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Velasquillo et al. Plast Aesthet Res 2020;7:31 I http://dx.doi.org/10.20517/2347-9264.2020.30 Page 5 of 14

Meniscal lesions generate knee instability and further cartilage damage favoring the development of OA.
Treatment for meniscal lesions is decided depending on the complexity and the location of the damage.
Repair strategies are used when the rupture is small, located in the vascular areas, and the meniscus can
be stabilized intra-articularly. However, partial meniscectomy or complete meniscectomy is required in
[42]
complex lesions. Meniscectomies cause an increase of 235% contact pressure , as well as an increase in
OA incidence [43-45] . The use of meniscal substitutes after partial meniscectomy has shown symptom relief, as
well as a slow decrease of articular degeneration; however, they do not prevent it [46,47] .

[46]
Leroy et al. reported a decrease in scaffold dimensions leading to a concern about the scaffold’s capacity
in the long term. The use of MSC in combination with meniscal substitutes have become of great interest
due to the evidence of meniscal-like tissue formation after implantation in rats, pigs, and rabbits [48,49] .
[50]
Olivos-Meza et al. conducted a comparative study between patients who received meniscal substitution
with acellular polyurethan meniscal scaffolds (APS) vs. polyurethane scaffold enriched with peripheral
blood MSC (MPS). They evaluated femoral and tibial articular cartilage status using MRI T2-mapping 3, 6,
9, and 12 months after surgery, as well as clinical evaluation using PROMs. No differences were observed
between APS and MPS during the 12-month follow-up; however, a longer follow-up is needed to see the
scaffold degeneration and tissue formation.

MSC exosomes: exosomes are extracellular vesicles that function as intercellular communication vehicles
transferring lipids, nucleic acids (mRNA and microRNAs) and proteins to generate a response in
[51]
recipient cells . Exosomes are rich in microRNA, which can bind specific sites in transcribed mRNA,
modifying their expression and transduction [51,52] . These properties have been studied to promote cartilage
[58]
[56]
regeneration and decrease pro-inflammatory molecules in OA [53-57] . Tao et al. and Toh et al. reported
several microRNAs (140-5p, 23b, 92a, 125b, 320, 145, 22 and 221) derived from human synovial MSC,
which promote cartilage regeneration, OA suppression, and cartilage/extracellular matrix homeostasis
in preclinical studies. The exosomes’ potential for OA treatment, good tolerance, and minimal risk of
immunogenicity and toxicity has made them one of the most important hotspots for future research.
However, further studies describing how to obtain large-scale purified exosomes as well as their clinical
efficacy and biosecurity are still needed.

Intra-articular injections: intra-articular injections of MSC have become the main modality of cell therapy
research for OA treatment due to their simple application thanks to their anti-inflammatory, immune-
regulatory, and regenerative abilities. MSC can be either injected with no other components or mixed with
hyaluronic acid (HA), platelet-rich plasma (PRP), or saline solution, to mention some examples. Preclinical
studies have shown cartilage repair, reduction in proinflammatory cytokines, and improved imaging,
morphology, and histology [59,60] . Mixed injections with PRP/MSC or HA/MSC have shown significantly
better results on the repaired cartilage than individual uses of any of them.

Several clinical trials have been developed worldwide using MSC derived from the stromal vascular
fraction (SVF), umbilical cord (UC-MSC), adipose tissue (AD-MSC) or bone-marrow (BM-MSC), the
latter being the most common site. BM-MSC have shown a better chondrogenic ability compared to AD-
[61]
MSC and have shown an improvement in cartilage quality and knee function, as well as a decrease in
[27]
pain and other symptomatologies . Most clinical trials that use AD-MSC and SVF have been conducted
using mixed injections combined with PRP. Results have been positive, showing an increase in cartilage
[62]
thickness, significant positive changes in MRI, and symptomatology improvement . Few trials have been
done using UC-MSC. Cartistem is the first approved allogeneic cell treatment for OA in the world. It was
®
[63]
approved by the Ministry of Food and Drug Safety in Korea and is now commercially available . It uses
UC-MSC combined with sodium hyaluronate. Up to 5000 patients have been treated with Cartistem and
®
around 97.67% of them have shown improved quality of life [63,64] .