
Research Monitor to permit verification of the enrollment criteria.  
 
2. Verify consent  
a. Data entry in Epi Info will require the member of the research team who is entering a given 
subject’s data to verify (yes/no) that written informed consent was obtained. This individual will also 
be required to enter his/her initials in Epi Info to confirm that consent was obtained. The Research 
Monitor will verify that each subject has been consented based on these data contained in the 
quarterly report.  

18 
 
 
3. Monitor adverse events  
a. Subjects will be monitored for adverse events by the research team during data collection, and 
will be instructed to inform the research team immediately if they experience adverse events after 
leaving the laboratory. Information related to adverse events will be entered in Epi Info as described 
below.  
i. Adverse Event? (yes/no)  
1. If yes, was there appropriate follow up by research team?  
a. Subjects will be contacted within 1 day of identification of an adverse event and again 
after 1 week. The dates of follow up by the research team will be documented in Epi 
Info.  
2. Appropriate documentation sent to UNC-CH Biomedical IRB?  
a. The dates of submission, IRB response, and resolution will be documented in Epi Info.  
3. The Research Monitor will determine if the adverse event is associated with 
participation in the study using the UNC-CH Biomedical IRB decision tree 
(http://research.unc.edu/files/2012/11/ccm3_018993.pdf). Documentation (e.g. 
description of the adverse event, symptoms, etc.) will be sent to the Research Monitor for 
evaluation of risk which will be used to determine the following:  
a. Severity of the adverse event as per US Department of Health and Human Services 
guidelines (http://www.hhs.gov/ohrp/policy/advevntguid.html#AA)?  
b. Is this a recurring problem (i.e. multiple adverse events of the same type)?  
c. Is this adverse event specific to one of the interventions?  
 
Authorities  
The Research Monitor’s primary responsibilities relate to the proper conduct of the investigation and 
the welfare of the subjects who are involved. As such, Dr. Berkoff will have the authority to suspend 
research associated with the project when any of the following occurs:  
1. Enrollment criteria are inconsistent with those specified in the research protocol in 2 or more 
enrolled subjects in 2 consecutive quarters of the funding period  
2. Written informed consent is not obtained for any subject in any quarter of the funding period  
3. Failure by the research team to report any adverse event appropriately as per UNC-CH Biomedical 
IRB guidelines  
4. Multiple adverse events are reported (3+) in a given quarter of the funding period  
5. Multiple adverse events are reported within a given intervention group (5+) across the entire 
funding period  
 
Any subjects who experience adverse events will be referred to UNC Student Health Services, the 
Stallings-Evans Sports Medicine clinic (located in the building adjacent to Fetzer Hall where the 
Neuromuscular Research Laboratory is located), or Emergency Medical Services depending on the nature 
and severity of the adverse event. All individuals involved with data collection are certified in CPR and 
First Aid. 
 
10 
DATA COLLECTION AND MANAGMENT  
 All data will be deidentified. Subjects will be identified only by a subject ID# to which their personal information 
will not be linked. Deidentified data files (e.g. gait biomechanics data trials) will be stored and backed up in 
numerous password-protected locations including computers in the Neuromuscular Research Laboratory, 
external hard drives, and the UNC-CH Research Computing Mass Storage System.  

19 
 
 
11 
RECRUITMENT STRATEGY 
The ACLR cohort for this investigation will consist of volunteers from the faculty, staff, and student 
populations at UNC-CH and the surrounding area. Potential subjects will be recruited verbally from 
classes following approval by course instructors. At this time, potential subjects will be read a standard 
recruitment script and will be allowed to ask any questions pertaining to the investigation. Individuals 
who are interested in participating will be provided the PI’s contact information and asked to contact the 
PI to address any additional questions regarding the study and to schedule data collection. Additionally, 
subjects will be recruited via informational flyers posted on the UNC-CH campus and in local 
rehabilitation clinics, including the Durham VA Medical Center, and via an informational email posted on 
the UNC-CH server. Subjects will also be recruited from UNC Orthopedics (Jeff Spang, MD) and Triangle 
Orthopaedic Associates (Jeff Solic, MD). All subjects must receive physician approval to return to regular, 
unrestricted physical activity to be eligible for participation. Drs. Spang and Solic will provide subjects 
with information regarding participation in the study following the subject’s clinical visit at which this 
approval is obtained. Dr. Kelli Allen (joint appointment at Durham VA Medical Center) will serve in this 
same capacity for recruiting subjects from the Durham VA Medical Center. We will also submit a request 
to the Carolina Data Warehouse for Health to generate a list of patients with ACL reconstruction within 
the past 5 years. This patient list will include names and multiple forms of contact information that will 
be used to contact potential subjects via telephone, letter/US Mail, or email depending on the available 
contact information to determine the individual’s interest in participating in the study. Dr. Solic will 
perform similar retrospective chart reviews at Triangle Orthopaedic Associates to identify potential 
subjects. The Healthy Control cohort for this investigation will consist of volunteers from the faculty, 
staff, and student populations at UNC-CH and the surrounding area. Potential subjects will be recruited 
verbally from classes following approval by course instructors. At this time, potential subjects will be read 
a standard recruitment script and will be allowed to ask any questions pertaining to the investigation. 
Individuals who are interested in participating will be provided the PI’s contact information and asked to 
contact the PI to address any additional questions regarding the study and to schedule data collection. 
 
