Microfragmented Adipose Tissue Versus Platelet-rich Plasma for Knee Osteoarthritis: a Randomized Comparative Trial
Phase: NA
Conditions: Osteoarthritis, Knee, Microfragmented Adipose Tissue, Platelet-Rich Plasma
Sponsor: Ohio State University

 
Official title: Microfragmented Adipose Tissue Versus Platelet-rich Plasma for Knee 
Osteoarthritis: a Randomized Comparative Trial 
NCT number: NCT04351087 
Document date: March 30, 2023 
 

Platelet-rich plasma versus Adipose-derived stem cell for knee osteoarthritis: A 
randomized, comparative trial 
 
Principle Investigator (s): Michael Baria, MD MBA & Robert Magnussen MD MPH 
Co-Investigators:  
Sushmitha Durgam, BVsC PhD 
Christopher Kaeding, MD.  
Robert Duerr, MD 
Meghan Miller, MS ATC 
James Borchers, MD MPH 
 
Background 
 
Knee osteoarthritis is a leading cause of disability worldwide.1,2  Standard of care 
treatments for knee OA include activity modification, weight loss, therapeutic exercise 
and injections like corticosteroids and viscosupplement.  These commonly used non-
operative treatments focus on symptom palliation, but are not disease modifying.3   
 
Orthobiologics have emerged as a promising treatment for knee OA.  The most widely 
studied orthobiologic is platelet-rich plasma (PRP).4  PRP is a dense concentration of 
platelets derived from autologous whole blood and platelets are concentrated 2-5x 
compared to baseline.5  The platelets have demonstrated anti-inflammatory and 
chondroprotective properties.6  PRP has been shown superior to placebo and 
viscosupplement for knee OA in several clinical trials.7-10   
 
While PRP is the most widely studied and used orthobiologic, it contains only platelets, 
but no mesenchymal stem cells.  Therefore, a simple, office-based intervention able to 
collect stem cells to treat knee OA would be ideal.  Adipose (fat) is a known source of 
mesenchymal stem cells and it can be easily and safely aspirated in the clinic.11  The 
adipose tissue aspiration and processing is accomplished through a simple process.  
After local anesthesia to the site of adipose aspiration (lower abdomen or buttock), 30ml 
of adipose is aspirated through a cannula.  That adipose is then processed in 
accordance with FDA guidelines including minimal manipulation (adipose only goes 
through a short, simple centrifugation to remove oils and leaves behind the fraction that 
contains mesenchymal stem cells).12  Using of minimally manipulated, adipose derived 
stem cells has been shown safe for use as injection therapy for knee OA for 3 years.13,14    
 
Aim: To conduct a randomized trial comparing the clinical outcomes of PRP (standard 
intervention) versus Adipose-derived stem cells (investigational).   
 
Hypothesis: Both interventions will result in significant improvement in patient-reported 
outcomes.  We hypothesize that adipose-derived stem cells will provide superior 
outcomes.   
 
Methods: 
 

Participants  / Outcome Measures / Sample size: Participants  with symptomatic knee 
OA will be recruited from the sports medicine and orthopedics clinics, as well as 
advertising flyers within the clinic.   
 
Inclusion / Exclusion Criteria 
Inclusion criteria 
Age 25-75 years 
BMI < 40 
Diagnosis of knee OA (primary and post-traumatic) 
 
(Note: Participant  may have OA in both knees, but only the most symptomatic 
knee will be treated as part of this trial so that patient reported outcomes are clearly 
defined for a single joint.  The non-study knee may undergo all usual care prior to 
enrollment in the study, but no additional interventions can be performed during the 
course of the trial.  If participant  requires additional treatment, the participant  will be 
unenrolled in the study).  
Radiographic evidence of OA of the target knee (Kellgren-Lawrence grades 1-4) 
Continued OA pain in the target knee despite at least 6 weeks of 1 of the following 
nonoperative treatments: activity modification, weight loss attempt, physical therapy, or 
NSAID / acetaminophen.  
Knee Osteoarthritis Outcomes Score (KOOS)-Pain subscale 20-65 
Working knowledge of English language (to be able to complete all outcome scores) 
Ability to attend all follow-up appointments 
 
