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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