Bone Marrow Versus Adipose Autologous Mesenchymal Stem Cells for the Treatment of Knee Osteoarthritis: A Randomized Non Blind Controlled Clinical Trial
Phase: PHASE3
Conditions: Osteo Arthritis Knee
Sponsor: Universidad Catolica Santiago de Guayaquil

1 
 
 
 
 
 
 
Bone marrow versus adipose autologous 
mesenchymal stem cells for the treatment of 
knee osteoarthritis: A randomized non blind 
controlled clinical trial. 
 
Sponsor: Universidad Católica de Santiago de Guayaquil.  
Principal Investigator: Dr. Carlos Chiriboga-Accini 
NCT ID not yet assigned 
Document Date: March 3, 2020 
 
 
 
 
 
 
 
Guayaquil - Ecuador 
RESEARCH 

2 
 
 
Bone marrow versus adipose autologous mesenchymal 
stem cells for the treatment of knee osteoarthritis: A 
randomized non blind controlled clinical trial 
Carlos Chiriboga-Accini
1, George Vles
2, Mario Murgueitio-Eguez
1, Iván Chérrez-
Ojeda
3, Emanuel Vanegas-Valverde
3, Pieter Emans
2, Eduardo Guzmán-Nuquez
6, Aurora 
Romero-Coronel
5, Santiago Trujillo-Acosta
1, Peter A. Chedraui, MD, PHD
4, Antonio 
W.D. Gavilanes, MD, PHD.
2 
1Omnihospital, Guayaquil, Ecuador 
2 Maastricht University 
3 Respiralab Research Center, Guayaquil, Ecuador                    
4Instituto de Investigación e Innovación de Salud Integral, Facultad de Ciencias Médicas, 
Universidad Católica Santiago de Guayaquil, Guayaquil, Ecuador  
5Sociedad de Lucha contra el Cáncer. SOLCA 
6Interhospital, Guayaquil, Ecuador 
 
Abstract 
Mesenchymal stem cells (MSC) are stromal cells that have the ability to self-renew and 
also exhibit multilineage differentiation. MSCs can be isolated from a variety of tissues, 
such as umbilical cord, bone marrow, and adipose tissue. The multipotent properties of 
MSCs make them a promising option for the treatment of osteoarthritis (OA). 
Bone marrow mesenchymal stem cells (BM-MSC) and adipose derived mesenchymal 
stem cells (AD-MSC) have been used separately to treat OA. The aim of the present 
study will be to compare in a randomized non blind controlled clinical trial two types 
of intra-articular injections containing  MSC populations obtained from three 
clinically relevant sources: BM-MSC or AD-MSC or a combination of both of them 
AD-MSC + BM-MSC. 
Background 
Mesenchymal stem cells (MSC) represent an archetype of multipotent somatic stem 
cells that hold promise for the application in regenerative medicine
1. During the last 
decade there has been intensive investigation and an increasing number of reports 
regarding the treatment of OA using MSC
2-4. 
OA is the most common degenerative joint disease, involving progressive degeneration 
of the articular cartilage and sub-chondral bone along with synovitis
5. Cartilage 
degeneration may occur in response to inappropriate mechanical stress and low-grade 
systemic inflammation associated with trauma, obesity, and genetic predisposition, 
which are major risk factors of OA development and progression
6,7. 