Exclusion criteria 
Isolated patellofemoral OA 
3+ effusion of the target knee (stroke test grading system) 
Significant (10 degree) valgus or varus deformities 
Prior injection therapy: 
Steroid injection in target knee in the last 3 months 
Viscosupplementation in target knee in the last 6 months 
PRP in the target knee in the last 1 year 
Cellular treatments in index knee (bone marrow, amniotic suspensions etc) all 
time 
Participation in any experimental device or drug study within 1 year before 
screening visit 
Oral or IM steroids for last 3 months 
Medical condition that may impact outcomes of procedure including: 
anemia  
thrombocytopenia 
bleeding disorders 
inflammatory disorders like rheumatoid arthritis, lupus 
diabetes 
any history of cancer (other than non-melanoma skin malignancies) 
taking anticoagulants (aspirin, Plavix, eliquis, Xarelto, warfarin, lovenox) 
Taking immunosuppressants, having a severe systemic infection  

Previous cartilage repair procedure on the injured cartilage surface (ie, OATS, ACI, 
MFX) 
Previous surgery at the target knee within the past 1 year 
Any degree of cognitive impairment. 
OA of either hip 
Pregnancy, lactating, or intent to become pregnant during treatment period 
Gout 
History of infection or current infection at the affected joint 
Smoking 
 
Sample Size Calculation:  
A total of 88 (44/group) participants  will complete this two-treatment parallel-design 
study. The probability is 80 percent that the study will detect a treatment difference at a 
two-sided 0.05 significance level, if the true difference between treatments is 9 units. 
This is based on the assumption that the standard deviation of the response variable is 
15. 
 
We will enroll 110 (55/group) participants  to ensure that 88 complete their 6 month  visit 
assuming 80% follow up at the primary endpoint of the study. 
 
 
 
 
 
Outcomes and Follow Up 
 
Demographics collected 
 
Age 
 
Body mass index 
 
Race 
 
OA grade (as determined by KL stage on x-rays) 
 
MRI severity (only if MRI within 1 year exists; no additional MRI will be 
ordered if participant  does not have it) as determined by MOAKS score 
 
The following outcomes will be collected at baseline,1,3,6, and 12 months.   
Adverse events 
KOOS 
VAS Pain (with ADLs)   
Tegner 
 
Additional baseline only measures: knee pain diagram and the pain 
catastrophizing scale 
 
Additional 6 and 12 month only measures: failure (defined by failure to improve 
KOOS-P score, desire to seek additional treatment including injections or surgery) with 
failure at 6 months representing the primary outcome variable. 
 
Follow-up plan: 

All participants’  first visit will be standard of care to provide a medical evaluation and 
assess best treatment plan for that participant , regardless of candidacy for this study.  
This evaluation includes x-rays of their knees as a standard part of the evaluation.  This 
will be billed through insurance.  If they meet criteria and choose to enroll, their 
procedure and all follow up visits will be covered by the research study funds.  The 
schedule will be as follows (by group): 
 
PRP:  
1) Baseline (at time of enrollment during initial clinical evaluation, billed to 
insurance as standard evaluation, RedCap surveys administered in 
clinic) 
2) Injection (REDCap surveys in clinic) 
3) 1 month  (REDCap surveys in clinic) 
4) 3 months  (REDCap surveys in clinic) 
5) 6 months  (REDCap surveys in clinic) 
6) 12 months  (REDCap surveys in clinic) 
Adipose: 
1) Baseline (at time of enrollment during initial clinical evaluation, billed to 
insurance as standard evaluation, RedCap surveys) 
2) Injection  
3) 2 weeks (in clinic wound-check, covered by research fund, no surveys) 
4) 1 month (REDCap surveys in clinic) 
5) 3 months (REDCap surveys in clinic)  
6) 6 months (REDCap surveys in clinic) 
7) 12 months (REDCap surveys in clinic) 
 
 
Primary outcome: KOOS-Pain 6 months 
 
Data will be housed in RedCap on a password protected, location secured medical 
center computer. 
This study will utilize REDCap (Research Electronic Data Capture), a software toolset 
and workflow methodology for electronic collection and management of clinical and 
research data, to collect and store data. The Ohio State Center for Clinical and 
Translational Science (CCTS) Research Informatics Services will be used as a central 
location for data processing and management. REDCap provides a secure, web-based 
application that provides an intuitive data manipulation interface, custom reporting 
capabilities, audit trail functionality, real-time data monitoring/querying of participant 
records, and variations of data exporting/importing. REDCap is hosted by OSUWMC IT 
in the Ackerman Datacenter (640 Ackerman Road; Room 345) 
REDCap instance is located on an internal OSUWMC network. Remote access to this 
network can be obtained over an encrypted VPN tunnel (AnyConnect). This VPN uses 

Protocol: DTLS and Cipher: RSA_AES_128_SHA1. Background checks are performed 
on all staff that are on the network or obtaining VPN access. 
 
