Investigation of Mesenchymal Stem Cell Therapy for the Treatment of Osteoarthritis of the Knee: Effect on Pain and Quality of Life
Phase: PHASE2
Conditions: Knee Osteoarthritis
Sponsor: OhioHealth

Investigation of mesenchymal stem cell therapy for the treatment of 
osteoarthritis of the knee: Effect on pain and quality of life
Principal Investigator:
Joseph J. Ruane, DO
Medical Director, McConnell Heart Health Center
McConnell Spine, Sport, and Joint Physicians
Study Site:
McConnell Spine, Sport, and Joint Center
3773 Olentangy River Road
Columbus, OH 43214
614-566-3810
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TABLE OF CONTENTS
1.0
Introduction
1.1
Background
1.2
Specific Aims/Rationale
2.0
Methods
2.1
Study Population
2.2
Hypotheses
2.3
Study Variables & Outcomes of Interest
2.4
Study Design
2.5
Statistical Analysis
3.0
References
4.0
Appendices
4.1
Knee injury and Osteoarthritis Outcome Score (KOOS)
4.2
Numeric Pain Rating Scale (NPRS)
4.3
Patient Reported Outcome Measurement Information System (PROMIS) Global 
Health scores (short form, version 1.1)
4.4
Relevant past medical history regarding the patient’s knee
4.5
Study Calendar
4.6
Post-Procedure Care Instructions
4.7
Adverse Event Collection Form
4.8
Other relevant therapies since study treatment
4.9
Patient recruitment information
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1.0 – INTRODUCTION 
1.1 – Background 
Arthritis has been identified as one of the leading causes of disability in the United States.1 Osteoarthritis, 
the most common form of arthritis2, is most prevalent in the knee3 and the lifetime risk of symptomatic 
knee osteoarthritis (KOA) is nearly 45%.4 Osteoarthritis affects greater than 50% of individuals over the 
age of 65, and the increasing life expectancy will continue to rapidly increase the cases of KOA and 
subsequent substantial economic burden to society, payers, and patients.5 Different non-surgical treatment 
options exist in the symptomatic management of KOA, yet KOA is a chronic and progressive disease 
state and the portfolio of non-surgical treatment options available have notable limitations. 
Conservative treatment options such as self-management programs, physical exercise, and weight loss are 
recommended as a first option to address KOA.6 However, available conservative treatment modalities for 
KOA merely ameliorate symptoms, and convey variable and often short-term efficacy.7-8 The pain 
associated with KOA is most often treated with non-steroidal anti-inflammatory drugs (NSAIDs), which 
have come under intense scrutiny with respect to their safety in patients with cardiovascular disease as 
NSAIDs can increase the risk of having a heart attack or stroke.9 Since nearly one in two Americans with 
heart disease also have arthritis,10 there is a necessity to apply non-drug therapies in the treatment of 
KOA.
Intraarticular therapies including hyaluronic acid (i.e., viscosupplementation) and corticosteroid injections 
are commonly used in the treatment of KOA.11-12 Available evidence demonstrates symptom reduction 
with hyaluronic acid and corticosteroid injections in the short term13-22; however, evidence does not 
consistently support long term improvement nor prevention or reversal of the disease    state.13-16,18,21 
Several surgical techniques are used to address cartilage and joint surface lesions but limitations exists. 
Autologous chondrocyte transplantation and microfracture techniques, which are used to repair isolated 
lesions, are not applicable to a more widespread disease state such as KOA.7,20,23 Additionally, 
arthroscopic procedures involving lavage or debridement of the joint surfaces are not recommended with 
a primary diagnosis of KOA.6
The accepted option for KOA when previously highlighted options fail is total knee arthroplasty (TKA). 
Considering the aging demographic in the United States, the demand for primary TKA is expected to 
increase 673% by 2030, with associated costs increasing exponentially.8.24 This prognostication may 
reflect the lack of effective options available to prevent or reverse the progression of KOA. The growing 
costs25 added to the risk of significant complications associated with TKA have created a staggering need 
for a lower risk and lower cost, non-surgical approach.26
The field of orthobiologic therapy, specifically mesenchymal stem cell (MSC) therapy, holds promise in 
the non-surgical treatment of chronic degenerative disease such as osteoarthritis.7 Currently the most 
widely used method of obtaining MSCs is by way of bone marrow aspirate concentrate (BMAC). 
Published human data demonstrates no significant adverse events related to injection of MSCs or other 
regenerative biologic therapies into osteoarthritic human knee joints.27-28 Available research suggests MSC 
injection demonstrates benefits in pain and function at 2 years, and may possibly change the course of the 
disease, slowing progression or even regenerating cartilage to a small degree.8,29-31 In addition, the 
conceptual advantage and early success of using a platelet-rich plasma (PRP) injection as a complement 
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therapy has been documented.7,32-35 Despite early promise, further evidence is required in order to 
determine if MSC injection in patients with KOA can fill a void in effective non-surgical management of 
KOA with the intention of delaying or preventing the need for surgical management. 
To our knowledge this is the first randomized controlled trial to determine the effect of non-surgical, 
autologous BMAC and PRP intraarticular injections for primary KOA with comparison to a control group 
receiving a current and common injectable treatment.
1.2 – Specific Aims/Rationale
The purpose of this study is to determine the clinical response to autologous BMAC and PRP injections 
for KOA with respect to pain, function, and quality of life at up to 1 year following the intervention. This 
is a prospective randomized controlled trial with the following aims:
Specific Aim 1: To determine if BMAC and PRP treatment of KOA improves Knee injury and 
Osteoarthritis Outcome Score (KOOS) subscales for patients measuring pain, function, and 
quality of life at 3 months, 6 months, and 12 months post treatment compared to Gel-One® 
hyaluronate injections and relative to baseline.
A change in 10 points has been suggested36 and utilized37 to demonstrate a minimal clinically 
important difference (i.e., decline or improvement) in each KOOS subscale. In this study, we 
expect to see a mean improvement of greater than 10 points at 3 months post treatment in the 
patients receiving BMAC and PRP injections as well as those receiving the Gel-One® 
hyaluronate injection. However, we expect to see greater improvement in favor of the group 
receiving the BMAC and PRP treatment at 6 months and 12 months post treatment.
Specific Aim 2a: To determine if BMAC and PRP treatment of KOA improves pain scores 
measured by the Numeric Pain Rating Scale (NPRS) at 3 months, 6 months, and 12 months post 
treatment compared to Gel-One® hyaluronate injections and relative to baseline.
Specific Aim 2b: To determine if BMAC and PRP treatment of KOA improves Patient Reported 
Outcome Measurement Information System (PROMIS) Global Health scores (short form, version 
1.1) at 3 months, 6 months, and 12 months post treatment compared to Gel-One® hyaluronate 
injections and relative to baseline.
2.0 – METHODS 
2.1 – Study Population
The study population will consist of patients presenting to McConnell Spine, Sport, and Joint Physicians, 