3 
 
Current treatments options for OA are aimed at relieving inflammation and pain, but 
have no effect on the natural progression of the disease
8. Despite many available 
treatments, in many cases, surgically substitution with metallic implants is inevitable. In 
2013, 930,000 hip and knee joint replacements were performed in the United States. A 
16.6% of them were subject to septic and aseptic surgical revisions, resulting in a cost 
of millions of dollars to the health care system
9. The complications observed during 90 
days after a knee prosthesis surgery include mortality (1.1%), hospital admission 
(4.7%), pulmonary embolism (0.5%), wound infection (1.8%), pneumonia (1.4%), and 
myocardial infarction (1%)
10. 
There are many surgical treatments options to repair an articular cartilage defect 
including abrasion chondroplasty, subcondral drilling, microfracture, mosaicoplasty 
among many other techniques. These procedures are, however, limited to the repair of 
focal defects and consequently there is a lack of reparative technique for the more 
global/diffuse pathology of OA. 
Knee OA is not just an articular cartilage defect; it involves the entire joint including 
subchondral bone thickening, osteophyt formation, synovial inflammation, and the 
degeneration of ligaments and menisci
11. OA is a multifactorial disease that involves 
alterations in cellular and metabolic activities, resulting in tissue degeneration
12.   
To this date, there are no available drugs to structurally modify the OA processes or 
prevent progression of the disease
13. In this sense, the use of MSC as a regenerative 
cartilage treatment option is under extensive investigation.  
Whilst evidence of the capacity of MSCs to differentiate along a chosen cell lineage 
represents great promise in the area of regenerative medicine. It is postulated that their 
beneficial effect is also achieved through an immunomodulatory and paracrine 
mechanism and hence manipulation of the disease process
14. 
In an inflammatory environment, MSCs secrete factors which cause multiple anti-
inflammatory effects and influence matrix turnover in the synovium and cartilage 
explants. The whole panel of bioactive factors probably works conjunctly to achieve the 
anti-osteoarthritic observed effects
15. 
Stem cells have an important role in the maintenance and regeneration of tissues and 
they are located in a specific microenvironment, defined as niche
16. Extracellular matrix 
(ECM) or micro cellular environment or "Niche" has a fundamental role in regulating 
cellular behavior, through direct or indirect action.  The ECM is a dynamic and versatile 
compartment that modulates the production, degradation and remodeling of its 
components, thus giving support for the development, function and repair of tissues
16.  
 
The key role of ECM in regulating cell behavior now represents a well-established fact 
and this concept is especially critical for stem cells, which are defined by a unique and 
specialized niche in which ECM represents an essential player
16. 
  

4 
 
The use of intra-articular injections of MSC in combination with Platelet Rich Plasma 
(PRP) may represent a treatment of the “whole joint”. Along with their 
immunomodulatory and differentiation potential, MSCs have shown to express essential 
cytokines including Transforming Growth Factor beta (TGFβ), Vascular Endothelial 
Growth Factor (VEGF), Epidermal Growth Factor (EGF) and an array of bioactive 
molecules that stimulate local tissue repair
15,16.  These trophic factors, and the direct cell 
to cell contact between MSCs and chondrocytes, have been observed to influence 
chondrogenic differentiation and cartilage matrix formation
17,18. 
Recent data indicate that these paracrine factors, due to their inmune modulation and 
differentiation potential, may play a key role in MSC-mediated effects; thus, modulating 
various acute and chronic pathological conditions
19. 
Like MSC from bone marrow (BM-MSC), adipose tissue-derived adult stem cells (AD-
MSC) can differentiate into several lineages and present therapeutical potential for 
repairing damaged tissues
19,20.    
The standard site for obtaining human MSC is the bone marrow; however, one 
limitation of obtaining MSC from bone marrow is the difficulty of achieving enough 
number of cells required for clinical studies. Adipose tissue can be obtained by less 
invasive methods and in larger quantities than bone marrow cells, making the use of 
AD-MSC as a source of stem cells very appealing
21.  
Justification 
We wish to demonstrate that the use of with autologous MSCs is effective as a 
treatment option for  knee OA grades, II and III. In a large number of cases it is possible 
to improve the pain, function and quality of life of patients without the side effects of 
conventional treatments. In other cases, avoid progression to more severe stages that 
require joint replacement surgery. This research aims at contributing with a low-cost 
regenerative technique in order to change the course of the disease and significantly 
reduce public and private sector expenses generated by conservative and surgical OA 
treatments. 
Main goals 
a. The aim of the present study will be to compare three types of intra-articular 
injections of MSC populations obtained from two clinically relevant sources: 
injections containing BM-MSC or AD-MSC or a combination of both of them   
BM-MSC and AD-MSC, in a randomized non blind clinical trial. 
b.  To assess the efficacy and safety of treatment with containing BM-MSC or 
AD-MSC or a combination of both of them   BM-MSC and AD-MSC, in 
relation to pain, function and quality of life in patients with knee OA. 
Hypothesis Testing 

