Efficacy of Bone Marrow Aspirate Concentrate Compared With Platelet Rich Plasma for the Treatment of Symptomatic Knee Osteoarthritis: A Randomized, Controlled Clinical Trial
Phase: PHASE4
Conditions: Knee Osteoarthritis
Sponsor: Andrews Research & Education Foundation

Efficacy of bone marrow aspirate concentrate compared with platelet rich plasma for the treatment of symptomatic 
knee osteoarthritis: A randomized, controlled clinical trial.  
Joshua Hackel, MD  
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Title:                                
Efficacy of bone marrow aspirate concentrate compared with 
platelet rich plasma for the treatment of symptomatic knee 
osteoarthritis: A randomized, controlled clinical trial 
 
 
Principal Investigator:            Joshua Hackel, MD 
  
 
 
Co-Investigators:                   Adam Anz, MD 
 
James R. Andrews, MD 
 
 
 
 
  Charles E. Leddon, PhD 
 
 
 
 
   
 
 
 
 
  Nicole Rendos, PhD 
 
Funding Mechanism:             Emcyte Corporation 
  
 
 
Institution(s):                     
 Andrews Research and Education Foundation (AREF) 
1020 Gulf Breeze Pkwy. 
Gulf Breeze, FL 32561 
(850) 916-8790 
 
Andrews Institute 
1040 Gulf Breeze Pkwy. 
Gulf Breeze, FL 32561 
(850) 916- 8790 
 
1         Background / Scientific Rationale 
  
In the United States it is estimated that 47 million people have been diagnosed with arthritis. 4.3 
million have been diagnosed with isolated osteoarthritis of the knee and knee arthritis accounts 
for 20% of disability claims
1. Prevalence of the disease continues to climb and is expected to 
double by 2030. In addition 4 out of 5 patients with osteoarthritis have movement limitations
1. 
Currently there are no curative treatments for osteoarthritis. Surgical options include arthroscopy,  
osteotomies,  and  total  joint  replacement,  but  not  all  patients  with  knee osteoarthritis  
are  candidates  for  surgical  treatments,  and  others  choose  non-operative treatments 
instead of undergoing a procedure. Non-surgical treatment options include medications such as 
non-steroidal anti-inflammatory’s (NSAIDs), injectables such as corticosteroids and visco-
supplementation,  or  physical    treatments  such  as  rehabilitative therapy, unloading braces,

Efficacy of bone marrow aspirate concentrate compared with platelet rich plasma for the treatment of symptomatic 
knee osteoarthritis: A randomized, controlled clinical trial.  
Joshua Hackel, MD  
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and activity modifications (i.e. canes or walkers). Additionally weight loss can help in the battle 
to reduce pain in cases of knee osteoarthritis. 
 
The clinical efficacy of hyaluronic acid or corticosteroid injections has been reported, but effects 
are short lived. This has led to additional injection options such as autologous derived blood 
products which have been documented to alleviate symptoms related to knee osteoarthritis, with 
recent comparative studies suggesting a greater, long-lasting effect with these blood derived 
products like platelet rich plasma (PRP).
2-8 Additionally some studies have suggested an 
increased positive effect with a combination of medications with PRP.9-12 
 
While PRP shows promise in helping restore function to these patients, there are still concerns 
with PRP's long term outcomes. Another option that has become more popular for physicians 
treating this debilitation condition is bone marrow aspirate concentrate (BMA), which use's 
undifferentiated cells found in the bone marrow to promote healing and tissue 
regeneration.13 These cells have the ability to replicate into a multiple different tissue types. 
With BMA, the marrow is concentrated provide better healing of the damaged tissue and aid 
in growth and repair. The full benefits of BMA are still unknown, but studies have shown the 
treatment can reduce swelling, relieve pain, and improve healing in articular cartilage and bone 
grafts.
14
 
 
 
Autologous BMA has shown promising clinical potential as a therapeutic agent in regenerative 
medicine, including the treatment of osteoarthritis and cartilage defects,
13-14 and the clinical 
efficacy platelet rich plasma has been documented to alleviate symptoms related to knee 
osteoarthritis.
2-8  However, randomized, prospective comparison of the two techniques has not 
been reported in the literature and long term follow-up for both treatments is limited, and 
especially limited in the use of BMA for osteoarthritis treatment. 
 
 
2         Objectives 
 
The main objective of this study is to compare the effectiveness of bone marrow aspirate 
concentrate  (BMC)  to  platelet  rich  plasma  (PRP)  injections  for  the  treatment  of  knee 
osteoarthritis in regards to pain and function at multiple time points up to 24 months post 
injection. 
 