which is focused on conservative, non-surgical solutions for orthopedic issues. The clinic is located in a 
diverse and large geographic area.  
All participating patients will be patients of the McConnell Spine, Sport, and Joint Physicians. Patients 
participating in the study may be patients of the study physician, referred from an outside practice to the 
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study physician, or referred from other physicians of the McConnell Spine, Sport, and Joint Physicians to 
the study physician.
The study population will consist of patients who have been diagnosed with KOA (i.e., ICD 10 diagnosis 
code M17) and have failed initial conservative treatment options. If the patient has bilateral KOA the 
patient would be excluded unless the patient had only unilateral symptoms. The study will not include 
patients who have end-stage KOA (i.e., Kellgren-Lawrence grade 4) for which surgical intervention 
would be more appropriate. Determining a Kellgren-Lawrence grade is a standard of care for diagnosing 
KOA and is done by reading a standing radiograph of the knee.
The clinic completes an average of approximately 630 office visits per month, 25% of which is related to 
the care of osteoarthritis. We anticipate that 50% of patients with KOA will satisfy inclusion and 
exclusion criteria and 80% of eligible patients will be willing to participate in the study. We anticipate 
enrollment of four patients per month over a maximum enrollment period of 16 months from the start 
date.
Number of Subjects to be included in the study: 45
We expect that up to 1 of every 3 patients consented will need to be withdrawn prior to the treatment 
intervention. Withdrawal criteria include use of NSAIDs or corticosteroids within 2 weeks prior to the 
treatment intervention date, or if a patient’s platelet count is found to be <150,000 platelets per microliter 
of blood or >450,000 platelets per microliter of blood. Withdrawal criteria will be further discussed in 
section 2.4. We will apply the treatment intervention to only 30 total patients (i.e., n = 15 per treatment 
group); however, we anticipate consenting up to 45 patients based on possibility of withdrawal from the 
study. We will discontinue screening and consenting of patients if 30 patients have undergone one of the 
two treatment interventions.
As attrition following the treatment intervention is only expected to be due to a patient undergoing TKA 
prior to the 1 year follow-up or due to unforeseen illness, we do not anticipate this having an effect on our 
population. To further ensure visit compliance, compensation (i.e., a $25 gift card) will be offered with 
completion of the 3, 6, and 12 month research follow-up visits.
Proposed Study Start Date:  October 1, 2016
Proposed Study End Date:  April 1, 2019
Inclusion Criteria:
1) Male and female patients 40 to 70 years old 
2) Diagnosed with KOA based on the American College of Rheumatology criteria including 
symptomatic reports and radiographic findings 
3) Kellgren-Lawrence grade 1-3 based on a radiograph within 6 months of presentation to the 
clinic
4) Symptomatic evidence of tibiofemoral osteoarthritis for ≥6 months
5) Average numeric pain rating of 4 – 8 on a scale of zero to 10 (defined as moderate level) 
over the past week 
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6) Previous trial of 6 weeks minimum of conservative therapy including physical therapy, 
weight loss, anti-inflammatory medication, or injection therapy
Exclusion Criteria
1) Grade 4 KOA according to the Kellgren-Lawrence scale
2) History of intraarticular viscosupplementation or steroid injection in the target knee in the 
past 6 months at the time of the baseline visit or intraarticular injection planned during the 
trial 
3) History of arthroscopic surgery in the target knee in the past 12 months at the time of 
presentation to the clinic or planned surgery during the trial period (e.g., scheduled 
for/awaiting arthroscopy or a knee replacement procedure)
4) Bilateral KOA (unless the contralateral knee involvement is limited to radiographic 
osteoarthritis and not symptomatic)
5) Ipsilateral (same side) or contralateral (opposite side) symptomatic osteoarthritis of hip or 
ankle
6) Clinically apparent tense effusion or other acute inflammation of the target knee at the time 
of presentation to the clinic
7) Active infection of either lower extremity such as cellulitis or any skin disease or infection 
in the area where BMAC is aspirated, blood is drawn, or an injection is given
8) History of diagnosis of any of the following: 1) septic osteoarthritis of any joint, 2) 
inflammatory arthropathy such as rheumatoid arthritis, gout, pseudogout, lupus, crystalline 
arthropathy, chondrocalcinosis and other rheumatology diagnoses
9) Cruciate/collateral knee ligament instability, ligament laxity, or meniscal instability of the 
target knee
10) Significant alignment deformity such as varus/valgus of the target knee in the judgment 
of the investigator
11) Currently pregnant, nursing, or planning to become pregnant during the trial period
12) Previous or known allergic reaction or hypersensitivity to heparin; sodium citrate; 
hyaluronan products or specifically Gel-One®; cinnamon; bird products such as feathers, 
eggs, or poultry; avian proteins 
13) Not suitable for BMAC tissue allograft injection per physician (e.g., blood dyscrasia)
14) Unable to be prescribed stable dose of NSAIDs and/or tramadol based on medical history 
as ad lib use of OTC analgesics will be allowed in both groups after treatment
15) Current cigarette smoker
       16) Unable to give informed consent
       17) Non-English speaking
2.2 – Hypotheses
Hypothesis 1: We hypothesize that patients that are treated with BMAC and PRP will have improved 
KOOS subscale scores at 6 months and 12 months post treatment compared to patients treated with Gel-
One® hyaluronate injections and relative to baseline. We hypothesize that both patients treated with 
BMAC and PRP and patients treated with Gel-One® will have improved KOOS subscale scores at 3 
months post treatment relative to baseline.
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A sample size of 30 total patients undergoing the treatment intervention has been established based on the 
power calculation (α = 0.05, β = 0.20) of a previous study comparing allogeneic bone marrow MSCs to 
hyaluronic acid in 30 patients with knee osteoarthritis30 and a preceding pilot study.38 The primary 
outcome tool used in the study by Vega et al. has been demonstrated to have similar effect sizes at 6 and 
12 months and similar smallest detectable differences compared to the KOOS scale in two different 
populations with knee-related deficits.39,40 A post-hoc power analysis will be completed, if necessary, to 
evaluate current findings and potentially plan for future studies with this specific study population.
Hypothesis 2a: We hypothesize that patients that are treated with BMAC and PRP will have improved 
NPRS scores at 3 months, 6 months, and 12 months post treatment compared to patients treated with Gel-
One® hyaluronate injections and relative to baseline.
Hypothesis 2b: We hypothesize that patients that are treated with BMAC and PRP will have improved 
PROMIS Global Health scores at 3 months, 6 months, and 12 months post treatment compared to patients 
treated with Gel-One® hyaluronate injections and relative to baseline.
2.3 – Study Variables & Outcomes of Interest
Treatment Groups:

