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Page 6 of 12 Chen et al. Plast Aesthet Res 2020;7:49 I http://dx.doi.org/10.20517/2347-9264.2020.28

MSCs, they are isolated and expanded in the laboratory, thereafter being injected into the OA knee for
treatment.

[9]
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In a study from Jo et al. , they present a 2-year follow-up result of IA injection of low (1 × 10 ), medium
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(5 × 10 ), and high (1 × 10 ) dose of ADSCs into the knee, respectively (NCT01300598). They report that
MSCs improved knee function, as measured with the WOMAC, Knee Society clinical rating system, and
KOOS, with patients experiencing reduced knee pain. In addition, there was a statistical significance of
improvement found mainly in the high-dose group. However, in Pers’s study (NCT01585857), they found
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the group of patients having injections of 2 × 10 cells exhibiting the best response, and they had higher
baseline pain and WOMAC scores compared with those receiving higher doses . In 2019, Lee et al.
[56]
[57]
presented a prospective double-blinded, randomized controlled, phase IIb clinical trial, where they injected
high-dose autologous ADSCs (1 × 10 cells) intra-articularly into the patients’ knee, and found that a single
8
injection of ADSCs led to a significant improvement of the WOMAC score at 6 months. Furthermore,
there was no significant change in cartilage defect at 6 months in ADSCs group which contrasted with the
[58]
increased defect size in the control group. Lu et al. also conducted a double-blind, active-controlled,
phase IIb knee OA clinical trial by using 5 × 10 ADSCs. Results showed that most patients achieved a 70%
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improvement rate in the ADSCs receiving group after 12 months. Moreover, there was a notable increase
in articular cartilage volume in the ADSC group, as compared with the hyaluronic acid (HA) group after
12 months as measured by MRI.

Recently, another type of fat tissue known as PFP has become a popular research topic due to its ability to
diminish inflammation and cartilage degenerative grade. The IPFP is an intra-capsular structure within the
[59]
3
anterior knee compartment, composed of approximately 20 cm of ADSCs , and may be easily harvested
[60]
arthroscopically or during open knee surgery . During embryonic development of the knee, researchers
found that IPFP initiates from interzone formation between the femur and tibia, progressing to cavitation
between this region, and finally a IPFP site formation. This is described to be a triangular space composed
[61]
of a mesenchymal tissue formation below the patella at the 9th week of human development . IPFP
occupies space in the joint, maintaining the articular cavity, allowing the synovial fluid to circulate over the
[62]
joint thus contributing to lubrication. In an experimental animal model of OA, Toghraie et al. used direct
IA injection of IPFP-MSCs into the OA knees of rabbits. The IPFP-MSCs used had been expanded and
grown in vitro and were delivered 12 weeks after the operation in a single dose of 1 million cells suspended
in 1 mL of medium. Twenty weeks after surgery, rabbits that received IF-MSCs demonstrated less cartilage
degeneration, osteophyte formation, and subchondral sclerosis than did those in the control group.

[60]
In 2012, Koh published a Level III clinical study article with the use of IPFP-MSCs for OA therapy ,
where they collected the IPFP (average weight, 9.4 g; range, 6.9-11.2 g) by skin incision extension, further
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isolating the IPFP-MSCs by tissue mincing, collagen digestion, and centrifugation. An average of 1.89 × 10
stem cells were prepared with 3.0 mL of PRP and injected into the selected knees of patients in the study
group. The mean Lysholm and VAS scores of patients in the study group improved significantly at the final
follow-up (mean follow-up, 24.3 months; range, 24 to 26 months). Radiography demonstrated that the
[63]
[64]
whole-organ MRI score had significantly improved from 60.0 points to 48.3 points . Spasovski et al.
have also reported that the use of IPFP-MSCs in knee OA improves clinical symptoms and reduces pain at
3 months, obtaining the best results at 6 months. Currently, a phase 1 clinical study entitled “Treatment of
Knee Osteoarthritis with Autologous Mesenchymal Stromal Cell Product (RegStem®)” is being conducted
in Taiwan, which has been approved by Taiwan Food and Drug Administration on May, 2017 (ClinicalTrials.
gov Identifier number: NCT03007576). The study has enrolled 12 subjects who have Kellgren-Lawrence
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grade 2~3 OA knee, and use 5 × 10 IPFP-MSCs for therapy. At the culmination of 1, 3, 6, 12 and 24 months,
the VAS, KOOS and IKDC scores of subjects will be further evaluated.