Open Access

Stem cells in articular cartilage regeneration

  • Giuseppe Filardo1,
  • Francesco Perdisa1,
  • Alice Roffi2Email author,
  • Maurilio Marcacci1, 2 and
  • Elizaveta Kon1, 2
Journal of Orthopaedic Surgery and Research201611:42

https://doi.org/10.1186/s13018-016-0378-x

Received: 16 February 2016

Accepted: 29 March 2016

Published: 12 April 2016

Abstract

Background

Mesenchymal stem cells (MSCs) have emerged as a promising option to treat articular chondral defects and early OA stages. However, their potential and limitations for clinical use remain controversial. Thus, the aim of this systematic review was to examine MSCs treatment strategies in order to summarize the current clinical evidence for the treatment of cartilage lesions and OA.

Methods

A systematic review of the literature was performed on the PubMed database using the following string: “cartilage treatment” AND “mesenchymal stem cells”. The filters included publications on the clinical use of MSCs for cartilage defects and OA in English language up to 2015.

Results

Our search identified 1639 papers: 60 were included in the analysis, with an increasing number of studies published on this topic over time. Seven were randomized, 13 comparative, 31 case series, and 9 case reports; 26 studies reported the results after injective administration, whereas 33 used surgical implantation. One study compared the 2 different modalities. With regard to the cell source, 20 studies concerned BMSCs, 17 ADSCs, 16 BMC, 5 PBSCs, 1 SDSCs, and 1 compared BMC vs PBSCs.

Conclusions

The available studies allow to draw some indications. First, no major adverse events related to the treatment or to the cell harvest have been reported. Second, a clinical benefit of using MSCs therapies has been reported in most of the studies, regardless of cell-source, indication or administration method. Third, young age, lower BMI, smaller lesion size for focal lesions and earlier stages of OA joints, have been shown to correlate with better outcomes, even though the available data strength doesn’t allow to define clear cutoff values.

Keywords

MSCs Mesenchymal stem cells Osteoarthritis Cartilage Osteochondral

Background

Articular cartilage lesions are a debilitating disease, often resulting in fibrillation and subsequent degradation of the surrounding articular surface, possibly involving the subchondral bone as well, thus favoring the development of osteoarthritis (OA). OA affects up to 15 % of the adult population and represents the second greatest cause of disability worldwide [1], with a massive impact on society both in terms of quality of life for the individuals and high costs for the healthcare system [2]. Several approaches have been proposed for the management of cartilage degeneration, ranging from pharmacological to surgical options, aimed at reducing symptoms and restoring a satisfactory knee function [3, 4]. However, none of them has clearly shown the potential of restoring chondral surface and physiological joint homeostasis in order to prevent OA, which in the final stage often requires prosthetic replacement.

Among the solutions proposed to delay the need for metal resurfacing of the damaged articular surface, mesenchymal stem cells (MSCs) have recently emerged as a promising option to treat articular defects and early OA stages [5]. MSCs are multipotent progenitor cells that can differentiate into selected lineages including chondrocytes, with capability of self-renewal, high plasticity, and immunosuppressive and anti-inflammatory action [6, 7]. Moreover, Caplan and colleagues [8] recently underlined that these cells, derived from perivascular cells called “pericytes”, have a key role in the response to tissue injuries not just by differentiating themselves, but also by inducing repair/regeneration processes at the injury site through the secretion of several bioactive molecules [9]. In light of these properties, MSCs represent an excellent candidate for cell therapies and their healing potential has been explored also in terms of cartilage tissue regeneration and OA processes modulation [6]. The first investigations involved MSCs derived from bone marrow, which have been applied either as a cell suspension after being expanded by culture (BMSCs), or used as a simple bone marrow concentrate (BMC), thanks to their relative abundance [6]. Despite an extensive preclinical research and promising clinical results, some drawbacks related to the cell harvest and culture led to the development of different alternative options, with stem cells derived from adipose tissue (ADSCs), synovial tissue (SDSCs), and peripheral blood (PBSCs) [10, 11]. Besides these sources already explored and reported in the clinical use, cells derived from fetal tissues are being currently investigated at preclinical level [12]. Although numerous advancements have been made, the understanding of MSCs mechanism of action as well as their potential and limitations for the clinical use remain controversial. Many questions are still open on the identification of patients who might benefit more from this kind of treatment, as well as the most suitable protocol of administration (no. of cells, concentrated or culture-expanded, best harvest source, etc.).