5 
 
H1: The combined use of BM-MSC and AD-MSC is superior for pain 
management in knee OA, than the use of BMSC or AD-MSC alone.  
H0: The combined use of MSC from bone marrow and adipose tissue is not 
superior to the use of MSC derived solely from bone marrow or solely from 
adipose tissue in the treatment of pain and function in patients with knee OA.  
MATERIALS AND METHODS 
1. Study design 
The present study will be conducted from June 2020 to December  2021 at the 
Omnihospital, an affiliated center to the Universidad Católica de Santiago de 
Guayaquil Ecuador, and the support of the Instituto de Investigación e Innovación 
de Salud Integral, Medical Faculty of the same University and Maastricht 
University, The Netherlands. This will be a phase III trial, triple arm randomized 
open label dose to be conducted as a single intra-articular  injection of MSC in 3 
groups of patients with the diagnosis of knee OA grade II and III (Ahlbäck 
classification),
22 one receiving BM-MSC other receiving AD-MSC and the other 
BM-MSC + AD-MSC.  
 
2. Study population 
A total of 54 patients with the  diagnosis of knee OA grade II and III will be 
recruited to receive a single intra-articular injection of MSC:  Group 1 (n 18 
patients) will receive BM-MSC and  Group 2 (n 18 patients) will receive AD-MSC, 
and Group 3 (n 18 patients) will recieve BM-MSC + AD-MSC.  
a. Inclusion criteria: 
i. Patients aged 18 to 70 years, with grade II and III knee OA, 
according to the Ahlbäck classification will be included. Identified 
by two different observers.  
ii. Minimal VAS pain score of 4.  
iii. Chronic knee pain of mechanical origin. 
iv. All patients who sign a specially prepared informed consent for this 
clinical trial. 
b.  Exclusion criteria: 
i. Varus or valgus knee mal alignment superior to 10°.  
ii.  OA grade IV according Ahlbäck classification.  
iii. Bone marrow cancer like lymphoma.  
iv. Severe anemia. 
v. Active infections. 
vi. Pregnant patients. 
vii. Inmune diseases such as Rheumatoid arthritis, gout or pseudogout 
arthritis, psoriasis. 
viii. Bone diseases such as Kahler and Paget. 
ix. Corticoesteroid and hyaluronic injections within the last 3 months.  
x. Knee surgery in the last 6 months.  

6 
 
 
3. Ethical considerations 
a. All patients will be informed of the study aims and have the choice to 
complete an informed consent.  
b. All patients will be informed about alternative treatments. 
c. This study will be approved by the Ethical Committee of Catholic 
University of Santiago de Guayaquil (UCSG). 
 
4. Evaluations 
a. Pre-Operative:  
i. Complete clinical and orthopedic evaluation.  
ii. Laboratory diagnostic tests (biometrics, coagulation parameters glycemia, 
and liver, pancreatic, renal and lipid profile). 
iii. Radiological exams: Knee X Rays with weight bearing.   
iv.  Magnetic resonance of the knee with cartilage measurement. T2 
Map.  MRI T2 mapping of the cartilage is a non-invasive functional imaging 
technique delivering cartography of the T2 relaxation time of the cartilage without 
any contrast injection. It is sensitive to tissue anisotropy, and provides 
compositional information on the cartilage collagen network, water content and 
proteoglycans concentration. 
v. Application of the WOMAC Questionnaire (Western Ontario and 
McMaster Universities Osteoarthritis Index)
23. The Index contains 24 
questions  five items for  pain (score range 0–20), two for stiffness (score range 0–
8), and 17 for functional limitation (score range 0–68).   Individual question 
responses are assigned a score of between 0 (extreme) and 4 (None). Individual 
question scores are then summed to form a raw score ranging from 0 (worst) to 96 
(best). Finally, raw scores are normalized by multiplying each score by 100/96. 
This produces a reported WOMAC Score of between 0 (worst) to 100 (best). 
 