Drs. Spang and Solic each perform approximately 50 ACLR procedures annually, and each of their 
orthopaedic practices (UNC Orthopaedics and Triangle Orthopaedic Associates, respectively) performs 
more than 200 ACLR procedures annually. The Durham VA Medical Center performs approximately 10 
ACLR procedures each year in veterans who meet the inclusion criteria. These data indicate that as many 
as 1,230 potential subjects will be available for recruitment via our clinical collaborations during the 
funding period (410/year x 3 years). Additionally, we will perform retrospective chart reviews in each of 
these clinical settings to identify potential subjects. Lastly, we will also recruit potential subjects from 
local rehabilitation clinics and from the University community. As part of ongoing research in our 
laboratories we have recruited 40+ individuals in the past year who meet these criteria from the 
University community alone without taking advantage of the aforementioned clinical collaborations that 
have been established for the project or targeting local rehabilitation clinics. As such, we are highly 
confident that we can recruit the necessary sample for the investigation. 
 
12 
CONSENT PROCESS 

20 
 
Upon reporting to the laboratory, and prior to screening and data collection procedures, all subjects will 
be required to read and sign the approved informed consent document. Members of the research team 
will oversee this process to ensure any questions subjects have are answered prior to providing written 
informed consent.  Drs. Blackburn (PI), Padua (Co-Investigator), and Pietrosimone (co-investigator), and 
all research assistants will be obtaining consent.  As the PI teaches courses in which potential subjects 
may be currently enrolled or enrolled in the future, these individuals will be informed that their 
participation or the lack thereof will not influence their academic standing. Similarly, UNC-CH employees 
will be informed that their participation or the lack thereof will not influence their employment status. 
Lastly, subjects recruited from orthopaedic and rehabilitation clinics will be informed their clinical care 
will not be influenced by their participation or the lack thereof. 
 
13 
PLANS FOR PUBLICATION 
We intend to draft 3 primary manuscripts for publication that will detail, respectively, 1) the effects of the 
interventions on gait biomechanics, 2) the effects of the interventions on somatosensory function, and 3) patient 
characteristics that influence the efficacy of the interventions. 
 