Based on these premises, the aim of this systematic review was to examine the literature on MSCs treatment strategies in the clinical setting, in order to summarize the current evidence on their potential for the treatment of cartilage lesions and OA.

Materials and methods

A systematic review of the literature was performed on the PubMed database by two independent reviewers using the following string: “cartilage treatment” AND “mesenchymal stem cells”. The filters included publications on the use of MSCs for cartilage defects and OA in the clinical field and in English language, published from 2000 to the end of 2015. Articles were first screened by title and abstract. Subsequently, the full texts of the resulting articles were screened and those not reporting clinical results of MSCs for cartilage and OA treatment were excluded. The reference lists of the selected articles were also screened to obtain further studies for this review.

Results

Our search identified 1639 papers after the screening process, 60 were included in the analysis (Fig. 1), which showed an increasing number of studies published on this topic over time (Fig. 2). Among the 60 selected studies, 7 were randomized, 13 comparative, 31 case series, and 9 case reports; 26 studies reported the results after injective administration, whereas 33 used surgical implantation. One study compared the two different modalities. With regard to the cell source, 20 studies concerned BMSCs, 17 ADSCs, 16 BMC, 5 PBSCs, 1 SDSCs, and 1 compared BMC versus PBSCs. While all the included studies are summarized in detail in Table 1 according to cell source and treatment strategy, the most relevant findings will be discussed in the following paragraphs.
Fig. 1

Scheme of research methodology

Fig. 2

The systematic research showed an increasing number of clinical studies published over time

Table 1

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

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

BMSCs

An increasing number of papers have been focused on this cell source in the past few years, both as BMSCs and BMC. Cultured BMSCs and BMC differ for composition, since adult bone marrow contains heterogeneous blood cells at various differentiation stages [13]. Thus, the harvest includes plasma, red blood cells, platelets, and nucleated cells, a small fraction of which contains adult MSCs that can be isolated through culture expansion [14]. However, even if not expanded, the heterogeneity of cell progenitor types in BMC might positively influence tissue regeneration [15]. Moreover, cell culture not only offers a higher number of cells but also presents high costs and some regulatory problems, since these products might be considered as pharmacological treatments by regulatory agencies. Thus, one-step techniques using BMC for the delivery of autologous cells in a single time are gaining increasing interest in the clinical setting. Besides these considerations, positive findings are leading the research towards the use of both cell-based strategies.

Cultured BMSCs: injective treatment

In 2008, Centeno and colleagues [16] first reported the promising clinical and MRI improvements at early follow-up after single intra-articular (i.a.) injection of autologous cultured BMSCs in a patient with knee degenerative cartilage disease, and similar findings at short term were later shown also by the groups of Davatchi [17], Emadedin [18], and Sol Rich [19]. Orozco et al. confirmed a rapid and progressive clinical improvement of knee OA in the first 12 months [20], which was maintained at 24-month follow-up, together with improved cartilage quality at MRI [21]. Finally, Davatchi et al. [22] updated their report, showing gradual mid-term deterioration of the outcomes in advanced OA.

Among comparative studies, Lee et al. [23] tested two administration strategies for focal knee cartilage defects and found no differences either by using BMSCs implantation under periosteum flap or microfractures (MFX) plus BMSCs i.a. injection, thus endorsing the less invasive approach.