N = 30 patients that will undergo treatment

Group A: BMAC and PRP injections to target knee (n=15)

Group B: Gel-One® hyaluronate injection to target knee (n=15)
The following data points will be collected for patients who choose to participate in the study at 
McConnell Spine, Sport, and Joint Center (see Table 1).  Patient data will be collected via the electronic 
medical record at the study physician’s practice, as well as by means of study specific data collection 
forms (see Appendices).  Only the study staff will have access to the paper data collection forms and the 
Research Electronic Data Capture (REDCap) database created solely for use in this study.  Exported 
REDCap patient data will be de-identified upon study completion, prior to statistical analysis using SAS 
9.4 (SAS Institute Inc., Cary, NC, USA).
Demographics:

Age, gender, and body mass index (BMI)
Relevant clinical information or past medical history:

Relevant past medical history related to the involved knee including previous surgical procedures, 
previous intraarticular injections, other treatments, and course of knee pain

Kellgren-Lawrence grade of KOA via standing radiograph of the target knee 

Platelet count via complete blood count (Group A only)
Other relevant therapies received following the study treatment:

Therapies received for the target knee including use of over the counter medications (i.e., Advil, 
Motrin, or Tylenol), prescription anti-inflammatories or NSAIDs (i.e., Mobic, Naprosyn, 
Celebrex, or Voltaren), narcotics (i.e., Tramadol, Percocet, Vicodin, or others), or physical therapy
Primary outcome measures:
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
Change in KOOS subscale scores which will objectively measure pain, function, and quality of 
life indicators at 3 months, 6 months and 12 months post treatment (see appendix 4.1 for KOOS 
scale)
Mean values for the KOOS subscales have been studied in a population-based sample (i.e., not 
specific to whether those surveyed actually had knee complaints).41 The population-based sample 
of subscale scores (i.e., range of 0-100 with a score of 100 representing the best possible score) in 
the approximate age group of this study ranged from 61 to 89.5, which also varies by gender.41 A 
change in 10 points has been suggested36 and utilized37 to demonstrate a minimal clinically 
important difference (i.e., decline or improvement) in each KOOS subscale.
Secondary outcomes measures:

Change in pain scores as measured by the NPRS at 3 months, 6 months, and 12 months post 
treatment (see appendix 4.2 for NPRS scale)
A two-point change has been established as the minimal clinically important difference as 
measured by the NPRS.42 Each patient will have an average pain rating of 4-8 on a 0-10 scale 
over the past week prior to completion of baseline information to be included in the study.

