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Table 1 Details of the 60 clinical trials identified by the systematic review focusing on MSCs use for the treatment of cartilage pathology

From: Stem cells in articular cartilage regeneration

MSCs Publication Study type Treatment Additional information Pathology N patients Follow-up Results
Cultured BMSCs Davatchi [22] 2015
Int Journal of Rheum Disease
Case series IA injection Previous study update Knee OA 3 60 months Still significant improvement at 5 years, but gradual worsening after 6-month follow-up
Vega [26] 2015
Transplantation
RCT IA injection Allogeneic BMSCs Knee OA 15 BMSCs
15 HA
12 months Significant better functional and cartilage quality improvements in MSCs group vs. control
Sol Rich [18] 2015
J Stem Cell Res Ther
Case series IA injection   Knee OA 12 24 months Excellent clinical and quantitative MRI outcome measures at 2 years
Vangsness [25] 2014
JBJS Am
RCT IA injection Allogeneic BMSCs
After medial meniscectomy
Knee OA 18 low-dose MSCs + HA
18 high-dose MSCs + HA
19 HA
24 months Knee pain improvement and evidence of meniscus regeneration at MRI for both doses vs. control
Orozco [21] 2014
Transplantation
Case series IA injection Previous study update Knee OA 12 24 months Pain improvement at 12 months maintained at 24 months.
The quality of cartilage further improved at MRI at 24 months
Wong [24] 2013
Arthroscopy
RCT IA injection Comb HTO + MFX and post-op injection Knee OA 28 BMSCs + HA
28 HA
24 months BMSCs i.a. injection produced superior clinical and MRI outcomes at 24 months
Ricther [35] 2013
Foot & Ankle
Case series Surgical delivery MAST
Collagen membrane
Ankle chondral defects 25 24 months No adverse events.
Clinical scores improvement
Positive findings at histology
Orozco [22] 2013
Transplantation
Case series IA injection   Knee OA 12 12 months No safety issues. Rapid and progressive clinical improvement at 12 months
11/12 patients increased cartilage quality at MRI
Lee [23] 2012
Ann Accad Med Singapore
Comparative IA injection   Knee cartilage defects 35 MFX + BMSCs + HA
35 BMSCs + periosteal patch
24 months MFX + BMSCs + HA had comparable results vs. BMSCs + periosteal patch, but lower invasivity
Emadedin [19] 2012
Arch Iran Med
Case series IA injection   Knee OA 6 12 months No local or systemic adverse events.
Decreased pain, improved function and walking distance
3/6 increased cartilage thickness at MRI
Kasemkijwattana [29] 2011
J Med Assoc Thai
Case report Surgical delivery MAST
Collagen membrane
Knee cartilage defects 2 31 months Significant clinical improvement
Good filling, tissue stiffness, and integration at 2nd look
Davatchi [17] 2011
Int J Rheum Dis
Case series IA injection   Knee OA 4 12 months Encouraging clinical results no X-Rays improvement
Haleem [28] 2010
Cartilage
Case series Surgical delivery MAST
PRF as scaffold
Knee cartilage defects 5 12 months 5/5 symptoms improvement
Complete defect filling and surface congruity with native cartilage in 3/5 at MRI
Nejadnik [34] 2010
AJSM
Comparative Surgical delivery BMSCs + periosteal flap Knee cartilage defects 36 ACI
36 BMSCs + periosteal flap
24 months Comparable improvement in quality of life, health, and sport activity. M better than F, older than 45 years lower improvement only in ACI group.