vi. Pain measurement with the Visual Analogue Scale (VAS). Visual 
analogue scales (VAS) are psychometric measuring instruments designed to 
document the characteristics of disease-related symptom severity in individual 
patients and use this to achieve a rapid (statistically measurable and reproducible) 
classification of symptom severity and disease control.  
a) Restriction of pain medication. Any NSAID 15 days before procedure; and 12 
months after. 
vii. Extracelular Matrix (ECM) preparation 3 weeks prior to procedure. 
Infiltration with  procaine 2% by repolarization of the cell membrane in order to 
improve ECM at the areas to work. 
* Each patient from all groups will receive 2 injections of procaine before the 
procedure. On week 1 and 3.  
ix. 
No cortisone injections will be permitted before or even 3 months 
previous to the procedure. 
 
b. Intra-operative: 
i.  Independent of MSC source and in order to know the amount and 
types of injected MSCs, flow cytometry will be used  processing of  
the cells immediately after extraction and prior to the injection into 

7 
 
the knee.  In 2006, the International Society for Cellular Therapy 
proposed minimal phenotypic criteria for the definition of cultured 
MSCs: expression of CD73, CD90, and CD105, and lack of CD11b 
or CD14, CD19 or CD79, CD45, and HLA-DR expression
24. It 
should be noted that the main criteria for MSCs are (1) plastic 
adhesion; (2) the above described phenotype; and (3) their tri-lineage 
differentiation potential
24. 
ii. CD90 FITC, CD73 PE, CD105 PerCP-Cy5.5   phenotypic expression 
are measured regarding quantity and viability for all groups of patients. 
iii.  CD34PE, CD11b PE, CD19 PE, CD45 PE, HLADR PE, lack of 
phenotypic expression, will be measured. 
 
c. Post-operative: 
i.  Pain, function and quality of life will be assessed using VAS and 
WOMAC scales. All patients will be evaluated before treatment, and  
at  1, 3, 6, 9 and 12 months. 
ii. Magnetic resonance with T2 Map imaging will be performed at 
baseline to analyze cartilage damage and at 6 months control.  This 
test allows the early diagnosis of areas of cartilage degeneration. In 
addition it evaluates the relaxation times of water, collagen and 
proteoglycans. Sequence to assess the structure of the cartilage
25. 
 
5. Randomization. 
A randomized non blind clinical trial with active control. For this purpose, the 
random number generator, found on the RANDOM.ORG ® website (available 
at https://www.random.org/integers/)
26 will be used to generate 31 random 
numbers. Value between 0 and 1. Format: 5 columns. 
 
 
 
 

8 
 
6.  Procedures  
a. Stem cell obtaining procedures. 
All the procedures will be performed in the operating rooms of the 
Omnihospital by Dr. Carlos Chiriboga-Accini and Dr. Mario Murgueitio-
Eguez, both certified orthopedic surgeons. Both will know about the 
randomization in order to know the source from which MSCs will be 
obtained, in an ambulatory procedure under local anesthesia and sedation. 
Average procedure time to obtain de MSCs will be approximately 75 
minutes.  
 