 
Randomization 
Participants will be randomized using randomization function available in RedCap.  
 
Statistics 
 
Continuous variables will be checked for normality and subsequently compared using 
either unpaired t-tests (for normally distributed data) or Mann-Whitney U test (for non-
normally distributed data) at 6 months for the primary outcome.  The variables will be 
analyzed again at 12 months..  
 
 
After randomization, participants , medical staff and research team will note treatment 
arm allocation.  
All participants  will receive the following pre-procedural instructions 
 
Avoid non-steroidal anti-inflammatories (NSAIDs) and aspirin for 14 days before 
the procedure. 
 
No exercise the day before and the day of the procedure 
 
Arrive to the procedure well-hydrated 
 
Procedural Details 
Platelet rich plasma 
157mL of whole blood will be harvested via standard venipuncture from the antecubital 
fossa and mixed with 24mL ACD-A (manufacturer recommends 8mL ACD-A per 52mL of 
whole blood).  156ml of whole blood will be processed in the FDA Cleared Angel cPRP 
system at 2% hematocrit.   
 
1ml of whole blood and the resultant PRP will be analyzed in the Sysmex XN-350 for 
complete analysis (platelet, leukocyte [total and differential], red blood cell counts).  This 
data will be housed in the same RedCap system.  The PRP left over after the Sysmex 
testing will be frozen in de-identified tubes in the -80C degree freezer on the 2nd floor of 
the Jameson Crane Sports Medicine Institute which is locked and only study staff have 
access to. At the conclusion of the study, this PRP will be thawed and sent for growth 
factor quantification (measuring transforming growth factor, platelet derived growth factor 
and interleukin-1). This analysis requires that all samples be completed in a single batch.  
For that reason, all samples will be kept in the freezer until the end of the study.    
 
The remaining PRP (estimated 4-6mL) will be injected under sterile technique using 
ultrasound-guidance through a superolateral approach.  For participant  comfort, 2mL of 
1% lidocaine can be administered using a 26-gauge needle (into soft tissues only).  PRP 
will then be injected using a 25-guage needle.  A maximum of 6ml of PRP will be injected.  
Injection site will be cleaned and bandaged and participant  will be dismissed with post-
injection precautions and 1 month follow-up scheduled.  

 
Adipose-derived stem cell  
Adipose will be aspirated from the subcutaneous tissue of the buttock or abdomen 
(depending on best available specific to each participant ).  Once the area is prepared 
using standard sterile precautions, the aspiration site will be injected with 10ml 1% 
lidocaine with epinephrine.  A small poke incision will be made with an 11-blade scalpel 
(to allow for aspiration cannula to be easily inserted).  Then 120ml of Klein solution will 
be injected into the adipose tissue (facilitates ease of aspiration).  Solution will sit for 15 
minutes to allow for adequate anesthesia.  Aspiration cannula will be inserted and 
carefully moved in a back and forth motion for 2 minutes to allow for ease of adipose 
aspiration.  Then under continued sterile conditions, 30ml fat will be aspirated using13G 
cannula.  Aspiration site will be cleaned and bandaged.  The aspirated fat will be 
immediately processed using the Lipogems system ™ (Lipogems, Norcross, GA).  This 
is a FDA cleared device that efficiently processes adipose to remove oil and leave 
mesenchymal stem cells for injection.  Briefly, the 30ml of adipose is transferred to the 
device, saline is run through the device to remove oils and then approximately 5-7ml of 
adipose tissue is removed and ready for injection. This isolates the fraction of tissue that 
contains stem cells.  The adipose derived cells are then injected in identical fashion to 
the PRP above (except an 18-gauge needle will be used for the injection due to higher 
viscosity).      
 
0.5ml of adipose derived stem cells will be analyzed in the comparative orthopedics 
laboratory for total stem cell count and viability.   
 
For both groups, if there is excess synovial fluid (an effusion), this will be removed 
(standard of care) prior to injecting the PRP or ADSC.  This synovial fluid will be 
immediately analyzed for a complete blood count and then frozen in de-identified tubes 
in a locked -80C freezer on the second floor of the Jameson Crane Sports Medicine 
Institute.  Only approved study staff will have access to this.  At the conclusion of the 
study, all frozen samples will be analyzed for inflammatory proteins (IL-1, IL-8, TNF) 
This analysis requires that all samples be completed in a single batch.  For that reason, 
all samples will be kept in the freezer until the end of the study.    
 