3         Subject Eligibility 
 
Patients between the ages of 18 and 80, with evidence of knee osteoarthritis will be screened for 
eligibility in the study. All subjects must present with pain or swelling of the knee of at least 4 
months in duration and a Kellgren-Lawrence score between 1 

Efficacy of bone marrow aspirate concentrate compared with platelet rich plasma for the treatment of symptomatic 
knee osteoarthritis: A randomized, controlled clinical trial.  
Joshua Hackel, MD  
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and 3 upon x-ray evaluation. Potential subjects must be willing and able to provide informed 
consent and be willing and able to return for scheduled follow-up visits. 
 
Exclusion criteria include: Patients with major mechanical axis deviation of more than 50% into 
either compartment (varus or valgus ) or that have had a corticosteroid injection within 3 months 
or a hyaluronic acid injection within 6 months will not  be  eligible.  Patients  will  be  excluded  
if  they  have  a  history  of  the  following  medical conditions - diabetes, autoimmune disorders, 
disorders requiring immunosuppression, rheumatoid arthritis, hemophilic arthropathy, infectious 
arthritis, Charcot’s knee, Paget’s disease of the femur or tibia, or history of cancer. In addition 
anyone with an ongoing infectious disease or significant cardiovascular, renal or hepatic disease 
will be excluded. 
 
4         Subject Enrollment 
 
120 patients will be recruited through physician practices and with print, flyer or web based 
advertisements (AREF and EmCYTE websites). Those patients who contact the clinical trials 
department through the physician’s office or by referral from an advertisement or otherwise 
will be prescreened for adherence to the inclusion and exclusion criteria via phone or in 
person.  
 
Once the potential participant has been prescreened for inclusion and exclusion criteria, and 
agreed to be screened for participation in the study they will be instructed on study enrollment 
protocols which will include a visit with one of the physician investigators for evaluation, x-ray’s 
and confirmation of adherence to the inclusion criteria. Subjects will also be instructed that they 
must not take any prescription or over the counter non-steroidal anti-inflammatory drugs 
(NSAIDS) for 3 weeks prior to the evaluation appointment. Following the physician 
evaluation and confirmation subjects will again have all study requirements explained to them 
and go through the described informed consent process. The subject will then be randomly 
placed in one of the two study groups and be scheduled to receive either a PRP injection or BMC 
injection in their affected knee. 
 
5         Study Design and Procedures 
 
Upon enrollment and completion of the informed consent process, patients will be randomized 
into the 2 study groups of 60 each, based on a list compiled by a random number generator 
prior to initiation of the study. Both Groups will complete the Western Ontario and 
McMaster Universities Osteoarthritis Index (WOMAC),  and  the  Subjective  International  Knee 
Documentation Committee Subjective Score (IKDC) questionnaires prior to any treatment. Due 
to the invasive nature of obtaining marrow aspirate blinding of the subjects and clinicians will not 
be performed.  Group 1 [PRP]: Will receive a single (1) intra-articular injection of PRP. Group 2 
[BMC]: Will receive a single (1) intra-articular injection of BMC after obtaining informed 
consent.  Both types of injections and all associated procedures will be performed in the clinic 
or lab setting with local anesthesia. Following the injection patients will be asked  to  complete  a  
short  questionnaire  documenting  the  BMC  or  PRP  collection, preparation and injection 
experience. Ten patients will be randomly selected from both (20 total subjects) the PRP and 

Efficacy of bone marrow aspirate concentrate compared with platelet rich plasma for the treatment of symptomatic 
knee osteoarthritis: A randomized, controlled clinical trial.  
Joshua Hackel, MD  
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2017 
 
 
BMC groups to have analysis performed on the BMC and PRP as described below. This 
analysis will not be performed on patients not randomly selected. In patients randomly selected 
after the BMC or PRP have been prepared for injection, a small sample (1 mL) of the BMC or 
PRP will be separated and sent to an independent lab (Biosciences Research Associates, Inc) for 
analysis. The PRP will be analyzed with a CBC and the BMC will be analyzed for TNC, human 
CD34+ hematopoietic stem/progenitor cell assay, CFU-F, plasma free hemoglobin, cell viability 
percent, and hemolysis percent. Evaluation, a 4 view x-ray series (long leg, lateral, sunrise, and 
bilateral Rosenberg), and injections will be provided at no charge to the patients. Patients will 
then be given standard follow-up care instructions that include no use of NSAIDS for at least 7 
days and partial weight bearing on the limb for 2-3 days, followed by the initiation of a standard 
physical therapy program at one week following injection. 
 
After the injection subjects will be required to complete the WOMAC and IKDC 
questionnaires as well as report any medications they are using via email or phone (paper method 
will be available on request) at 1, 3, 6, 9, 12, 18, and 24 months following the injection.  
 