Change in the PROMIS Global Health scale (short form, version 1.1) at 3 months, 6 months, and 
12 months post treatment (see appendix 4.3 for PROMIS Global Health scale short form, version 
1.1)
The PROMIS Global Health scale (short form, version 1.1) will be useful to describe changes in 
the study population. The scale has been described as a useful summary of physical and mental 
health in clinical studies with patient-reported outcomes.43
Study Variables Table:
Table 1.  Study Variables.
Category
Data points
Demographics
1.
Age
2.
Gender (0-male, 1-female)
3.
BMI
Relevant clinical 
information or past 
medical history
1.
Previous surgery on target knee (0-no, 1-yes)
2.
Previous injection on target knee (0-no, 1-yes)
3.
Previous physical therapy for target knee (0-no, 1-yes)
4.
Onset/course of target knee pain (0-traumatic, 1- insidious)
5.
Kellgren-Lawrence grade (0-grade 1, 1-grade 2, 2-grade 3)
6.
Platelet count -Group A only (in thousands per ml of blood)
Other relevant 
therapies received 
following the study 
treatment
1.
Pain medications for the target knee (0-no, 1-yes)
2.
Over the counter medications for the target knee (0-no, 1-yes as 
needed, 2-yes daily)
3.
Prescription anti-inflammatories or NSAIDs for the target knee (0-no, 
1-yes as needed, 2-yes daily)
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4.
Narcotics for the target knee (0-no, 1-yes as needed, 2-yes daily)
5.
Physical therapy for the target knee (0-no, 1-yes)
Primary outcome 
measures
1.
KOOS pain subscale
2.
KOOS symptoms subscale
3.
KOOS ADL subscale
4.
KOOS sport and recreation subscale
5.
KOOS quality of life subscale
Secondary outcome 
measures
1.
NPRS
2.
PROMIS Global Health scale score
2.4 – Study Design
Overall Design
This study will be a prospective, 1:1 randomized, controlled trial. The two treatment groups 
(Group A: BMAC and PRP injections and Group B: Gel-One® hyaluronate injection) will be 
compared to one another. 
A study calendar is included within section 2.4 or can be found in Appendix 4.5.
Patient Identification Procedures
Potential patients can contact the clinic to be screened and will present to the clinic as 
appropriate. Patients may learn of the clinical trial through routine informational postings in the 
McConnell Heart Health Center monthly newsletter. Other potential study subjects will be 
identified by their presentation to the clinic. The physician or study staff will then screen the 
patient that has presented to the clinic to ensure that the patient satisfies all inclusion and 
exclusion criteria prior to introducing the trial to the patient. 
Consent Process
Patients presenting to the clinic who satisfy inclusion and exclusion criteria will be introduced to 
the study by the physician or study staff. After the study has been thoroughly explained, the 
patient has had his/her questions answered, and the patient has agreed to participate in the study, 
informed consent will be obtained by the study staff.
Patients will be consented at the beginning of their baseline visit. Patients will be given the 
consent form by either the study physician or a research team member. The patient will be given 
appropriate time to read through the consent form and have any questions answered. An 
explanation will be provided to patients along with written documentation regarding their rights 
as a research patient and how to withdraw authorization for participation in this study. Patients 
will receive a copy of their consent form for their records. Next, the consented patients will 
complete the baseline primary and secondary outcome tools, as well as a form asking for relevant 
past medical history regarding the patient’s knee (see Appendix 4.4). Baseline demographic 
information (i.e., gender, age, body weight, and height) and clinical information (i.e., Kellgren-
Lawrence grade) will be obtained from the patient’s medical record. The patients will complete 
the baseline forms with either the study physician or a research team member. Informed consent 
and baseline procedures will be completed within 14 days of a patient presenting to the clinic and 
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verbalizing interest in the study. However, informed consent and baseline procedures may be 
performed on the day of the patient’s initial presentation to the clinic.
Randomization
Patients completing informed consent will be randomized in a 1:1 single-blinded fashion. The 
randomization allocation schedule will be developed by the research team member performing 
the statistical analyses and will not be shared with the remainder of the research team. Following 
the completion of informed consent and collection of baseline information for each patient, the 
research team member responsible for scheduling the treatment procedure will be made aware of 
group allocation. This research team member will assign a random number to each patient and 
independently maintain a key to be able to link the patient to the data collected as well as identify 
the group membership of each patient. This research team member will not be involved in the 
collection of 3 month, 6 month, or 12 month study variables. The designated research team 
member who will collect study variables at 3, 6, and 12 months will remain blinded to group 
allocation throughout the duration of the study. The primary investigator (i.e., the physician 
providing the treatment) will not be blinded to group allocation as knowledge of group allocation 
will be essential to deliver two distinctly different treatment procedures and to provide the 
participant with an explanation of the clinical procedure prior to initiating the treatment. 
However, the primary investigator will be unaware of the randomization allocation schedule. 
Randomization will be blocked to prevent selection and accidental bias while ensuring equal 
allocation to each treatment group.
Study Treatment/Interventions
After randomization, the patient will be scheduled for the treatment intervention within the next 
30 days after the completion of informed consent and baseline procedures. All patients will be 
restricted from use of NSAIDs or oral corticosteroids for 2 weeks prior to the planned treatment 
procedure. 
At the baseline visit, patients randomized to Group A (BMAC and PRP injections to target knee) 
will have venous blood sampled by the clinic staff in order to determine the patient’s platelet 
count via a complete blood count (CBC) in the lab based on established procedures. Specifically, 
the venous blood will be drawn in a lavender-top ethylenediamine tetraacetic acid tube. The 
sample will be mixed by gently inverting 8 times. The sample will be sent to OhioHealth 
Laboratory Services and be received within 24 hours at ambient temperature. 
Following the baseline procedures and prior to treatment intervention, patients will be withdrawn 
from the study if one of the following occur:
1) a patient uses NSAIDs or corticosteroids within 2 weeks prior to the treatment 
intervention date, or
2) a patient’s platelet count is found to be <150,000 platelets per microliter of blood 
or >450,000 platelets per microliter of blood.
If a patient’s platelet count is <150,000 platelets per microliter of blood or >450,000 platelets per 
microliter of blood, the patient will be referred appropriately for proper medical follow-up. If a 
patient is withdrawn prior to the treatment intervention for any of the reasons outlined above, we 
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will continue enrollment of patients until we have reached a total of 30 patients (i.e., 15 patients 
per group).
Within 30 days after the completion of informed consent and baseline procedures, the patient will 
return for appropriate treatment based on group allocation. The treatment procedure for each 
group is outlined below.
Procedures:
Group A: (BMAC and PRP injections to target knee)
For BMAC preparation, 60 ml of bone marrow will be aspirated from the posterior superior iliac 
crest by the study physician and handled by the clinic staff utilizing a BC60 PURE BMC® 
Concentrating System 60mL single use disposable kit (EmCyte Corporation, Fort Meyers, FL, 
USA). During this procedure, the patient will lie prone. The bone marrow will be aspirated 
through a single site portal using a T handle Jamshidi™ bone aspiration needle (Becton, 
Dickinson and Company, Franklin Lakes, NJ, USA). Ultrasound will be used to localize the site 
of aspiration. The limited aspiration will be performed under a local anesthetic. No conscious 
sedation will be used. The bone marrow will be transferred to the Executive Series Centrifuge II 
(EmCyte Corporation, Fort Meyers, FL, USA) for centrifugation and resulting bone marrow cell 
concentration, an approximately 25-minute process. The concentration process will yield 
approximately 5-6 ml of stromal fluid to be used for injection, under ultrasound guidance, into the 
subject’s target knee by the study physician. Immediately following the injection of the 
concentrated cells, 4-5 ml of previously separated PRP will be introduced under ultrasound 
guidance to the subject’s target knee (preparation described below) by the study physician.
For PRP preparation, 60 ml of venous blood will be withdrawn from either upper extremity by the 
appropriate clinical staff. The PRP will be handled using a AB60 Pure, Accellerated Biologics 
60mL PURE Concentrating System single use disposable kit (Accelerated Biologics, Tequesta, 
FL, USA). 
Ultrasound guided injection procedures: 
Sterile probe preparation will be used in addition to routine sterile techniques using chlorhexadine 
cleansing solution and aseptic technique. All blood handling, harvesting and interventions will be 
done using strict aseptic protocol. 
Group B: (Gel-One® hyaluronate injection to target knee)
Patients will receive a single injection of Gel-One® (Zimmer, Inc., Warsaw, IN, USA) into the 
target knee. Injections will be performed by the study physician under real-time dynamic 
ultrasound guidance. Pre-injection aspirations will be carried out if clinically indicated, however, 
corticosteroids will not be introduced at any time during the trial.
After identifying anatomical landmarks and marking the injection site, the area will be carefully 
prepared with a chlorhexidine solution, and allowed to dry. Landmarks will then be re-
established. The prepared area will be swabbed with alcohol.  Skin will be anesthetized with a 
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vapo-coolant spray for 3-5 seconds. Immediately after evaporation, a needle will be advanced to 
the target area and safe placement will be achieved with real time ultrasound guidance. 
Introduction of the injectate (3 ml syringe of Gel-One® - 1% solution [10 mg/mL], 30mg total 
hyaluronan) will follow without significant resistance or complaints of pain by the patient. The 
needle will then be withdrawn, the area cleaned, and a band-aid applied.
Following the treatment based on group allocation, all patients regardless of group allocation will 
be provided and/or will complete the following:
1. A handout will be provided with instructions to follow and tips of what to expect prior to the 2 
week visit follow-up with the study physician (see Appendix 4.6). 
2. All patients will complete a visit with the study physician to monitor response to joint injection 
at 2 weeks (+/- 7 days) and 3 months (+/- 7 days) following the treatment date. At the 3 month 
visit, all patients will also complete the primary and secondary outcome tools with the study staff. 
3. All patients will complete a follow up visit at approximately 6 months (+/- 14 days) following 
the date of the treatment provided for completion of the primary and secondary outcome tools. 
4. All patients will complete a follow up visit at approximately 12 months (+/- 14 days) following 
the date of the treatment provided for completion of the primary and secondary outcome tools. 
Data Collection
Time point
Measurement
Baseline 
≤14d from presentation or at 
presentation
1.Demographic information including gender, age, and BMI
2.Relevant past medical history related to the involved knee including 
previous surgical procedures, previous intraarticular injections, other 
treatments, and course of knee pain (i.e., primary osteoarthritis or from 
previous traumatic injury)
3. Kellgren-Lawrence grade 
4. Platelet count -Group A only 
5. KOOS subscales
6. NPRS 
7. PROMIS Global Health (short form, version 1.1) scale 
RANDOMIZATION – 15 patients per group
Treatment Delivered 
≤30d from Baseline
Group A (n=15)
Single episode of BMAC and 
PRP injections to the target knee
Group B (n=15)
Single injection of Gel-One® 
hyaluronate to the target knee
3 months (+/- 7 days) after 
treatment 
1. KOOS subscales
2. NPRS 
3. PROMIS Global Health scale 
4. Other relevant therapies received following the study treatment 
6 months (+/- 14 days) after 
treatment 
1. KOOS subscales
2. NPRS 
3. PROMIS Global Health scale 
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4. Other relevant therapies received following the study treatment
12 months (+/- 14 days) 
after treatment 
1. KOOS subscales
2. NPRS 
3. PROMIS Global Health scale 
4. Other relevant therapies received following the study treatment
Risks:
Risks are typical for bone marrow aspiration, blood draw, and intraarticular knee injection and 
include the following:
Common or likely for blood draw in Group A (participants who will receive BMAC and PRP 
injections to the target knee):