14 
REFERNECES  
1. 
Patzkowski JC, Rivera JC, Ficke JR, Wenke JC. The changing face of disability in the US Army: the Operation 
Enduring Freedom and Operation Iraqi Freedom effect. J Am Acad Orthop Surg 20(Suppl 1): S23-30, 2012. 
2. 
Rivera JC, Wenke JC, Buckwalter JA, Ficke JR, Johnson AE. Posttraumatic osteoarthritis caused by battlefield 
injuries: the primary source of disability in warriors. J Am Acad Orthop Surg 20 (Suppl 1): S64-9, 2012. 
3. 
Wilkinson D, Blacker S, Richmond V, Horner F, Rayson M, Spiess A, Knapik J. Injuries and injury risk factors 
among British army infantry soldiers during predeployment training. Inj Prev 17: 381-387, 2011. 
4. 
Hauret KG, Taylor BJ, Clemmons NS, Block SR, Jones BH. Frequency and causes of nonbattle injuries air 
evacuated from operations Iraqi freedom and enduring freedom, U.S. Army, 2001-2006. Am J Prev Med 38(1 
Suppl): S94-107, 2010. 
5. 
Friel NA Chu CR. The role of ACL injury in the development of posttraumatic knee osteoarthritis. Clin Sports Med 
32(1): 1-12, 2013. 
6. 
Suomalainen P, Järvelä T, Paakkala A, Kannus P, Järvinen M. Double-bundle versus single-bundle anterior 
cruciate ligament reconstruction: a prospective randomized study with 5-year results. Am J Sports Med 40(7): 
1511-8: PMID: 22691456, 2012. 
7. 
von Porat A, Roos EM, Roos H. High prevalence of osteoarthritis after an anterior cruciate ligament tear in male 
soccer players: a study of radiographic and patient relevant outcomes. Ann Rheum Dis 63(3): 269-273, 2004. 
8. 
Ewers BJ, Jayaraman VM, Banglmaier RF, Haut RC. Rate of blunt impact loading affects changes in retropatellar 
cartilage and underlying bone in the rabbit patella. J Biomech 35(6): 747-55, 2002. 
9. 
Yang KH, Boyd RD, Kish VL, Burr DB, Caterson B, Radin EL. Differential effect of load magnitude and rate on the 
initiation and progression of osteoarthrosis. in Proceedings of the 35th Orthopaedic Research Society Annual 
Meeting. 1989. Las Vegas, NV. 
10. 
Hart JM, Pietrosimone B, Hertel J, Ingersoll CD. Quadriceps activation following knee injuries: a systematic 
review. J Athl Train 45(1): 87-97, 2010. 
11. 
Mikesky AE, Meyer A, Thompson KL. Relationship between quadriceps strength and rate of loading during gait in 
women. J Orthop Res 18(2): 171-5, 2000. 
12. 
Jefferson RJ, Collins JJ, Whittle MW, Radin EL, O'Connor JJ. The role of the quadriceps in controlling impulsive 
forces around heel strike. Proc Inst Mech Eng H 204(1): 21-8, 1990. 
13. 
Tourville TW, Jarrell KM, Naud S, Slauterbeck JR, Johnson RJ, Beynnon BD. Relationship between isokinetic 
strength and tibiofemoral joint space width changes after anterior cruciate ligament reconstruction. Am J Sports 
Med 42(2): 302-311, 2014. 