Three randomized controlled trials (RCTs) have also been published. Wong et al. [24] treated knee unicompartmental OA with varus malalignment by combined high tibial osteotomy (HTO) and MFX. Patients randomly received post-operative i.a. injection of BMSCs-hyaluronic acid (HA) or HA alone as control. Both groups improved their scores, but BMSCs produced better clinical and MRI outcomes. Vangsness et al. [25] administered a single i.a. injection in patients after medial partial meniscectomy. Patients were randomized in two treatment groups (low- or high-dose allogeneic cultured BMSCs with HA) and a control group (HA-only). Both treatment groups showed improved clinical scores versus control, and MRI showed signs of meniscal volume increase at 24 months. Finally, Vega et al. [26] randomized two treatment groups for knee OA: a significantly greater improvement was shown after a single allogeneic BMSCs injection compared to control HA.

Cultured BMSCs: surgical delivery

Adachi et al. [27] observed cartilage and bone regeneration in a biopsy after cultured BMSCs implantation on hydroxyapatite-ceramic scaffold for osteochondral knee lesion (OLK). Haalem et al. [28] implanted BMSCs on a platelet fibrin glue (FG) scaffold, showing significant improvement and complete MRI filling of the cartilage defect. Kasemkijwattana et al. [29] seeded cells on a collagen scaffold with positive results in two traumatic knee lesions. Similarly, Kuroda et al. [30] had good results implanting BMSCs on collagen membrane with periosteum coverage in a judo-player knee, with hyaline-like tissue at a 12-month histology evaluation. Wakitani et al. used the same technique with positive findings also for patellofemoral lesions [31], stable at mid-term follow-up [32]. They also performed a comparative evaluation of this technique for focal defects in OA knees: two groups were treated with HTO, with or without BMSCs augmentation [33]. BMSCs-group showed better histology, but clinical scores comparable to the cell-free group. Nejadnik et al. compared BMSCs implantation with first-generation ACI in two groups of patients and observed comparable benefits [34].

Finally, Richter et al. [35] investigated the outcomes offered by BMSCs onto a collagen matrix for chondral ankle lesions, confirming no complications and a promising clinical improvement at 24 months of follow-up.

BMC: injective treatment

A single study by Varma et al. [36] reported promising results with BMC injection after arthroscopic debridement for knee OA, with increased benefits compared to debridement alone.

BMC: surgical delivery

The group of Giannini published several studies of scaffold-associated BMC implantation in knee and ankle joint defects. In their first study [37], they showed clinical and MRI improvements at 24 months after BMC implantation into collagen powder or HA matrix for osteochondral lesions of the talus (OLTs). Later [38], they reported a significant worsening between 24 and 48 months of follow-up, but the final result was still satisfactory compared to the basal level. Patients with longer symptoms before surgery had worse clinical outcomes. They also observed no degeneration progression at 24 months in five hemophilic ankle lesions [39], and similar results were confirmed in a larger group of patients treated for OLTs or ankle OA defects [40]. Also, this study showed a worsening trend after 24 months with a higher failure rate, which underlined the influence of OA degree and patient BMI. Moreover, a further study by Buda et al. [41] confirmed a similar trend of gradual worsening up to 72 months after scaffold-assisted BMC implantation.

Giannini et al. [42] also performed comparative evaluations: positive and similar clinical outcomes were found in three groups of patients treated with one-step BMC-HA matrix implantation versus open ACI or arthroscopic MACT for OLTs at 36 months of follow-up. These results were later confirmed at 48 months after collagen scaffold implantation, seeded either with BMC or cultured chondrocytes, with better tissue quality at MRI for the BMC group [43]. Moreover, a RCT by Cadossi et al. [44] highlighted that biophysical stimulation with pulsed electromagnetic fields (PEMFs) might improve the results at 12 months after collagen matrix-BMC implantation for OLTs.

Matrix-assisted BMC implantation was also investigated for the treatment of OLKs. The promising results using BMC on HA matrix were first reported by Buda et al. at short-term follow-up, with positive MRI and histology findings [45, 46], and then confirmed by Gobbi et al. [47], who observed superior outcomes using BMC instead of chondrocytes for the treatment of large patellofemoral defects. Similar results were obtained also by seeding BMC on collagen scaffolds: Gigante et al. [48] used BMC-enhanced AMIC technique with positive short-term clinical results, but limited tissue quality at histology [49], and Gobbi et al. [50] observed hyaline appearance and better short-term improvement in patients younger than 45 years and with single and smaller lesion. Finally, Skowronski et al. [51] documented stable mid-term outcomes after the treatment of large chondral lesions.