b.  BM-MSC PROCEDURE.  GROUP 1  
i. Bone marrow aspiration will be performed using a standard surgical 
technique: fluoroscopically guided percutaneous puncture of posterior 
iliac crest bone.  
ii. A total of 60 ml of blood from bone marrow will be aspirated with a 
heparinized syringe.  
iii. Attach the heparinized syringe to a 150 um filter. Gentle push the bone 
marrow through the filter to another syringe.  
iv. Attach   45   degree   dispensing   tip   to   filtered   bone marrow    60 
cc   syringe.   
v. Slowly   transfer   the   BMA   into   the   Neogenesis 60 cc kit    
concentrating   device   until   you   have reached   the   60 cc   mark. 
Secure   the   green   cap   and   clear   safety   cap. 
vi. Centrifugation   of   Neogenesis 60 cc concentrating   device.   Match   
counterbalance   for   each  concentrating   devices   +/-   1.0g.  Spin   at   
4200 rpm / 2800 rcf   for   10   minutes.  
vii. Place   the   concentrating   device   on   the   BPS (Benchtop   
processing   station),   secure   the   device   with   your   right hand   
and   slowly   turn   the   knob   with   your   left   hand   
counterclockwise,  until   the   bone   marrow   aspirate   has   reached   
the   bottom   of   the   luer   slip   fitting. 
viii. Place   the   “waste   60cc   syringe”   vertically   on   the   Neogenesis 
60 cc   concentrating   device.  Using   the   BPS,   push   the   PPP   
into   the   60cc   syringe   until   the   buffy   coat  reaches   20ml   
outlined   on   the   concentration   device.  
ix. Remove  the   “60cc   waste   syringe”.  Place   the   “60cc   Bone 
marrow   collection”   syringe   on the concentrating   device.  
x.  Using   the   BPS   push   the   remaining   bone marrow   until   the   
syringe   captures   the buffy   coat,   a   total   volume   of  10 - 20 cc. 
Cap   the bone marrow  collection   syringe.          
xi. One ml of the total bone marrow  will be sent for flow cytometry 
testing. 
xii. Subsequently, a single percutaneous intra-articular injection of the 
obtained MSCs will be done into the affected knee. 

9 
 
 
c.   AD-MSC PROCEDURE. GROUP 2. 
i. Local anesthesia with Klein tumescent solution will be applied in the 
region of greater trochanter of hip and gluteus. 
ii. A 40 ml of pure fat will be extracted with two 60 ml syringe and 2.5 
to 3 mm diameter cannula with equal luer lock spike. Physiological 
solution will be added and subsequently decanted in order to discard 
infranatant and remove traces of tumescence and blood (Repeat 2-3 
times). 
iii. The obtained adipose tissue will be introduced into two 50 ml 
conical tubes. Reconstituted collagenase will be added with a 0.22 
micron filter, 15 ml to each tube.   
iv. The tubes will be shaken for 20 minutes by placing them in the 
heater block or shaker. Then the two tubes will be centrifuged at 900 
g for 5 minutes. 
v. Adipose tissue and saline supernatant will be carefully removed until 
the remaining pellet be approximately 5 ml. Using a pipette 
connected to the 20 ml syringe the pellet of stromal vascular factor 
will be extracted. 
vi. The obtained pellet will be transferred into two new sterile 50 ml 
tubes. Saline solution will be added until 45 ml be completed. 
vii. The cells of conical bottom of each of the tubes will be aspirated 
with a 20 ml syringe and pipette. A total volume of about 5 ml will 
be  obtained.  
viii. In a new sterile 50 ml tube we will place a 100 µm cell strainer in 
order to gently transfer the cell suspension.  Stromal vascular 
fraction (SVF) will be aspirated. 
ix. A 1 cc of the adipose tissue stem cell concentrate will be sent to the 
Molecular Biology Laboratory for quantification by flow cytometry 
in order to determine the volume and viability of obtained stem cells. 
 
d. BM-MSC  + AD-MSC PROCEDURE. GROUP 3. 
i. AD-MSC will be joined with BM-MSC in a same syringe for 
application of the percutaneous injection (AD MSC + BM MSC 
group) into the affected knee.  
 
7. FOLLOW UP. 
All patients will be evaluated measuring scores of the WOMAC (Western 
Ontario and McMaster Universities Osteoarthritis Index)
23 and the VAS (Visual 
Analogue Scale), before treatment and then at 1, 3, 6, 9 and 12  months. 