Momentary discomfort at the site of the blood draw

Bruising, redness, swelling, or bleeding at the site of the blood draw

Feeling of lightheadedness when the blood is drawn
Rare for blood draw in Group A (participants who will receive BMAC and PRP injections to the 
target knee):

Infection at the site of the blood draw
Rare for bone marrow aspiration in Group A (participants who will receive BMAC and PRP 
injections to the target knee):

Excessive bleeding, particularly in people with low numbers of a certain type of blood cell 
(platelets)

Infection, especially in people with weakened immune systems

Long-lasting discomfort at the site

Penetration of the internal organs if the aspiration needle is pushed too deeply into and 
through the hip bone
Common or likely for Group A (BMAC and PRP injections to the target knee):

Increased temporary pain at the collection and/or injection site

Swelling, redness, warmth, stiffness, and/or bruising at the collection and/or injection site
Rare for Group A (BMAC and PRP injections to the target knee):

Bleeding, infection, reaction to local anesthetic, hypersensitivity or allergic reaction to 
heparin or anticoagulant sodium citrate
      
      
Common or likely for Group B (Gel-One® hyaluronate injection to target knee):

Increased temporary pain at the injection site

Swelling, redness, warmth, stiffness, and/or bruising at the injection site

Hip or knee pain
    
      Less common but serious for Group B (Gel-One® hyaluronate injection to target knee):

Increased swelling to the knee requiring joint aspiration (removal of fluid)
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
Increased pain to the knee requiring an intraarticular steroid injection

Worsening arthritis related to the injection

Upper respiratory tract infection
      Rare for Group B (Gel-One® hyaluronate injection to target knee):

Bleeding; infection; muscular weakness; spasms; dizziness; rash; itching; back pain; 
headache; migraine; high blood pressure; burning sensation; gait disturbance; increased blood 
liver enzyme, alkaline phosphatase, alanine aminotransferase, urea, and increased or 
decreased white blood cell count

Reaction to local anesthetic, 

Allergic/non-allergic reaction to Gel-One® accompanied by cold sweat, paleness, or low 
blood pressure