PRP protocols 
 
All subjects who will receive a PRP injection will be treated under the normal standards of care 
for such a treatment. These procedures include drawing of blood from the patient using a standard 
aseptic technique (step by step instructions found in appendix A - Technique Manual) into a 
syringe with anticoagulant (see appendix B – MSDS sodium citrate USP).  From the syringe of 
patients randomly selected for analysis  1 mL of blood will be separated and sent to a lab for 
analysis. The remaining blood in the case of patients randomly selected or all of the blood in 
those not randomly selected will then be placed into a single concentrating device and placed 
in a centrifuge for 1.5 minutes at 3800 RPM which will separate the red blood cells from the 
plasma and platelets (see appendix C – centrifuge Op Manual). The plasma and platelets will 
then be separated off with a syringe and re-spun for 5 minutes at 3800 RPM in the centrifuge to 
separate the platelets from the plasma. The platelets will then be separated off for injection into 
the patient’s knee (step by step instructions found in appendix A - Technique Manual). The PRP 
preparation procedure results in 7 mL of product in patients randomly selected for analysis  1 
mL will be separated and sent to a lab for analysis leaving 6 mL for injection. Both the 1 mL 
of blood and the 1 mL of PRP of patients randomly selected for analysis will be sent to an 
independent lab (Biosciences Research Associates, Inc) to undergo analysis for CBC.   The 
treating physician will then inject the PRP into the affected knee joint following standard aseptic 
technique per the physician’s normal standard of care. The above mentioned processes will be 
performed using the EmCyte GenesisCS Component Concentrating System Pure PRPâ II-60 
mL 2015kit (product number (GS60-PURE-II) (EmCyte Corporation, Fort Myers, Florida) which 
has been approved by the FDA for use in PRP treatments (see Appendix D – FDA letter). This 
entire process will be completed in a single patient visit. Any unused portion of a sample in the 
physician’s office will be disposed of through standard biohazard waste disposal systems as 
required by law. 
 
BMA Protocols 
 
Subjects who receive a BMA injection will again be treated under the normal standards of care for 
such a treatment. These procedures include a bone marrow harvest from the posterior iliac

Efficacy of bone marrow aspirate concentrate compared with platelet rich plasma for the treatment of symptomatic 
knee osteoarthritis: A randomized, controlled clinical trial.  
Joshua Hackel, MD  
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2017 
 
 
crest using a prone and posterior approach. The trocar will be rinsed with 15 mL of heparin (see 
MSDS heparin). A total of 50 mL of bone marrow will be drawn into a syringe containing 10 mL 
of anticoagulant (see appendix B – MSDS sodium citrateUSP). The filter will be rinsed with 3 mL 
of heparin.  The bone marrow will then be filtered.  From the syringe with filtered bone marrow, 
for patients randomly selected for analysis, 1 mL of filtered BMA will be separated and sent to 
a lab for analysis.  The remaining bone marrow will be separated into a single concentrating 
device, counterbalanced and placed in a centrifuge for 2.5 minutes at 3800 RPM for separation of 
the bone marrow concentrate. The plasma and cell concentrate will then be separated off with a 
syringe and stopcock, then transferred into the concentrating accessory, counterbalanced and re-
spun for 7 minutes at 3800 RPM in the centrifuge to separate the cell concentrate from the plasma. 
After the plasma is drawn off and swirled to resuspend, the BMC will be drawn into a syringe 
for injection into the patient’s knee (step by step instructions found in appendix A - Technique 
Manual). The BMC production procedure results in 7 mL of product for patients randomly 
selected for analysis 1 mL will be separated and sent to a lab for analysis. Both the 1 mL of BMA 
and the 1 mL of BMC of patients randomly selected for analysis will be sent to an independent 
lab (Biosciences Research Associates, Inc) to undergo analysis for TNC,human CD34+ 
hematopoietic stem/progenitor cell assay and CFU-F, plasma free hemoglobin, cell viability 
percent, and hemolysis percent..   This sample will be packaged in the company’s standard sample 
packaging and shipped per instructions (see appendix F – BSR Quality Evaluation Program 
Specimen Preparation Kit) for delivery to the lab to undergo verification testing.  The treating 
physician will then inject the BMC into the affected knee joint following standard aseptic 
technique per the physician’s normal standard of care. The above mentioned processes will be 
performed using the EmCyte GenesisCS Pure BMC®-60 ml 2015kit (product number BC60-
PURE) (EmCyte Corporation, Fort Myers, Florida) which has been approved by the FDA for use 
BMC treatments (see Appendix E – FDA Letter). This entire process will be completed in a 
single patient visit. Any unused portion of a sample in the physician’s office or in the lab will be 
disposed of through standard biohazard waste disposal systems as required by law. 
 