21 
 
14. 
Fu CL, Yung SH, Law KY, Leung KH, Lui PY, Siu HK, Chan KM. The effect of early whole-body vibration therapy on 
neuromuscular control after anterior cruciate ligament reconstruction: A randomized controlled trial. Am J 
Sports Med 41(4): 804-814, 2013. 
15. 
Reider B, Arcand MA, Diehl MH, Mroczek K, Abulencia A, Stroud CC, Palm M, Gilbertson J, Staszak P. 
Proprioception of the knee before and after anterior cruciate ligament reconstruction. Arthroscopy 19(1): 2-12, 
2003. 
16. 
Holla JF, van der Leeden M, Peter WF, Roorda LD, van der Esch M, Lems WF, Gerritsen M, Voorneman RE, 
Steultjens MP, Dekker J. Proprioception, laxity, muscle strength and activity limitations in early symptomatic 
knee osteoarthritis: results from the CHECK cohort. J Rehabil Med 44(10): 862-8, 2012. 
17. 
Riskowski JL, Mikesky AE, Bahamonde RE, Alvey TV, 3rd, Burr DB. Proprioception, gait kinematics, and rate of 
loading during walking: are they related? J Musculoskelet Neuronal Interact 5(4): 379-87, 2005. 
18. 
Shakoor N, Lee KJ, Fogg LF, Wimmer MA, Foucher KC, Mikolaitis RA, Block JA. The relationship of vibratory 
perception to dynamic joint loading, radiographic severity, and pain in knee osteoarthritis. Arthritis Rheum 
64(1): 181-6, 2012. 
19. 
Hurley MV, Jones DW, Newham DJ. Arthrogenic quadriceps inhibition and rehabilitation of patients with 
extensive traumatic knee injuries. Clin Sci (Lond) 86(3): 305-10, 1994. 
20. 
Hart JM, Turman KA, Diduch DR, Hart JA, Miller MD. Quadriceps muscle activation and radiographic 
osteoarthritis following ACL revision. Knee Surg Sports Traumatol Arthrosc 19(4): 634-640, 2011. 
21. 
Tihanyi TK, Horvath M, Fazekas G, Hortobagyi T, Tihanyi J. One session of whole body vibration increases 
voluntary muscle strength transiently in patients with stroke. Clin Rehabil 21(9): 782-93, 2007. 
22. 
Luo J, McNamara BP, Moran K. Influence of resistance load on electromyography response to vibration training 
with sub-maximal isometric contractions. Int J Sports Sci Eng 1(1): 45-54, 2007. 
23. 
Pamukoff DN, Ryan ED, Blackburn JT. The acute effects of local muscle vibration frequency on peak torque, rate 
of torque development, and electromyography J Electromyogr Kinesiol (In Review)2014. 
24. 
Blackburn JT, Pamukoff DN, Sakr M, Berkoff DJ. Whole body and local muscle vibration reduce quadriceps 
arthrogenic inhibition Arch Phys Med Rehabil (In Review)2013. 
25. 
Moezy A, Olyaei G, Hadian M, Razi M, Faghihzadeh S. A comparative study of whole body vibration training and 
conventional training on knee proprioception and postural stability after anterior cruciate ligament 
reconstruction. Br J Sports Med 42(5): 373-378, 2008. 
26. 
Brunetti O, Filippi GM, Lorenzini M, Liti A, Panichi R, Roscini M, Pettorossi VE, Cerulli G. Improvement of posture 
stability by vibratory stimulation following anterior cruciate ligament reconstruction. Knee Surg Sports 
Traumatol Arthrosc 14(11): 1180-7, 2006. 
27. 
Collins A, Blackburn JT, Olcott C, Yu B, Weinhold P. The impact of stochastic resonance electrical stimulation and 
knee sleeve on impulsive loading and muscle co-contraction during gait in knee osteoarthritis. Clin Biomech 
(Bristol, Avon) 26(8): 853-8, 2011. 
28. 
Collins AT, Blackburn JT, Olcott CW, Miles J, Jordan J, Dirschl DR, Weinhold PS. Stochastic resonance electrical 
stimulation to improve proprioception in knee osteoarthritis. Knee 18(5): 317-22, 2011. 
29. 
Qin J, Chow SK, Leung K, Cheung W. The effect of low-magnitude high-frequency vibration on protecting 
cartilage degradation on anterior cruciate ligament transection-induced osteoarthritis rat model. in Orthopaedic 
Research Society Annual Meeting. 2013. San Antonio, Tx. 
30. 
Rubin C, Pope M, Fritton JC, Magnusson M, Hansson T, McLeod K. Transmissibility of 15-hertz to 35-hertz 
vibrations to the human hip and lumbar spine: determining the physiologic feasibility of delivering low-level 
anabolic mechanical stimuli to skeletal regions at greatest risk of fracture because of osteoporosis. Spine (Phila 
Pa 1976) 28(23): 2621-7, 2003. 
31. 
Rice DA McNair PJ. Quadriceps arthrogenic muscle inhibition: neural mechanisms and treatment perspectives. 
Semin Arthritis Rheum 40(3): 250-66, 2010. 
32. 
Palmieri-Smith RM, Kreinbrink J, Ashton-Miller JA, Wojtys EM. Quadriceps inhibition induced by an experimental 
knee joint effusion affects knee joint mechanics during a single-legged drop landing. Am J Sports Med 35(8): 
1269-75, 2007. 
33. 
Griffin LY, Albohm MJ, Arendt EA, Bahr R, Beynnon BD, Demaio M, Dick RW, Engebretsen L, Garrett WE, Jr., 
Hannafin JA, Hewett TE, Huston LJ, Ireland ML, Johnson RJ, Lephart S, Mandelbaum BR, Mann BJ, Marks PH, 