Need for arthroscopy (surgical inspection) of the knee related to the injection
Safety Endpoints: 
Patients who experience a significant complication from bone marrow harvest, blood draw, or 
injection therapy including infection, synovitis with effusion, or excessive pain, will be treated 
with the appropriate medical intervention. If a patient’s platelet count is found to be <150,000 
platelets per microliter of blood or >450,000 platelets per microliter of blood after the baseline 
visit, the patient will be withdrawn from the study and referred appropriately for proper medical 
follow-up. 
Safety Reporting Plan:
The study team or study physician will be responsible for gathering information related to 
adverse events. The PI will review, evaluate, and monitor AE/SAEs.
Non-serious adverse events that are considered to be related or possibly related to the research 
will be reported annually upon IRB renewal. Unanticipated problems that are not adverse events, 
protocol violations, or enrollment exceptions will be reported within 5 business days from the 
time the study team received knowledge of the event.
Some adverse events will be expected including those listed as “common or likely”, “less 
common”, or “rare” for each treatment group. Other adverse events that are unexpected and are 
possibly related to the study treatment will be reported within 5 business days of notification of 
the event. Adverse events that are found to be occurring at a higher rate than expected will be 
reported within 5 business days of noting a pattern of occurrence. Adverse events that are 
considered serious, unexpected, and possibly related to the study treatment (i.e., SAEs) will be 
reported within 1 business day of the notification of the event. SAEs will be reported to the 
OhioHealth IRB via e-mail reporting using the Adverse Event Template Form, per institutional 
and national guidelines. SAEs will be tracked for 90 days following notification via chart review. 
Recording of Adverse Events: 
At each contact with the subject following the treatment intervention, the study team will seek 
information on adverse events by patient completion of an Adverse Event Collection Form (see 
Appendix 4.7) and, as appropriate, by examination. Information on all adverse events will be 
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tracked throughout study participation using the collection form. All clearly related signs, 
symptoms, and abnormal diagnostic, laboratory or procedure results will be recorded.
The clinical course of each event will be followed until resolution, stabilization, or until it has 
been determined that the study treatment or participation is not the probable cause.
When an adverse event has been identified, the study team will take appropriate action necessary 
to protect the study participant and then complete the necessary paperwork and/or log. The 
primary investigator will evaluate the event and determine the necessary follow-up and reporting 
required.
Surveys/Questionnaires
As described previously, the patients’ knee pain, function, and quality of life measures will be 
assessed via standardized survey tools (i.e., KOOS subscales, NPRS, and PROMIS Global Health 
scale) at baseline, 3 months, 6 months, and 12 months.  The KOOS subscales (i.e., pain, 
symptoms, activities of daily living, function in sports and recreation, and knee related quality of 
life) combine for 42 questions in a 5 point rating scale format. The NPRS is a semantic 
differential scale ranging from zero (i.e., no pain) to ten (i.e., worst imaginable pain). The 
PROMIS Global Health scale (short form, version 1.1) is a five point rating scale consisting of 10 
questions. The patient will independently complete each clinical scale once comprehension is 
assured. The research team member administering the clinical scales will be available to answer 
patient questions regarding completing the scale. This research team member will be unaware of 
group allocation.
Study Calendar
Study Calendar
Presentation
Baseline 
≤14d from 
presentation 
or at 
presentation 
Withdrawal 
period
Treatment
≤30d from 
Baseline
2-Weeks
after 
treatment
+/- 7d
3-Months 
after 
treatment
+/- 7d
6-Months 
after 
treatment 
+/- 14d
12-
Months 
after 
treatment
+/- 14d
Screen for 
eligibility
x
Informed 
consent
x
Demographics
x
Past Medical 
History
x
KOOS 
subscales
x
x
x
x
NPRS
x
x
x
x
PROMIS 
x
x
x
x
Other relevant 
x
x
x
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therapies
Randomization
x
CBC (Group A) 
x
Withdrawala 
x
Treatment
x
Visits
x
x
x
x
x
x
x
SAE Evaluation
x
x
x
x
aNSAIDs or oral corticosteroids during the 2 weeks leading up to the treatment visit or platelet count <150,000 per 
microliter of blood or >450,000 per microliter of blood
Data Storage and Confidentiality
Data will be collected on paper and entered by a research team member assigned to the study who is 
blinded to group allocation. All paper forms will be identified by the random number assigned to each 
patient except the informed consent form which will contain the patient’s name as required. The data 
forms will be stored by the primary investigator or a research team member in a locked cabinet in an 
on-site office. REDCap (developed and first deployed at Vanderbilt University) will be used for data 
entry, and then the database will be pulled into SAS 9.4 (SAS Institute Inc., Cary, NC, USA) for 
analysis. The primary investigator and study staff will have access to the database through a password 
protected computer. This includes clinical, laboratory, and radiographic data. The information in the 
database will be linked to each patient by the random number assigned to that specific patient. The 
key used to link each patient to the assigned random number will be stored on a password protected 
computer. All publically available files (i.e., resulting publications or presentations) will contain only 
de-identified information.
Standard clinical protocol regarding patient confidentiality will be followed. Information about study 
patients will be kept confidential and managed according to the requirements of the Health Insurance 
Portability and Accountability Act of 1996 (HIPAA). Those regulations require a signed patient 
authorization informing the patient of the following: 
•
What protected health information (PHI) will be collected from patients in this study
•
Who will have access to that information and why
•
Who will use or disclose that information
•
The rights of a research patient to revoke their authorization for use of their PHI
Dual Enrollment, Risks & Benefits, Bias
Participation in this study will preclude enrollment into other trials. The potential risks with 
participation include loss of confidentiality and those risks outlined above specific to each treatment 
intervention. Risks of confidentiality will be minimized by limiting access to data (as outlined above) 
and following institutional protocol when releasing or destroying protected health information.
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Potential benefits of participation in this study include improvement in daily pain, function, and 
quality of life. The information learned from this study will be used to contribute to the literature 
regarding the treatment intervention outlined.
We recognize that there is risk for inherent bias within our study as patients are unable to be 
completely blinded to type of treatment he/she receives because each treatment procedure is distinctly 
different. Risk of selection bias is minimized by use of a randomized allocation schedule. Risk of 
influence on the patient when completing clinical outcome scales will be negated as the research team 
member administering the clinical outcome tools at 3, 6, and 12 months post-treatment will be blinded 