Centeno [16] 2008
Pain Physician
Case report IA injection   Knee cartilage defects 1 IA BMSCs + 2 weekly platelet lysate IA injections 24 months Improvement of range of motion and pain scores. Significant cartilage and meniscus growth at MRI
Kuroda [30] 2007
Osteoarthritis & Cartilage
Case report Surgical delivery BMSCs + collagen gel + periosteum Knee cartilage defects 1 12 months Hyaline-like tissue regeneration, improvement in clinical symptoms and return to previous activity level
Wakitani [31] 2007
J Tissue Eng Regen Med
Case report Surgical delivery BMSCs + collagen gel + periosteum or synovium Knee cartilage defect patella 3 17–27 months Improvement in clinical symptoms maintained over time. Fibrocartilaginous tissue at histology
Adachi [27] 2005
J Rheumatol
Case report Surgical delivery MAST
Hydroxyapatite ceramic
Knee osteochondral defect 1   Cartilage-like and bone tissue regeneration at 2nd look arthroscopy
Wakitani [32] 2004
Cell Transplant
Case report Surgical delivery BMSCs + collagen gel + periosteum Knee cartilage defect
Patella
2 5 years Short-term clinical improvement, then stable at 24 months fibrocartilage defect filling
Wakitani [33] 2002
Osteoarthritis & Cartilage
Comparative Surgical delivery Collagen gel sheet + periosteum Knee OA 12 BMSCs + HTO
12 cell-free control + HTO
16 months Comparable clinical outcomes, but better arthroscopic and histological score in cell-transplanted group
BM Concentrate Gobbi [47] 2015
Cartilage
Comparative Surgical delivery MAST
HA matrix
Knee cartilage defects patellofemoral 19 MACT
18 BMC
3 years Significant scores improvement in both groups.
Better IKDC subj for BMC. MACI: trochlea better than patella; BMC: site n.s.
Better filling at MRI for BMC
Buda [40] 2015
Arch Orthop Trauma Surg
Case series Surgical delivery MAST
HA matrix
OLTs and ankle OA 56 36 months Clinical outcome improvement at 12 months, further increase at 24 months and lowering trend at 36 months
Higher BMI and OA degree had worse results
Buda [39] 2015
Cartilage
Case series Surgical delivery MAST
HA matrix
Ankle osteochondral lesions (hemophilic patients) 5 24 months Clinical improvement at 2 years.
3 patients back to sports.
Signs of cartilage and bone tissue regeneration at MRI.
No radiographic joint degeneration progression
Buda R [43] 2015
Int Orthop
Comparative Surgical delivery MAST
HA matrix + PRF
OLTs 40 ACI
40 BMC
48 months ACI and MAST was equally effective for the treatment of OLT. MAST preferred for the 1 step procedure, and lower costs
Gobbi [50] 2014
AJSM
Case series Surgical delivery MAST
Collagen membrane
Knee chondral defects 25 3 years Significant scores improvement
Older than 45 and smaller or single lesions showed better outcomes.
Good implant stability and complete filling at MRI.
Cadossi [44] 2014
Foot Ankle Int
RCT Surgical delivery MAST
HA matrix
OLTs 15 BMDCs + HA + PEMF
15 BMDCs + HA
12 months Biophysical stimulation started soon after surgery aided patient recovery leading to pain control and a better clinical outcome with these improvements lasting more than 1 year after surgery
Buda [41] 2014
Joints
Case series Surgical delivery MAST
HA/collagen powder matrix + PRF
OLTs 41 BMAC + HA + PRF
23 BMAC + collagen powder + PRF
53 months Significant clinical improvement, gradual decrease after 24+ months
Skowronski [51] 2013
Orthop Traumatol Rehabil
Case series Surgical delivery MAST
Collagen membrane
Knee chondral defects 54 5 years Improvement in clinical scores in 52/54 patients without complications
After 5 years n.s. deterioration in 3 patients
Giannini [38] 2013
AJSM
Case series Surgical delivery MAST
HA membrane or collagen powder + PRF
OLTs 49 24–48 months Good clinical results at 24 months, then significant decrease at 36 and 48 months. T2 mapping similar to native hyaline cartilage and correlate with the clinical results
Buda [46] 2013
Muskuloskeletal Surg
Case series Surgical delivery MAST
HA matrix
OLKs 30 29 months Good clinical outcome osteochondral regeneration at control MRI and biopsies
Gigante [48] 2012
Arhtroscopy Technique
Case report Surgical delivery MAST
Collagen membrane + MFX
Knee chondral defects 1 24 months Pain free at 6 months, still asymptomatic at 24 months
Positive MRI tissue appearance at 12 months
Gigante [49] 2011
Int J Immunopathol Pharmacol
Case series Surgical delivery MAST
collagen membrane
Knee chondral defects 5 12 months Patients asymptomatic
Nearly normal arthroscopic appearance and satisfactory repair tissue at 12 months
Giannini [42] 2010
Injury
Comparative Surgical delivery MAST
HA matrix + PRF
OLTs 10 ACI open
46 arthroscopic MACT
25 arthroscopic MAST
36 months Similar clinical improvement among groups.