10 
 
 
 
Statistical Analysis.  
The sample size is determined using the tool of G*Power VERSION 3.0.10. The 
parameters are applied for the selected F test, two-way mixed ANOVA (repeated 
measures, with immediate interaction). Given that none of these approaches have been 
previously compared, either separately or combined, the calculation was conducted 
considering a medium effect size (f=0.25). We established an error probability α of 0.05 
and power of 0.95. We calculated the application of 3 repeated measures, even though 6 
measures will be conducted for some variables (i.e., the VAS or WOMAC 
questionnaire). 

11 
 
Based on this criteria, the sample size would be 54, meaning that each group will 
consist of 18 individuals. The information previously mentioned is represented in detail 
in the following table and illustrated in a graph below it.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This study applies descriptive statistics for determining the frequency and proportions 
for demographic variables (age, gender, education, and ethnicity) and clinical states 
(severity of knee osteoarthritis, time with disease, comorbidities). Likewise, for 
calculating the mean and standard deviation of age, WOMAC scores (and each element 
of the scale) and VAS. 
We utilize the two-way mixed ANOVA to compare the differences of means between 
treatment groups for each dependent variable (WOMAC scores, VAS, and radiological 
changes). With respect to the WOMAC scores, not only we will analyze the scores in 
general, but also each score value of the three different components separately (pain, 
stiffness, function). The tests will determine if there is an interaction between the 
dependent variable and the factors (independent variables). The factors will be the type 
of treatment (between subjects) and time (within subjects). For the type of treatment, it 
F tests - ANOVA: Repeated measures, within-between interaction 
Analysis: 
A priori: Compute required sample size  
Input: 
Effect size f 
= 
0.25 
 
α err prob 
= 
0.05 
 
Power (1-β err prob) 
= 
0.95 
 
Number of groups 
= 
3 
 
Repetitions 
= 
3 
 
Corr among rep measures 
= 
0.5 
 
Nonsphericity correction ε 
= 
1 
Output: 
Noncentrality parameter λ 
= 
20.250000 

12 
 
is categorized into: BMSCS only, AD-MSC only, and BM-MSC and AD-MSC 
combined.  
As for the time factor, this will differ according to the dependent variable held for 
analysis. For example, the analysis of WOMAC and EAV scores will be evaluated in 6 
different periods of time. The patients will be asked to respond to our questionnaires 
three weeks before the intervention and 1, 3, 6, 9, and 12 months after intervention 
(surgery). With respect to radiological changes, the T2 mapping MRI will be performed 
twice before the procedure and again six months later.  
To guarantee the reliability of the analysis, we will test the atypical values by utilizing 
box diagrams and the normality with the method of Shapiro-Wilk. Furthermore, the 
homogeneity of variations will be evaluated with inferential statistic Levene tests, while 
the homogeneity of covariances with multivariate statistical Box’s M test. 
Consequently, to comply with the hypothesis sphericity, a Mauchly’s test will be 
conducted. In the case of a violation of an assumption, different tests will be utilized.  
Finally, in the case of a treatment complication, there will be mixed lineal models 
generalized for determining the probability of each intervention. The complications 
considered in this investigation are pain and hematomas in the surgical place where 
stem cells were extracted, knee pain, and synovial effusion.  
Data will be analyzed using SPSS software version 24.0. for every test, a p-value lower 
than 0.05 will be considered as the statistical significance level.  
SAFETY 
Absence of immunological reaction and disease transmission due to the fact that MSCs  
belong to the same patient. Wakitani
27 from the University of Osaka Japan demonstrated 
in an 11-year follow-up study that MSC did not induce tumor growth or infection in any 
patient treated for cartilage lesions. 
Chris and colleagues
28 reported no adverse events after using intra-articular injection of 
1.0 × 108 AD MSCs in patients with knee OA, and showing improvement of joint 
function. 
Peeters et al
29. evaluated 8 studies that involved  844 MSC-treated patients with intra-
articular injected culture expansion. They concluded that there are no opposing 
arguments for the intra-articular application of MSC. 
Systematic reviews have all been in favor of the safety in intra-articular - injections of 
MSCs. However, great caution is warranted with culturing and expansion of MSCs
30. 
DISCUSION 
The function of MSCs has been explored under the influence of bioactive carriers such 
as platelet-rich plasma (PRP). Platelets contain greater than 1500 protein based factors 