to group allocation.
ClinicalTrials.gov 
As this study meets the FDAAA 801 definition of an “Applicable Clinical Trial” based on a drug and 
biologic, it is required that the study be registered on ClinicalTrials.gov.  The Principal Investigator 
will register and activate the study account prior to enrollment, and all results will be entered upon 
study completion, followings statistical analysis, per the Results Database Guidelines.
2.5 – Statistical Analysis
Aim 1: Change in mean KOOS subscale scores over time based on treatment group
Total scores will be calculated for each patient using the KOOS subscales. The validated analysis 
guidelines for the KOOS instrument will be used. Patient’s total scores will be compared at baseline, 3 
months, 6 months, and 12 months post treatment and compared by treatment group.
The statistical method that will be used is a Repeated Measures ANOVA (RM-ANOVA). This 
statistical strategy will allow us to control for the correlation in each individual’s measurements over 
time. The use of the standardized scales ensures that the outcome variable will be normally distributed, 
which will meet the underlying assumptions of the RM-ANOVA analysis. We will use the KOOS 
subscale score as the dependent variable, and the treatment assignment as the independent variable. If 
the distribution of gender is unequal across treatment groups after randomization, this statistical 
method will allow us to control for gender because changes in score will differ by gender. We will also 
be able to control for clinically meaningful variables such as patient age or BMI if there are differences 
in these variables between the two treatment groups at baseline.
Aim 2a: Change in mean NPRS score over time based on treatment group
Total scores will be calculated for each patient using the NPRS. The NPRS instrument will be 
processed using the tool’s validated analysis guidelines. Patient’s total scores will be compared at 
baseline, 3 months, 6 months, and 12 months post treatment and compared by treatment group.
The statistical method that will be used is a RM-ANOVA. This statistical strategy will allow us to 
control for the correlation in each individual’s measurements over time. The use of the standardized 
scales ensures that the outcome variable will be normally distributed, which will meet the underlying 
assumptions of the RM-ANOVA analysis. We will use the NPRS as the dependent variable, and the 
treatment assignment as the independent variable. If the distribution of gender is unequal across 
treatment groups after randomization, this statistical method will allow us to control for gender 
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because changes in score will differ by gender. We will also be able to control for clinically 
meaningful variables such as patient age or BMI if there are differences in these variables between the 
two treatment groups at baseline.
Aim 2b: Change in mean PROMIS – Global Health score based on treatment group
Total scores will be calculated for each patient using the PROM Global Health scale (short form, 
version 1.1). The PROMIS global health instrument will be processed using the tool’s validated 
analysis guidelines. Patient’s total scores will be compared at baseline, 3 months, 6 months, and 12 
months post treatment and compared by treatment group.
The statistical method that will be used is a RM-ANOVA. This statistical strategy will allow us to 
control for the correlation in each individual’s measurements over time. The use of the standardized 
scales ensures that the outcome variable will be normally distributed, which will meet the underlying 
assumptions of the RM-ANOVA analysis. We will use the PROMIS global heath scale as the 
dependent variable, and the treatment assignment as the independent variable. If the distribution of 
gender is unequal across treatment groups after randomization, this statistical method will allow us to 
control for gender because changes in score will differ by gender. We will also be able to control for 
clinically meaningful variables such as patient age or BMI if there are differences in these variables 
between the two treatment groups at baseline.
All data will be analyzed with an intention to treat approach. Any potential drop out patterns will be 
analyzed to determine whether it is ignorable or informative.
3.0 – REFERENCES 
1. Centers for Disease Control and Prevention. Prevalence of disabilities and associated health conditions 
among adults: United States, 1999. MMWR Morb Mortal Wkly Rep. 2001; 50:120–5.
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2.  Lawrence RC, Felson DT, Helmick CG, et al. Estimates of the Prevalence of Arthritis and Other 
Rheumatic Conditions in the United States, Part II. Arthritis and Rheumatism. 2008;58(1):26-35. 
doi:10.1002/art.23176.
3. Oliveria, SA, DT Felson, JI Reed, PA Cirillo, and AM Walker. "Incidence of Symptomatic Hand, Hip, 
and Knee Osteoarthritis Among Patients in a Health Maintenance Organization." Arthritis and 
Rheumatism. 38.8 (1995): 1134-41.
4. Murphy L, Schwartz TA, Helmick CG, et al. Lifetime Risk of Symptomatic Knee 
Osteoarthritis. Arthritis and rheumatism. 2008;59(9):1207-1213. doi:10.1002/art.24021.
5. White, AG, HG Birnbaum, C Janagap, S Buteau, and J Schein. "Direct and Indirect Costs of Pain 
Therapy for Osteoarthritis in an Insured Population in the United States."Journal of Occupational and 
Environmental Medicine / American College of Occupational and Environmental Medicine. 50.9 (2008): 
998-1005.
6. American Academy of Orthopedic Surgeons: Treatment of Osteoarthritis of the Knee: Evidence-Based 
Guidelie, 2nd Edition. Available at 
http://www.aaos.org/reserach/guidelines/TreatmentofOsteoarthritisoftheKneeGuideline.pdf
7. Freitag, Julien, Dan Bates, Richard Boyd, Kiran Shah, Adele Barnard, Leesa Huguenin, and Abi Tenen. 
"Mesenchymal Stem Cell Therapy in the Treatment of Osteoarthritis: Reparative Pathways, Safety and 
Efficacy - a Review." Bmc Musculoskeletal Disorders. 17.232 (2016).
8. Wolfstadt JI, Cole BJ, Ogilvie-Harris DJ, Viswanathan S, Chahal J.  Current concepts: the role of 
mesenchymal stem cells in the management of knee osteoarthritis.  Sports Health. 2015 Jan;7(1):38-44.
9. Taubert, KA.  Can Patients With Cardiovascular Disease Take Nonsteroidal Antiinflammatory Drugs?  
Circulation. 2008;117:e322-e324. DOI: 10.1161/CIRCULATIONAHA.107.749135
10. “Arthritis.” Chronic Disease Prevention and Health Promotion. Centers for Disease Control and 
Prevention. 2015. Accessed June 2, 2016.
11. Uthman, I, J.-P Raynauld, and B Haraoui. "Intra-articular Therapy in Osteoarthritis."Postgraduate 
Medical Journal. 79 (2003): 449-453.
12. Bannuru, RR, NS Natov, IE Obadan, LL Price, CH Schmid, and TE McAlindon. "Therapeutic 
Trajectory of Hyaluronic Acid Versus Corticosteroids in the Treatment of Knee Osteoarthritis: a 
Systematic Review and Meta-Analysis." Arthritis and Rheumatism. 61.12 (2009): 1704-11. 
13. Raynauld, JP, C Buckland-Wright, R Ward, D Choquette, B Haraoui, J Martel-Pelletier, I Uthman, V 
Khy, JL Tremblay, C Bertrand, and JP Pelletier. "Safety and Efficacy of Long-Term Intraarticular Steroid 
Injections in Osteoarthritis of the Knee: a Randomized, Double-Blind, Placebo-Controlled 
Trial." Arthritis and Rheumatism. 48.2 (2003): 370-7.
14. Chao, J, C Wu, B Sun, MK Hose, A Quan, TH Hughes, D Boyle, and KC Kalunian. "Inflammatory 
Characteristics on Ultrasound Predict Poorer Longterm Response to Intraarticular Corticosteroid 
Injections in Knee Osteoarthritis." The Journal of Rheumatology. 37.3 (2010): 650-5.
15. Bellamy, N, J Campbell, V Robinson, T Gee, R Bourne, and G Wells. "Intraarticular Corticosteroid 
for Treatment of Osteoarthritis of the Knee." The Cochrane Database of Systematic Reviews. (2006)