Good restoration of the cartilaginous layer with hyaline-like characteristics at MRI and histology
Varma [36] 2010
J Indian Med Assoc
Comparative IA injection Augmentation to debridement Knee OA 25 Debridement + BMC
25 Debridement alone
6 months BMC: higher improvement in symptoms, function, and quality of life
Buda [45] 2010
JBJS Am
Case series Surgical delivery MAST
HA matrix + PRF
OLKs 20 24 months Significant clinical improvement at 12 and 24 months. Associated procedures delayed recovery. Satisfactory MRI findings in 80 % of patients
Giannini [37] 2009
Clin Orthop Rel Res
Case series Surgical delivery MAST
HA matrix or collagen powder + PRF
OLTs 48 24 months Clinical improvement
Regenerated tissue in various degree of remodeling, none had complete hyaline-like features at histology
PBSCs Fu [55] 2014
Knee
Case report Surgical delivery PBSCs + autologous Periosteal flap + patellofemoral realignment Knee chondral defects 1 7.5 years Patient returned to competitive kickboxing
Smooth surface 8 months after surgery
Significant clinical and MRI improvements
Turajane [53] T 2013
J Med Assoc Thai
Case series IA injection PBSCs + GFs addition/preservation + HA + microdrilling Knee OA 5 6 months Improvement in all clinical scores without adverse events
Saw [54] 2013
Arthroscopy
RCT IA injection Subchondral drilling
PBSCs + HA vs. HA
5 IA injections post-op
3 more IA injections after 6 months
Knee chondral defects 25 drilling + (PBSCs + HA)
25 drilling + HA
2 years Comparable significant clinical improvement for both groups
PBSCs + HA had both MRI and histology superior vs. control group
Skowronski [56] 2012
Orthop Traumatol Rehabil
Case series Surgical delivery PBSCs covered by collagen membrane Knee chondral defects 52 6 years No adverse events
Improvement in all clinical scores at 12 months. Poor outcomes in 2 patients at 12 months
At 72 months minor deterioration in 2 more patients
Saw [52] 2011
Arthroscopy
Case series IA injection Subchondral drilling + 5 weekly IA injections Knee chondral defects 5 10–26 months No adverse events hyaline cartilage regeneration at histology
BMC vs. PBSCs Skowronski [77] 2013
Orthop Traumatol Rehabil
Comparative Surgical delivery PBSCs vs. BMC covered by collagen membrane OLKs 21 BMC
25 PBSCs
5 years Superior results in PBSCs group: good cartilaginous surface and integration. Slight clinical scores decrease in both groups at 60 months
SDSCs Sekiya [76] 2015
Clin Orthop Relat Res
Case series Surgical delivery Cultured cells
Scaffold free
Knee chondral defects 10 48 months Significant clinical improvement
Positive findings at MRI, and hyaline like in 3/4 at histology
ADSCs Kim [71] 2015
AJSM
Comparative Surgical delivery vs. IA injection Subcutaneous fat
SVF on FG scaffold vs. PRP-SVF injection
Isolated focal defects in knee OA 20 SVF-FG
20 SVF-PRP
28.6 months Significant improvement in both groups. Better clinical results at final f-up and 2nd look appearance at 12 months for SVF-FG. No. of cells correlated with outcomes only for injective group
Kim [72] 2015
Osteoarthritis Cartilage
Case series Surgical delivery Subcutaneous fat
SVF + FG scaffold
Isolated focal defects in OA knee 20 27.9 months Significant clinical and MRI scores improvement
MRI correlates with clinical outcomes
Michalek [67] 2015
Cell Transplant
Case series IA injection Subcutaneous fat
SVF
OA (various joints) 1114 17.2 months No adverse effects, safe, cost-effective
Clinical improvement at 3–12 months.