13 
 
with bioactive ability
31. This broad spectrum of compounds includes growth factors, 
peptide hormones, chemokines, fibrin and also proteins with anti-bacterial and 
fungicidal properties. 
Growth factors released by platelets may potentially play a positive role in the up 
regulation of MSCs. TGFβ1 is seen to reduce collagen type I gene expression and up 
regulate expression of collage type II and aggrecan genes
32. Further, TGFβ1 works in 
association with basic Fibroblast Growth Factor (FGF2) to assist in the migration of 
stromal cells to a site of injury
30,33. 
The combination of PRP with MSCs in intra-articular injections has shown increased 
collagen type II expression and reduced chondrocyte apoptosis
34. 
Most recently, Phase I and II trials using expanded adipose derived MSCs in the 
treatment of OA have shown MRI evidence of cartilage regrowth
31. Following a single 
intra-articular injection of 100 million MSCs, radiological (MRI) follow-up at 6 months 
showed increased cartilage volume
30. 
Using a combination of both isolated bone marrow MSCs, BMA and platelet lysate, 
Centeno and colleagues have published the observed improvement in both chondral 
volume and meniscus volume in two limited case studies
35,36. In 2011, Centeno later 
published a case series of 339 patients, reporting that of those patients requiring total 
knee replacement (69 % of the patient cohort) only 6.9 % still required replacement 
surgery after MSC therapy. Sixty percent of patients reported >50 % pain relief and 
40 % reported >75 % pain relief at 11 months
35. 
A recent Phase 1 dosing trial on the use of adipose derived MSCs in severe 
osteoarthritis indicated a significant effect over a 12 month follow-up on the need for 
total joint replacement with only 2 out of the 18 patients still requiring arthroplasty
30. 
This is similar to Centeno’s observation of the effect of MSC based therapy in delaying 
need for joint replacement. 
The success of such combination therapy has also been indicated by a limited case 
series assessing the benefits of adipose derived MSC, where MSC was combined with 
both a platelet lysate and a hyaluronic acid carrier with additional use of low dose 
dexamethasone
37. Again, both functional and disease modification was observed. 
CONCLUSIONS:  
Osteoarthritis is a leading cause of pain and disability. With an aging population its 
prevalence is even going to increase. Current standard treatments target symptomatic 
relief rather than the underlying mechanisms and hence prevention. Medical treatments 
do not change the natural course of this disease and involve the use of drugs with a high 
percentage of complications.  Often conducted surgical interventions are accompanied 
by significant risks. More advanced cases require very costly surgeries for health 
systems, and they also have many serious complications. 

14 
 
Encouraging results with MSC from pre-clinical and clinical trials have provided initial 
evidence of safety and efficacy for degenerative diseases- including OA.  Systematic 
reviews have all been in favor of the safety in intraarticular - injections of MSCs.  
Numerous clinical trials have been published on the use of MSC in osteoarthritis. None 
of them compare the results between the use of BM MSC origin and AD MSC + BM 
MSC.  Many of them adding Platelet Rich Plasma to increase the chondrogenic 
differentiation and cartilage matrix formation.
17,18 
The intervention is simple, does not require hospitalization or open surgery, provides 
pain relief,  would significantly improves cartilage quality, could change natural 
progression of the disease and improve quality of life of these patients. In the future 
treatments with MSC may become the treatment of choice in knee osteoarthritis. 
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