16. Jones, A, and M Doherty. "Intra-articular Corticosteroids Are Effective in Osteoarthritis but There Are 
No Clinical Predictors of Response." Annals of the Rheumatic Diseases. 55.11 (1996): 829-32.
17. Karlsson, J, LS Sjögren, and LS Lohmander. "Comparison of Two Hyaluronan Drugs and Placebo in 
Patients with Knee Osteoarthritis. a Controlled, Randomized, Double-Blind, Parallel-Design Multicentre 
Study." Rheumatology (oxford, England). 41.11 (2002): 1240-8.
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18. Zychowicz, Michael E. "Viscosupplementation for Knee Osteoarthritis." Journal of the American 
Association of Nurse Practitioners. 26.3 (2014): 163-175
19. Chevalier, X, J Jerosch, P Goupille, Dijk N. van, FP Luyten, DL Scott, F Bailleul, and K Pavelka. 
"Single, Intra-Articular Treatment with 6 Ml Hylan G-F 20 in Patients with Symptomatic Primary 
Osteoarthritis of the Knee: a Randomised, Multicentre, Double-Blind, Placebo Controlled Trial." Annals 
of the Rheumatic Diseases. 69.1 (2010): 113-9. 
20. Strand, V, H.S.B Baraf, P.T Lavin, S Lim, and H Hosokawa. "A Multicenter, Randomized Controlled 
Trial Comparing a Single Intra-Articular Injection of Gel-200, a new Cross-Linked Formulation of 
Hyaluronic Acid, to Phosphate Buffered Saline for Treatment of Osteoarthritis of the 
Knee." Osteoarthritis and Cartilage. 20.5 (2012): 350-356.
21. Bannuru, RR, NS Natov, IE Obadan, LL Price, CH Schmid, and TE McAlindon. "Therapeutic 
Trajectory of Hyaluronic Acid Versus Corticosteroids in the Treatment of Knee Osteoarthritis: a 
Systematic Review and Meta-Analysis." Arthritis and Rheumatism. 61.12 (2009): 1704-11. 
22. McAlindon, T.E, R.R Bannuru, M.C Sullivan, N.K Arden, F Berenbaum, S.M Bierma-Zeinstra, G.A 
Hawker, Y Henrotin, D.J Hunter, H Kawaguchi, K Kwoh, S Lohmander, F Rannou, E.M Roos, and M 
Underwood. "Oarsi Guidelines for the Non-Surgical Management of Knee Osteoarthritis." Osteoarthritis 
and Cartilage. 22.3 (2014): 363-388.
23. Bijlsma JWJ. Strategies for the prevention and management of osteoarthritis of the hip and knee.Best 
Pract Res Clin Rheumatol. 2007;Vol. 21(No. 1): 59e76.
24. Kurtz, S, K Ong, E Lau, F Mowat, and M Halpern. "Projections of Primary and Revision Hip and 
Knee Arthroplasty in the United States from 2005 to 2030." The Journal of Bone and Joint Surgery. 
American Volume. 89.4 (2007): 780-5.
25. Agency for Healthcare Research and Quality. Nationwide Inpatient Sample(NIS), Healthcare Cost and 
Utilization Project (HCUP). 2014 July 17; Available from: 
http://www.ahrq.gov/research/data/hcup/index.html.
26. Huddleston, James I, William J. Maloney, Yun Wang, Nancy Verzier, David R. Hunt, and James H. 
Herndon. "Adverse Events After Total Knee Arthroplasty: A National Medicare Study." The Journal of 
Arthroplasty. 24.6 (2009): 95-100.
27. Hernigou P, Desroches A, Queinnec S, Flouzat Lachaniette CH, Poignard A, Allain J, Chevallier N, 
Rouard H.  Morbidity of graft harvesting versus bone marrow aspiration in cell regenerative therapy.  Int 
Orthop. 2014 Sep;38(9):1855-60.
28. Hernigou P, Homma Y, Flouzat-Lachaniette CH, Poignard A, Chevallier N, Rouard H.  Cancer risk is 
not increased in patients treated for orthopaedic diseases with autologous bone marrow cell concentrate.  J 
Bone Joint Surg Am. 2013 Dec 18;95(24):2215-21
29. Orozco, L, A Munar, R Soler, M Alberca, F Soler, M Huguet, J Sentís, A Sánchez, and J García-
Sancho. "Treatment of Knee Osteoarthritis with Autologous Mesenchymal Stem Cells: Two-Year Follow-
Up Results." Transplantation. 97.11 (2014): 66-8. 
30. Vega, A, M.A Martin-Ferrero, F.D Canto, M Alberca, V Garcia, A Sanchez, J Garcia-Sancho, A 
Munar, L Orozco, R Soler, J.J Fuertes, and M Huguet. "Treatment of Knee Osteoarthritis with Allogeneic 
Bone Marrow Mesenchymal Stem Cells: a Randomized Controlled Trial." Transplantation. 99.8 (2015): 
1681-1690.
31. Jo, CH, YG Lee, WH Shin, H Kim, JW Chai, EC Jeong, JE Kim, H Shim, JS Shin, IS Shin, JC Ra, S 
Oh, and KS Yoon. "Intra-articular Injection of Mesenchymal Stem Cells for the Treatment of 
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Osteoarthritis of the Knee: a Proof-of-Concept Clinical Trial." Stem Cells (dayton, Ohio). 32.5 (2014): 
1254-66.
32. Zhu Y et al. Basic science and clinical application of platelet-rich plasma for cartilage defects and 
osteoarthritis: a review. Osteoarthritis Cartilage. 2013; 21(11):1627–37.
33.  Bernardo, ME, MA Avanzini, C Perotti, AM Cometa, A Moretta, E Lenta, Fante C. Del, F Novara, 
Silvestri A. de, G Amendola, O Zuffardi, R Maccario, and F Locatelli. "Optimization of in Vitro 
Expansion of Human Multipotent Mesenchymal Stromal Cells for Cell-Therapy Approaches: Further 
Insights in the Search for a Fetal Calf Serum Substitute." Journal of Cellular Physiology. 211.1 (2007): 
121-30.
34. Mifune Y, Matsumoto T, Takayama K, et al. The effect of platelet-rich plasma on the regenerative 
therapy of muscle derived stem cells for articularcartilage repair. Osteoarthritis Cartilage. 
2013;21(1):175–85.
35. Xie X, Wang Y, Zhao C, et al. Comparative evaluation of MSCs from bone
marrow and adipose tissue seeded in PRP-derived scaffold for cartilage regeneration. Biomaterials. 
2012;33:7008e18.
36. Roos, EM, and LS Lohmander. "The Knee Injury and Osteoarthritis Outcome Score (koos): from Joint 
Injury to Osteoarthritis." Health and Quality of Life Outcomes. 1 (2003).
37. Skou, S.T, E.M Roos, M.B Laursen, M.S Rathleff, L Arendt-Nielsen, O Simonsen, S Rasmussen. "A 
Randomized, Controlled Trial of Total Knee Replacement." New England Journal of Medicine. 373.17 
(2015): 1597-1606.
38. Orozco L, Munar A, Soler R, et al. Treatment of knee osteoarthritis with autologous mesenchymal 
stem cells: a pilot study. Transplantation. 2013;95:1535-1541.
39. Roos E.M, Toksvig-Larsen, S. "Knee Injury and Osteoarthritis Outcome Score (koos) - Validation and 
Comparison to the Womac in Total Knee Replacement." Health and Quality of Life Outcomes. 1.1 
(2003):17.
40. van, de G. V. A, N Wolterbeek, V A. B. Scholtes, E L. A. R. Mutsaerts, and R W. Poolman. 
"Reliability and Validity of the Ikdc, Koos, and Womac for Patients with Meniscal Injuries." The 
American Journal of Sports Medicine. 42.6 (2014): 1408-1416. 
41. Paradowski, PT, S Bergman, A Sundén-Lundius, LS Lohmander, and EM Roos. "Knee Complaints 
Vary with Age and Gender in the Adult Population. Population-Based Reference Data for the Knee Injury 
and Osteoarthritis Outcome Score (koos)." Bmc Musculoskeletal Disorders. 7 (2006).
42. Farrar, John T, James P. Young, Linda LaMoreaux, John L. Werth, and R.Michael Poole. "Clinical 
Importance of Changes in Chronic Pain Intensity Measured on an 11-Point Numerical Pain Rating 
Scale." Pain. 94.2 (2001): 149-158.
43. Hays, Ron D, Jakob B. Bjorner, Dennis A. Revicki, Karen L. Spritzer, and David Cella. "Development 
of Physical and Mental Health Summary Scores from the Patient-Reported Outcomes Measurement 
Information System (promis) Global Items." Quality of Life Research : an International Journal of 
Quality of Life Aspects of Treatment, Care and Rehabilitation - Official Journal of the International 
Society of Quality of Life Research. 18.7 (2009): 873-880.
4.0 – APPENDICES 
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4.1
Knee injury and Osteoarthritis Outcome Score (KOOS)
4.2
Numeric Pain Rating Scale (NPRS)
4.3
Patient Reported Outcome Measurement Information System (PROMIS) Global 
Health scores (short form, version 1.1)
4.4
Relevant past medical history regarding the patient’s knee
4.5
Study Calendar
4.6
Post-Procedure Care Instructions
4.7
Adverse Event Collection Form
4.8
Other relevant therapies since study treatment
4.9
Patient recruitment information
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