Follow-up at 12 months: 63 % patients had ≥75 % score improvement
91 % patients had ≥50 % score improvement
Slower healing for obese and worse OA
Koh [74] 2015
Arthroscopy
RCT Surgical delivery Subcutaneous fat
MFX + FG + SVF vs. MFX
Knee chondral defects 40 MFX + SVF-FG
40 MFX
27.4 months KOOS pain and symptoms better for SVF vs. control
2nd look: complete coverage 65 vs. 45 %
SVF better MRI scores
Kim [73] 2015
AJSM
Case series Surgical delivery Subcutaneous fat
SVF + FG
Isolated Focal defects in OA knee 49 26.7 months 74.5 % good/excellent results
Patient age >60 years or lesion size >6.0 cm2 are predictors of clinical failure
Jo [59] 2014
Stem cell
Case series IA injection Cultured subcutaneous
Phase I: low dose (1.0 × 107) vs. mid-dose (5.0 × 107) vs. high dose (1.0 × 108)
Phase II: 18 patients received only high dose
Knee OA Phase I: 9
Phase II: 18
6 months High-dose was more effective for knee function improvement
MRI: decreased defect size and improved cartilage volume
No adverse events related to cell dose
Kim [69] 2014
AJSM
Comparative IA injection Subcutaneous fat
SVF + marrow stimulation vs. marrow stimulation
OLTs 24 marrow stim + SVF
26 marrow stimulation
21.9 months All clinical and MRI scores in SVF group improved significantly with respect to marrow stimulation alone SVF gave better outcomes for patients older than 46.1 years, lesion size >152.2 mm2, or in presence of subchondral cysts
Kim [71] 2014
AJSM
Comparative Surgical delivery Subcutaneous fat
SVF local adherent vs. SVF + FG
Isolated focal defects in OA knee 17 FG
37 scaffold-free
28.6 months Both comparable clinical improvement
2nd look arthrosocopy at 12.3 months f-up: better ICRS scores for FG group
Bui [62] 2014
Biomed Res Ther
Case series IA injection Subcutaneous fat
SVF + PRP
Knee OA 21 8.5 months Significant clinical scores improvement. No side effects.
MRI: increased cartilage thickness
Koh [70] 2014
AJSM
Case series Surgical delivery Subcutaneous fat
SVF
Isolated focal defects in knee OA 35 26.5 months Clinical improvement
76 % abnormal repair tissue at 2nd look arthroscopy (12.7 months f-up)
Better outcomes if size <5.4 cm2 and/or BMI < 27.5
Koh [74] 2014
Arthroscopy
RCT IA injection Subcutaneous fat
HTO + PRP vs. HTO + PRP + SVF
Knee OA 23 HTO + PRP + SVF
21 HTO + PRP
24 months SVF produced better improvement of KOOS pain and symptoms and VAS pain
Fibrocartilage coverage SVF 50 vs. 10 % control
Pak [61] 2013
BMC Musculoskelet Disord
Case series IA injection Subcutaneous fat SVF + PRP OA (various joints) 91 26.7 months SVF/PRP injections are safe
Clinical improvement knee and hip
Kim [68] 2013
AJSM
Comparative IA injection Subcutaneous fat SVF + PRP Isolated defect in ankle OA 35 MFX
30 MFX + SVF
21.8 months Clinical improvement both groups
SVF group better results, especially applied to Tegner score
Large lesion and/or subchondral cysts affected outcomes only for MFX alone
Koh [65] 2013
KSSTA
Case series IA injection Subcutaneous fat
SVF + PRP
Knee OA 30 24 months Significant clinical improvement
14/16 (87.5 %) of 2nd look arthroscopy within 24 months improved or maintained cartilage status.
Further clinical improvement 24 vs. 12 months
Koh [64] 2013
Arthroscopy
Case series IA injection after debridement Fat pad
SVF + PRP
Knee OA 18 24 months function and pain improvement. Womac and MRI correlate with cell no.
Better if OA ≤ 3
Koh [63] 2012
Knee
Comparative IA injection
After debridement
Fat pad
SVF + PRP
Knee OA 25 debridement
+ SVF-PRP
25 debridement
12 months min Both improved scores.
SVF performed better in <55 years and OA ≤ 3 (ICRS)
  Pak [60] 2011
J Med Case Rep
Case report IA injection Subcutaneous fat
SVF + PRP + low dose dexamethasone
Knee OA 2 3 months Clinical improvement
Significant positive changes at MRI