Aftercare 
Tylenol and ice are permissible for immediate pain control. 
In the event of a post-injection flare (a possible risk), over-the-counter NSAIDs will be 
permitted until the flare resolves (standard of care).     
No impact lower limb activity (running, lifting) for the first 1 week.  Afterwards, activity as 
tolerated is encouraged.  
 
Compensation 
Participants  will be compensated for their time with a 20-dollar gift card at the injection 
visit and the 1,3, 6 month and 12 month follow up visits.  
 
References 

1. 
Cross M, Smith E, Hoy D, et al. The global burden of hip and knee osteoarthritis: 
estimates from the global burden of disease 2010 study. Annals of the rheumatic 
diseases. 2014;73(7):1323-1330. 
2. 
Liu Q, Niu J, Huang J, et al. Knee osteoarthritis and all-cause mortality: the 
Wuchuan Osteoarthritis Study. Osteoarthritis and cartilage. 2015;23(7):1154-
1157. 
3. 
Hermann W, Lambova S, Muller-Ladner U. Current Treatment Options for 
Osteoarthritis. Current rheumatology reviews. 2018;14(2):108-116. 
4. 
Dai WL, Zhou AG, Zhang H, Zhang J. Efficacy of Platelet-Rich Plasma in the 
Treatment of Knee Osteoarthritis: A Meta-analysis of Randomized Controlled 
Trials. Arthroscopy : the journal of arthroscopic & related surgery : official 
publication of the Arthroscopy Association of North America and the International 
Arthroscopy Association. 2017;33(3):659-670.e651. 
5. 
Marx RE. Platelet-rich plasma (PRP): what is PRP and what is not PRP? Implant 
dentistry. 2001;10(4):225-228. 
6. 
Moussa M, Lajeunesse D, Hilal G, et al. Platelet rich plasma (PRP) induces 
chondroprotection via increasing autophagy, anti-inflammatory markers, and 
decreasing apoptosis in human osteoarthritic cartilage. Experimental cell 
research. 2017;352(1):146-156. 
7. 
Cole BJ, Karas V, Hussey K, Pilz K, Fortier LA. Hyaluronic Acid Versus Platelet-
Rich Plasma: A Prospective, Double-Blind Randomized Controlled Trial 
Comparing Clinical Outcomes and Effects on Intra-articular Biology for the 
Treatment of Knee Osteoarthritis. The American journal of sports medicine. 
2017;45(2):339-346. 
8. 
Gormeli G, Gormeli CA, Ataoglu B, Colak C, Aslanturk O, Ertem K. Multiple PRP 
injections are more effective than single injections and hyaluronic acid in knees 
with early osteoarthritis: a randomized, double-blind, placebo-controlled trial. 
Knee surgery, sports traumatology, arthroscopy : official journal of the ESSKA. 
2017;25(3):958-965. 
9. 
Sanchez M, Fiz N, Azofra J, et al. A randomized clinical trial evaluating plasma 
rich in growth factors (PRGF-Endoret) versus hyaluronic acid in the short-term 
treatment of symptomatic knee osteoarthritis. Arthroscopy : the journal of 
arthroscopic & related surgery : official publication of the Arthroscopy Association 
of North America and the International Arthroscopy Association. 
2012;28(8):1070-1078. 
10. 
Smith PA. Intra-articular Autologous Conditioned Plasma Injections Provide Safe 
and Efficacious Treatment for Knee Osteoarthritis: An FDA-Sanctioned, 
Randomized, Double-blind, Placebo-controlled Clinical Trial. The American 
journal of sports medicine. 2016;44(4):884-891. 
11. 
De Francesco F, Ricci G, D'Andrea F, Nicoletti GF, Ferraro GA. Human Adipose 
Stem Cells: From Bench to Bedside. Tissue engineering Part B, Reviews. 
2015;21(6):572-584. 
12. 
Dragoo JL, Chang W. Arthroscopic Harvest of Adipose-Derived Mesenchymal 
Stem Cells From the Infrapatellar Fat Pad. The American journal of sports 
medicine. 2017;45(13):3119-3127. 

13. 
Russo A, Condello V, Madonna V, Guerriero M, Zorzi C. Autologous and micro-
fragmented adipose tissue for the treatment of diffuse degenerative knee 
osteoarthritis. Journal of experimental orthopaedics. 2017;4(1):33. 
14. 
Russo A, Screpis D, Di Donato SL, Bonetti S, Piovan G, Zorzi C. Autologous 
micro-fragmented adipose tissue for the treatment of diffuse degenerative knee 
osteoarthritis: an update at 3 year follow-up. Journal of experimental 
orthopaedics. 2018;5(1):52.