PBSCs

The possibility of using autologous PBSCs obtained by culture expansion from a venous sample was first introduced by Saw et al. [52], who treated chondral knee lesions with subchondral drilling and five postoperative i.a. injections of PBSCs and HA, reporting no adverse reactions and positive histological findings. Turajane and colleagues [53] showed short-term clinical improvement using the same technique in early knee OA patients. Later, the group of Saw [54] also performed a RCT, documenting comparable clinical outcomes at 24 months, but better MRI and histological evaluations versus HA control.

With regard to surgical application, Fu et al. [55] reported optimal results at 7.5 years in a lateral trochlea lesion treated with patellar realignment plus periosteum-covered PBSCs implantation in a kick boxer, and Skowronski et al. [56] implanted PBSCs with a collagen membrane in a group of patients, reporting a stable improvement up to 72-month follow-up.

ADSCs

ADSCs present a lower chondrogenic potential when compared with BMSCs [57]. Nonetheless, they can be obtained from liposuction, a simple and cheap procedure, and their clinical use is rapidly increasing, thanks to their easy availability and abundance [10]. Whereas the use of cultured cells has rarely been reported, the preferred technique involves cell harvest, collagenase digestion, and isolation of the stromal vascular fraction (SVF), a heterogeneous cell population that, among pre-adipocytes and immune cells, also includes ADSCs [58].

Injective treatment

Jo et al. [59] published the only available study on cultured ADSCs, applied at different doses: their preliminary clinical data showed no adverse events, and a clinical-MRI improvement at 6 months after injecting the highest dose.

Most of the literature focused instead on SVF. Regarding knee OA, Pak et al. [60] first obtained a promising clinical improvement 3 months after i.a. injection of subcutaneous SVF with HA, dexamethasone, and PRP in a patient. Later, they [61] confirmed safety and effectiveness of SVF injections in a larger cohort of patients treated into different joints. Bui et al. [62] also reported short-term clinical and MRI improvement after injection of SVF and PRP. However, the group of Koh was the main investigator of SVF use, starting from the infrapatellar fat pad source, in a case–control study [63]: all patients underwent debridement and the treatment group received an additional SVF-PRP injection. No major adverse events and a tendency for better outcomes were observed in the SVF group. The improvement was confirmed at 24 months in a further study [64]. The number of injected cells correlated with both clinical and MRI outcomes, while SVF had lower effects on the final stage OA. Later, the same group began to process subcutaneous fat with an analogous technique. They treated knee OA in elderly patients with arthroscopic lavage and SVF-PRP injection [65]: clinical improvement was obtained both at 12 and 24 months, and positive findings were reported at second look evaluation. Moreover, SVF injections significantly improved the benefits of high tibial osteotomy (HTO) for symptomatic varus knee, compared to control (HTO and PRP-only), both at clinical and second look evaluation [66].

Michalek et al. [67] administered single-dose SVF injections to the largest available group of patients, reporting no treatment-related adverse events and gradual clinical improvement between 3 and 12 months, with a slower recovery for obese and higher OA degrees.

Finally, the group of Koh also investigated SVF use in the ankle joint: Kim et al. injected SVF after marrow stimulation in two comparative studies, and observed higher clinical and MRI improvement both for ankle OA [68] or OLTs [69], compared to surgery alone. The benefit was greater for younger patients with smaller lesions, but the treatment was effective even in older patients.

Surgical delivery

Koh et al. [70] reported a significant clinical improvement 2 years after a scaffold-free SVF implantation for focal chondral lesions in OA knees, but abnormal repair tissue was observed in most cases at second look evaluation. In a subsequent study, the association with FG as scaffold significantly improved tissue quality, even though clinical results remained similar to SVF alone [71]. Later, they reported positive short-term results and correlation with MRI findings after SVF-FG implantation for OA [72]. Furthermore, a larger prospective study confirmed good/excellent results in 75 % patients at 24 months [73]. Interestingly, older age, higher BMI, and larger defect size were negative predictors in all these studies. SVF-FG augmentation also improved the outcome versus MF alone in an RCT, despite comparable histology findings [74].

