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Table 1 Included studies characteristics

From: Cell therapy efficacy and safety in treating tendon disorders: a systemic review of clinical studies

ID

Study (first author, year)

Study design

Type and Site of injury

Groups

Population

Cell type

Cell source

Follow up

Surgical techniques

Conclusion

Level of evidence

Rotator cuff

1

Ellera Gomes 2011

Case-series

Complete rotator cuff tear (Open surgical repair + injection BMMC)

BMMC group (N = 14)

no control group

14

Autologous BMMC

BMMC (from the

posterior iliac crest)

12 months

Open surgical repair

BMMC implantation in a patient with rotator cuff sutures is safe and has promising results compared to historical data (patients underwent surgical procedures without stem cells application).

4

2

Hernigou P 2014

Non-RCT

Rotator cuff tear with size of 1.5-3.5 cm (Arthroscopic surgical repair + MSCs)

1. MSC group (N = 45)

2. Control group (N = 45)

90 (45 each groups)

Autologous MSC

BMC (from anterior iliac crest bone)

10 years<

Arthroscopic surgical repair

More prominent and earlier (2 months earlier, p = 0.04) healing in MSC-treatment group, total healing more likely achieved when MSCs> 2500 cell.mL−1

3

3

C. J. Centeno 2015

Case series

Partial or full-thickness rotator cuff tear (< 1.5 cm)

BMC + PRP + PL (N = 102 patients with 115 involved shoulders which N = 81 arm with rotator cuff tear)

81

Autologous MSC

BMC (from posterior superior iliac crest)

11.2 ± 10 months

No surgery

Rotator cuff tear patients treated with BMC showed significant pain and functional improvement

4

4

Kim, Y. S 2017

Non-RCT

full-thickness rotator cuff tear (AD-MSC + Arthroscopic surgical repair)

1. Arthroscopic rotator cuff repair alone group (N = 35)

2. AD-MSC group + arthroscopic repair (N = 35)

70 (35 each groups)

Autologous AD-MSC

Buttock fat pad

28.3 ± 3.8 months

Arthroscopic rotator cuff repair

AD-MSC injection along with rotator cuff repair reduce retear rate significantly, but no clinical differences at the end of the follow up comparing to controls

3

5

S. J. Kim 2017

Case-series

Partial rotator cuff tear

BMC + PRP group (N = 12)

No control group

12

Autologous MSC

BMC (from anterior iliac crest bone)

3 months

No surgery

Injection of BMC–PRP to the rupture site leads to improvement of the reduction of the clinical symptoms of tear size.

4

6

S. J. Kim 2018

Non-RCT

Partial tear of the rotator cuff tendon

1. BMC + PRP group (N = 12)

2. Physical therapy (N = 12)

24 (12 each groups)

Autologous MSC

BMC (from anterior iliac crest bone)

3 months

No surgery

BMC-PRP injection improve VAS and ASES scores (improve pain and shoulder function), tear size changes, and MMT did not statistically differ among groups

3

7

J. R. Lamas 2019

(It was stopped due to adverse effects in both groups.)

RCT

Full-thickness rotator cuff tear

1. BM-MSCs + type I collagen membrane (OrthADAPT™) (N = 8)

2. Only type I collagen membrane (N = 5)

13

(8 intervention group and 5 controls)

Autologous BM-MSC

BMC (right posterior superior iliac spine)

12 months

Arthroscopic rotator cuff repair

The authors of the study decided to terminate the study prematurely because four patients experienced postoperative complications. A re-rupture was observed in 3/5 control subjects (60%) and in 5/8 treatment subjects (62.5%). The complications experienced by both study groups could not be related to the autologous MSCs but to the scaffold (OrthADAPTTM). However, the Constant score was significantly higher in the treatment group (p = 0.007).