22 
 
Marshall SW, Myklebust G, Noyes FR, Powers C, Shields C, Jr., Shultz SJ, Silvers H, Slauterbeck J, Taylor DC, Teitz 
CC, Wojtys EM, Yu B. Understanding and preventing noncontact anterior cruciate ligament injuries: a review of 
the Hunt Valley II meeting, January 2005. Am J Sports Med 34(9): 1512-1532, 2006. 
34. 
Losina E, Weinstein AM, Reichmann WM, Burbine SA, Solomon DH, Daigle ME, Rome BN, Chen SP, Hunter DJ, 
Suter LG, Jordan JM, Katz JN. Lifetime risk and age at diagnosis of symptomatic knee osteoarthritis in the US. 
Arthritis Care Res (Hoboken) 65(5): 703-11, 2013. 
35. 
Ageberg E, Forssblad M, Herbertsson P, Roos EM. Sex differences in patient-reported outcomes after anterior 
cruciate ligament reconstruction: data from the Swedish knee ligament register. Am J Sports Med 38(7): 1334-
42, 2010. 
36. 
Ageberg E, Thomee R, Neeter C, Silbernagel KG, Roos EM. Muscle strength and functional performance in 
patients with anterior cruciate ligament injury treated with training and surgical reconstruction or training only: 
a two to five-year followup. Arthritis Rheum 59(12): 1773-9, 2008. 
37. 
Chen CH, Chuang TY, Wang KC, Chen WJ, Shih CH. Arthroscopic anterior cruciate ligament reconstruction with 
quadriceps tendon autograft: clinical outcome in 4-7 years. Knee Surg Sports Traumatol Arthrosc 14(11): 1077-
85, 2006. 
38. 
Lynch AD, Logerstedt DS, Axe MJ, Snyder-Mackler L. Quadriceps activation failure after anterior cruciate 
ligament rupture is not mediated by knee joint effusion. J Orthop Sports Phys Ther 42(6): 502-10, 2012. 
39. 
Huang SC, Wei IP, Chien HL, Wang TM, Liu YH, Chen HL, Lu TW, Lin JG. Effects of severity of degeneration on gait 
patterns in patients with medial knee osteoarthritis. Med Eng Phys 30(8): 997-1003, 2008. 
40. 
Mundermann A, Dyrby CO, Andriacchi TP. Secondary gait changes in patients with medial compartment knee 
osteoarthritis: increased load at the ankle, knee, and hip during walking. Arthritis Rheum 52(9): 2835-44, 2005. 
41. 
Krishnan C Williams GN. Quantification method affects estimates of voluntary quadriceps activation. Muscle 
Nerve 41(6): 868-74, 2010. 
42. 
Miller M, Holmback AM, Downham D, Lexell J. Voluntary activation and central activation failure in the knee 
extensors in young women and men. Scand J Med Sci Sports 16(4): 274-81, 2006. 
43. 
Park J Hopkins JT. Quadriceps activation normative values and the affect of subcutaneous tissue thickness. J 
Electromyogr Kinesiol 21(1): 136-40, 2011. 
44. 
Drechsler WI, Cramp MC, Scott OM. Changes in muscle strength and EMG median frequency after anterior 
cruciate ligament reconstruction. Eur J Appl Physiol 98(6): 613-23, 2006. 
45. 
Drover JM, Forand DR, Herzog W. Influence of active release technique on quadriceps inhibition and strength: a 
pilot study. J Manipulative Physiol Ther 27(6): 408-13, 2004. 
46. 
Farquhar SJ, Chmielewski TL, Snyder-Mackler L. Accuracy of predicting maximal quadriceps force from 
submaximal effort contractions after anterior cruciate ligament injury. Muscle Nerve 32(4): 500-5, 2005. 
47. 
Collins AT, Blackburn JT, Olcott CW, Dirschl DR, Weinhold PS. The effects of stochastic resonance electrical 
stimulation and neoprene sleeve on knee proprioception. J Orthop Surg Res 4: 3, 2009. 
48. 
Shakoor N, Agrawal A, Block JA. Reduced lower extremity vibratory perception in osteoarthritis of the knee. 
Arthritis Rheum 59(1): 117-21, 2008. 
49. 
van Meer BL, Meuffels DE, Vissers MM, Bierma-Zeinstra SMA, Verhaar JAN, Terwee CB, Reijman M. Knee Injury 
and Osteoarthritis Outcome Score or International Knee Documentation Committee Subjective Knee Form: 
Which Questionnaire Is Most Useful to Monitor Patients With an Anterior Cruciate Ligament Rupture in the 
Short Term? Arthroscopy 29(4): 701-715, 2013. 
50. 
Wang D, Jones MH, Khair MM, Miniaci A. Patient-reported outcome measures for the knee. J Knee Surg 23(3): 
137-51, 2010. 
51. 
Briggs KK, Lysholm J, Tegner Y, Rodkey WG, Kocher MS, Steadman JR. The reliability, validity, and responsiveness 
of the Lysholm score and Tegner activity scale for anterior cruciate ligament injuries of the knee: 25 years later. 
Am J Sports Med 37(5): 890-7, 2009. 
52. 
Portney LG Watkins MP, Foundations of Clinical Research: Applications to Practice. 3rd ed. 2009, Upper Saddle 
River, NJ: Prentice-Hall, Inc. 
53. 
Blackburn JT, Pamukoff DN, Sakr M, Berkoff DJ. Whole body and local muscle vibration reduce quadriceps 
arthrogenic inhibition Arch Phys Med Rehabil (In Review)2014. 

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