6         Expected Risks and Benefits 
 
Risks and Discomforts: Potential risks include those expected with any injection including 
syncope, dizziness, headache, nausea, tachycardia, infection (septic arthritis, phlebitis, and 
osteomyelitis), bleeding, or pain. Additionally the patient may experience knee stiffness or 
inflammation associated with the procedures. For BMA harvest, there is the potential for pain, 
bleeding or infection at the harvest site, as well as the possibility of retroperitoneal hematoma.  
The filter and the trocar from the bone marrow aspiration kit will be rinsed with heparin.  Risks 
with 
the 
use 
of 
heparin 
include 
hypersensitivity, 
hemorrhaging, 
heparin-induced 
thrombocytopenia (HIT), heparin-induced thrombocytopenia and thrombosis (HITT), and 
delayed onset HIT and HITT.  As with any research involving patients there is the inherent risk of 
a breach in patient confidentiality though this will be minimized through the use of subject code 
numbers and adherence to all HIPAA guidelines. 
 
Benefits:  Direct benefits of the study include a physician visit, x-rays and an injection of BMA 
and/or PRP at no cost, as well as potential pain relief, improvement of knee function, and 
improvement of quality of life, which all could lead to the avoidance of surgical intervention.  It 
is also believed that the information obtained in this study will help advance treatment of 
osteoarthritis through the use of regenerative medicine. 

Efficacy of bone marrow aspirate concentrate compared with platelet rich plasma for the treatment of symptomatic 
knee osteoarthritis: A randomized, controlled clinical trial.  
Joshua Hackel, MD  
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November 15th, 
2017 
 
 
 
 
7         Data Management Procedures 
 
All personal information is strictly confidential and no names will be disclosed except as required 
by law.  All  research  information  will  be  managed  and  accessible  by  only  the  named 
investigators and their medical staff. Data sheets will have names and identifying information 
replaced with a subject code to protect the confidentiality of the subject. All information provided 
by the subject during this project will be recorded on the appropriate forms and stored in a 
locked room in the AREF research facility. In addition all subject data forms will be scanned and 
stored, along with summary information forms, spreadsheets, and photos, in a secure password 
protected folder on a laptop in which only study investigators will have access to, and will be 
permanently deleted following any and all publications or presentations have been completed 
related to this research. All records related to this research will be retained in a secure location for 
a period of 3 years following the completion of all study related activities, at which time they will 
be properly destroyed. 
 
 
8         Data Analysis 
 
All  data  will  be  entered  into  an  excel  spreadsheet  for  analysis  that  will  include  obtaining 
standard measures such as means and standard deviation. Data will be analyzed as scores on the 
two questionnaires as well as across subsets of the individual questionnaires for function, quality 
of life and pain scores. Additional determinations based on medication usage and failure rates 
will be examined as well. 
 
9         Statistical Considerations 
 
A power analysis was performed to determine sample size based upon recent clinical trials 
comparing PRP to HA for the treatment of osteoarthritis.  Analysis utilized the average of 
standard deviation to detect average of group mean effect at 80% power.  This determined that 
25 patients per group would be needed to reach statistical significance with the WOMAC and 
that 50 patients would be needed per group for the IKDC. Considering a potential dropout rate 
of 20%, 60 patients per group was chosen as the sample size. 
 
Data will be analyzed for differences between groups using a repeated measures ANOVA 
design,  using  a  significant  p-value  of  <  0.05  for  rejecting  the  null  hypothesis.  Additional 
subjective analysis will be performed on data involving the patient experience with regards to 
the injection. 
 
 
10       Quality Control and Assurance 
 
All protocols will be monitored and analyzed data will be checked for accuracy by the principal 
investigator and/or a designated AREF research team member. All medical data will be kept in 
compliance with HIPAA guidelines. 
 
11       Regulatory Requirements 
 

Efficacy of bone marrow aspirate concentrate compared with platelet rich plasma for the treatment of symptomatic 
knee osteoarthritis: A randomized, controlled clinical trial.  
Joshua Hackel, MD  
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November 15th, 
2017 
 
 
Informed Consent: 
 
The informed consent process will be performed by a study coordinator from the Andrews 
Research and Education Foundation. All subjects will have the study described to them and will 
be given as much time as they would like to read an approved, stamped version of the 
informed consent document. After signing the informed consent document, they will be given a 
copy for their records. 
 
 
Subject Confidentiality: 
 
Subject confidentiality information is listed above in #7 (Data Management Procedures). All 
medical data will be recorded and stored in compliance with HIPAA guidelines. 
 
12 
References 
 
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Efficacy of bone marrow aspirate concentrate compared with platelet rich plasma for the treatment of symptomatic 
knee osteoarthritis: A randomized, controlled clinical trial.  
Joshua Hackel, MD  
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November 15th, 
2017 
 
 
  
 
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