1

8

Hurd, J. L 2020

RCT

Partial-thickness rotator cuff tears

1. UA-ADRCs (N = 11)

2. Methylprednisolone (N = 5)

16

(11 intervention group and 5 controls)

unmodified, autologous adipose-derived regenerative cells (UA-ADRCs)

Periumbilical abdominal area, bilateral flanks, or medial thigh

13 months

No surgery

UA-ADRCs application in sPTRCT patients is safe and significantly improved function of the shoulder compared to the control group, with no side effects.

1

9

C. H. Jo 2020

Case series

Partial-thickness rotator cuff tear

1. AD-MSC Low dose (N = 3)

2. AD-MSC Mid dose (N = 3)

3. AD-MSC High dose (N = 13)

With no control group

19

Autologous AD-MSCs

Abdominal subcutaneous fat

24 months

No surgery

Intratendinous injection of AD-MSCs is a safe and effective treatment for partial tears of rotor cuff

3

10

L. N. Muench 2020

Case series

Rotator cuff tear (Arthroscopic rotator cuff repair)

Arthroscopic rotator cuff repair + BMC + PRP + subacromial bursa (N = 16)

16

Autologous BMC

BMC (from proximal humeral head)

12.6 ± 1.8 (12<) months

Arthroscopic rotator cuff repair

This study showed that arthroscopic rotator cuff repair augmented with BMC improves patient function

4

Elbow

11

D. Connell 2009

Case series

Refractory lateral epicondylitis (tennis elbow)

Elbow CEO tendinosis group (N = 12)

without control group

12

Autologous tenocyte-like cell (derived from dermal fibroblast)

Skin

6 months

No surgery

Tendon like cells have a therapeutic effect on refractory CEO tendinosis

4

12

A. Singh 2014

Case series

Previously untreated Lateral epicondylosis (tennis elbow)

Elbow CEO tendinosis BMC injected group (N = 26)

without control group

 

Autologous MSC

BMC (from anterior-superior iliac spine)

3 months

No surgery

significant improvement of pain relief and recovery from the disease following a single injection of BMC

4

13

A. Wang 2015

Case series

Severe refractory Lateral Epicondylitis (tennis elbow)

Tenocytes injection (N = 15)

15

Autologous Tenocytes

Patellar tendon

4.5 years (range, 3.1-5.2)

No surgery

Tenocyte injection for Lateral Epicondylitis treatment showed acceptable results in function and structure improvement.

4

14

Lee, S. Y 2015

Case series

Chronic and intractable Lateral epicondylosis (tennis elbow)

1. AD-MSC low dose (N = 6)

2. AD-MSC high dose (N = 6)

no control group

12 (6 each groups)

Allogenic AD-MSC

Human subcutaneous fat tissue

13 months

No surgery

Allogenic AD-MSC injection for lateral epicondylosis treatment is safe and effective.

4

15

M. Khoury 2021

Case series

Chronic, recalcitrant lateral elbow tendinopathy (LET)

AD-MSC (N = 18)

no control group

18

Autologous AD-MSC

Periumbilical zone

6 months

No surgery

Recalcitrant LET in tennis players showed clinical improvement and anatomical repair after autologous ASCs injection.

 

Achilles

16

K. Tate-Oliver 2013

Case- series

Achilles tendinosis and interstitial tears (N = 3)

1. HD-PRP + AD-tSVF (N = 2)

2. HD-PRP + AD-tSVF + BMC (N = 1)

3

Autologous adipose

graft (AD-tSVF) plus additive of HD-PRP

Lower abdomen-flank area (male and female) or

lateral thigh-buttock area (females)

3-4 years

No surgery

Use of AD-SVF and HD-PRP and/or BMAC is safe and a good option for Achilles tendonitis management without surgery

4

17

Stein, B. E 2015

Case-series

Sport-related Achilles tendon tear (open repair + BMC)

BMC injection group (N = 27)

No control group

27

Autologous MSC

BMC

29.7 ± 6.1 months

open repair

Patient with Achilles tendon repairs treated with BMAC injection shows a great functional rate of return to sport, rehabilitation progress, and single-limb heel raise outcomes.