Finally, a study on matched-paired groups found comparable clinical results but better ICRS macroscopic scores at 12 months for SVF surgical implantation versus injective delivery, whereas at the further follow-up, a significant clinical superiority was also obtained for surgical SVF delivery [75].

SDSCs

SDSCs are a promising source of stem cells for cartilage tissue engineering, thanks to the greatest chondrogenic and lowest osteogenic potential among MSCs [57]. Sekiya et al. [76] reported promising results up to mid-term follow-up using SDMSCs scaffold-free implantation into single knee cartilage defects, with ¾ biopsies showing hyaline cartilage.

Comparative studies

Skowronski et al. [77] performed the only clinical comparative study among stem cell types showing superior results with PBSCs rather than BMC under a collagen membrane for OLKs at 5-year follow-up.

Discussion

This systematic research highlighted that the use of mesenchymal precursors as a biological approach to treat cartilage lesions and OA has widely increased (Fig. 2), as confirmed by the growing number of clinical trials published on this topic. In addition to an intensive preclinical research, the use of these procedures has recently broken down the barriers towards clinical application, with more than half of the available papers published in the last 3 years. Different sources have been investigated for clinical application, especially targeting knee or ankle cartilage disease. Among them, the most exploited cell types are those derived from bone marrow and adipose tissue. Cells have been used either after culture expansion or simply concentrated for one-step procedures: in particular, adipose cells have been applied mainly through cell concentration, and cells derived from bone marrow are currently applied both after expansion or concentration, while PBSCs and SDSCs can be only exploited through in vitro expansion due to their low number.

Regardless of cell source and manipulation, cells have being administered either surgically or through i.a. injection, to target focal lesions as well as degenerative joint disease.

Overall, despite the increasing literature on this topic, there is still limited evidence about the use of MSCs for the treatment of articular cartilage, in particular as far as high-level studies are concerned: in fact, most of the available papers are case series, while only few papers reported RCTs. Moreover, the few high level studies do not allow to clearly prove the effective potential of MSCs, due to the limited number of patients treated and to the presence of several confounding factors (PRP concomitant use, cell use in combination with scaffolds, etc.). To this regard, while several studies applied cells in association with PRP, with the rationale to provide both cells and growth factors at the same time, there is no evidence that adding platelet-derived growth factors provides any increased benefit with respect to cell administration alone, and specifically designed studies are needed in order to clarify the role of PRP with respect to MSCs and/or scaffolds in cartilage treatment. Furthermore, the tissue harvest procedure poses practical and ethical limitations which prevent from performing studies with a blinded design, therefore leaving an important bias related to the placebo effect, which is an important issue in this field of new fashionable regenerative treatments.

On the other hand, the available studies still allow to draw some indications on potential and limitations of MSCs clinical use for the treatment of cartilage lesions and OA.

First, the use of MSCs in the clinical setting can be considered safe, since no major adverse events related to the treatment nor to the cell harvest have been reported, at least from the available reports at short- to mid-term follow-up. Second, a clinical benefit of using MSCs therapies has been reported in most of the studies, regardless of cell source, indication, or administration method. This effectiveness has been reflected by clinical improvement but also positive MRI and macroscopic findings, whereas histologic features gave more controversial results among different studies. Third, different studies also gave a few indications regarding the patients who might benefit more from MSCs treatment: young age, lower BMI, smaller lesion size for focal lesions, and earlier stages of OA joints have been shown to correlate with better outcomes, even though the available data strength does not allow to define clear cutoff values.

The systematic analysis of the literature also allowed to underline other interesting findings that deserve to be discussed. Definite trends can be observed with regard to the delivery method: while different combinations of products and delivery methods have been investigated over the years, currently cultured cells are mostly being administered by i.a. injection, while one-step surgical implantation is preferred for cell concentrates. The different trends observed in this field are explained both by the controversial preclinical and clinical findings, which still leaves space for clinical investigations in opposite direction, but also by practical considerations, both in terms of economical, ethical, and regulatory limitations [6]. Many aspects are taken in consideration for the treatment choice, with physicians and researchers exploring different strategies, each one presenting potential advantages and possible drawbacks. To this regard, while culture expansion guarantees a selected MSC lineage to be delivered, but presenting high costs and some contamination risks related to cell manipulation, cell concentration offers a lower number of MSCs, in a heterogeneous cell population, and can be performed in one step, thus simplifying the procedure, reducing costs, and increasing patient compliance. To date, no clear evidence of superior outcome between the two cell manipulations is available, and also their most effective delivery method remains to be defined, with only a single retrospective study reporting better results for surgical delivery compared to i.a. SVF injection in a matched-paired analysis of two groups treated for single focal defects in knee OA [75]. Regarding surgical implantation, the use of solid scaffolds has been shown to be beneficial for SVF implantation [71], and it is the gold standard for the application of BMC [3741, 43, 47, 48, 50, 51]. The good results obtained with scaffolds implanted with BMC have been compared with chondrocyte-based surgical techniques, showing similar outcomes, but with the advantage of the one-step approach [42, 43, 47].

Finally, regardless of cell source, manipulation and delivery method, the optimal cell dose is still under investigation. After a first preliminary study reported no complications related to high dose of cultured ADSCs [59], only a single clinical study specifically focused on this aspect, suggesting benefits and absence of side effects by using higher dose of BMSCs for the treatment of post-meniscectomized knees [25]. However, the lack of standardization and the heterogeneity of the studies reported in the current literature do not allow to extend these findings to the several proposed MSCs treatment strategies.

The clinical application of MSCs for the treatment of articular cartilage defects and OA shows promising results, but too many questions still remain open. Even though no complications have been reported, longer follow-ups on broader patient population are needed to confirm the safety of these procedures. Likewise, while promising results have been shown, the potential of these treatments should be confirmed by reliable clinical data through double-blind, controlled, prospective, and multicenter studies with longer follow-up. In addition, specific studies should be designed to identify the best cell sources, manipulation, and delivery techniques, as well as pathology and disease phase indications, with the aim of optimizing the outcome for a treatment focused on focal chondral defects or joint degeneration.

Conclusions

This systematic review revealed a high interest of researchers in the clinical use of MSCs for cartilage and OA treatment, as testified by the increasing number of reports published over time. Whereas the lack of contraindication and generally promising clinical outcomes have been reported, the prevalence of low-quality studies, with many variables, shows several aspects that still need to be optimized, such as the best cell source and the most appropriate processing method, the most effective dose and delivery procedure. On the other hand, the first hints on the kind of patients who might benefit more from these procedures are being drawn. High-level studies with large number of patients and long-term follow-up are mandatory to evaluate the real potential of this biological approach for cartilage repair.

Abbreviations

ADSCs: 

mesenchymal stem cells derived from adipose tissue

BMC: 

bone marrow concentrate

BMSCs: 

bone marrow expanded stem cells

FG: 

fibrin glue

HA: 

hyaluronic acid

HTO: 

high tibial osteotomy

i.a.: 

intra-articular

MAST: 

matrix-assisted stem cells transplantation

MFX: 

microfractures

MSCs: 

mesenchymal stem cells

OA: 

osteoarthritis

OLK: 

osteochondral knee lesion

OLTs: 

osteochondral lesions of the talus

PBSCs: 

stem cells derived from peripheral blood

PEMFs: 

pulsed electromagnetic fields

RCT: 

randomized controlled trial

SDSCs: 

mesenchymal stem cells derived from synovial tissue

SVF: 

stromal vascular fraction

Declarations

Acknowledgements

This project received institutional support by the Italian Ministry of Health Ricerca Finalizzata (RF-2011-02352638).

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
II Orthopaedic and Traumatologic Clinic, Rizzoli Orthopaedic Institute
(2)
Nanobiotechnology Laboratory, Rizzoli Orthopaedic Institute

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© Filardo et al. 2016

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