4

18

Usuelli, F. G

2017

RCT

Recalcitrant non-insertional Achilles tendinopathy

1. PRP group (N = 23)

2. SVF group (N = 21)

44 (21 intervention group and 23controls)

Autologous Adipose-derived SVF

Subcutaneous adipose tissue

6 months

No surgery

We can use both PRP and SVF to treat recalcitrant Achilles tendinopathy, and it’s safe and effective. However, we can obtain results faster in SVF treatment.

1

Patellar

19

A. W. Clarke 2011

RCT

Refractory patellar tendinosis

Patellar tendinopathy (N = 60, in 46 patients)

1. Plasma-only injection group (N = 27)

2. Tenocyte-like Cell + plasma injection group (N = 33)

60 knees (46 patients, 33 in the intervention group)

Autologous skin-Derived Tenocyte-like Cells

Skin

6 months

No surgery

Patellar tendinopathy treated with skin-derived tendon-like cells can be safely treated in the short term, with a significantly better outcome than that achieved with plasma alone.

1

20

C. Pascual-Garrido 2012

Case series

Chronic patellar tendinopathy

BM-MNC group (N = 8)

No control group

8

Autologous BM-MNC

BMC (from anterior iliac crest bone)

5 years (range, 3–6)

No surgery

BM-MNC therapy improves chronic patellar tendinopathy after nonoperative treatment’s failure

4

21

G. Rodas 2021

RCT

Initial, unilateral, chronic patellar tendinopathy with an intratendinous lesion > 0.3 mm

1. Lp-PRP group (N = 10)

2. MSC group (N = 10)

20 (10 each groups)

Autologous BM-MSC

Bone marrow

12 months

No surgery

This study confirmed that treatment with BM-MSC or Lp-PRP could reduce the pain; however, BM-MSC is more effective

2

Gluteal

22

D. A. V. Rosário 2021

RCT

Gluteal tendinopathy

1. Corticosteroid group (N = 25)

2. BMC group (N = 15)

40 (15 intervention group and 25 controls)

Autologous MSC

BMC

6 months

No surgery

This study approve that BMAC is safe and effective to treat gluteal tendinopathy

2

  1. Abbreviations: BMC Bone marrow concentrate, PRP Platelet-rich plasma, VAS Visual analog scale, MMT Manual muscle test, ASES American Shoulder and Elbow Surgeons, NSAID Non-steroidal anti-inflammatory drugs, BM-MNC Bone marrow mononuclear cell, IKDC International knee documentation committee, KOOS Knee injury ad osteoarthritis outcome score, SF12 Short Form-12, ADL Activities of daily living, QOL Quality of life, AD-MSC Adipose-derived MSC, EGF Epidermal growth factor, SPADI Safety and the shoulder pain and disability index, NCI – CTCAE v4.0 National Cancer Institute - Common Terminology Criteria for Adverse Events version 4.0 scale, AE Adverse event, PRTEE Patient-Rated Tennis Elbow Evaluation, IQR Interquartile range, RCT Randomized controlled trial, CEO Common extensor origin, KSS Knee Society Score, OA Osteoarthritis, PL Platelet lysate, DASH Disabilities of the arm, shoulder and hand, NPS Numeric pain scale, MCID Minimal clinically important difference, UCLA University of California, Los Angeles, MEPI Modified Mayo clinic performance index for the elbow, TEAEs Treatment emergent adverse events, VISA Victorian Institute of Sport Assessment, sPTRCT Symptomatic, partial-thickness rotator cuff tears, UA-ADRC Uncultured, unmodified, autologous adipose-derived regenerative cell, SVF Stromal vascular fraction, BMMC Bone marrow mononuclear cells, US Ultrasound, HD-PRP High-density platelet rich plasma, AD-tSVF Autologous adipose-derived tissue stromal vascular fraction, Lp-PRP Leukocyte-Poor Platelet-Rich Plasma, SANE Single Assessment Numerical Evaluation, UA-ADRCs Unmodified, autologous adipose-derived regenerative cells, UEFS Upper Extremity Functional Scale