Open Access

The use of mesenchymal stem cells for cartilage repair and regeneration: a systematic review

Journal of Orthopaedic Surgery and Research201712:39

DOI: 10.1186/s13018-017-0534-y

Received: 2 January 2017

Accepted: 13 February 2017

Published: 9 March 2017

Abstract

Background

The management of articular cartilage defects presents many clinical challenges due to its avascular, aneural and alymphatic nature. Bone marrow stimulation techniques, such as microfracture, are the most frequently used method in clinical practice however the resulting mixed fibrocartilage tissue which is inferior to native hyaline cartilage. Other methods have shown promise but are far from perfect. There is an unmet need and growing interest in regenerative medicine and tissue engineering to improve the outcome for patients requiring cartilage repair. Many published reviews on cartilage repair only list human clinical trials, underestimating the wealth of basic sciences and animal studies that are precursors to future research. We therefore set out to perform a systematic review of the literature to assess the translation of stem cell therapy to explore what research had been carried out at each of the stages of translation from bench-top (in vitro), animal (pre-clinical) and human studies (clinical) and assemble an evidence-based cascade for the responsible introduction of stem cell therapy for cartilage defects.

Main body of abstract

This review was conducted in accordance to PRISMA guidelines using CINHAL, MEDLINE, EMBASE, Scopus and Web of Knowledge databases from 1st January 1900 to 30th June 2015. In total, there were 2880 studies identified of which 252 studies were included for analysis (100 articles for in vitro studies, 111 studies for animal studies; and 31 studies for human studies). There was a huge variance in cell source in pre-clinical studies both of terms of animal used, location of harvest (fat, marrow, blood or synovium) and allogeneicity. The use of scaffolds, growth factors, number of cell passages and number of cells used was hugely heterogeneous.

Short conclusions

This review offers a comprehensive assessment of the evidence behind the translation of basic science to the clinical practice of cartilage repair. It has revealed a lack of connectivity between the in vitro, pre-clinical and human data and a patchwork quilt of synergistic evidence. Drivers for progress in this space are largely driven by patient demand, surgeon inquisition and a regulatory framework that is learning at the same pace as new developments take place.

Keywords

Matrix-induced autologous chondrocyte implantation Autologous chondrocyte implantation Mesenchymal stem cells

Background

Articular cartilage is a highly specialised tissue acting as a shock absorber, enabling synovial joints to articulate with low frictional forces. Due to its avascular, aneural and alymphatic state, it has a limited repair potential [1]. Surgical options to manage damaged articular cartilage include arthroscopic debridement [25], bone marrow stimulation techniques [68], chondrocyte implantation [913], osteochondral autografts (mosaicplasty) [2, 14, 15], osteochondral allograft [1618] and, in the presence of osteoarthritis, joint replacement [19].

Bone marrow stimulation techniques, such as microfracture, are the most frequently used method in clinical practice for treating small symptomatic lesions of the articular cartilage [68]. However, the resulting tissue has shown to be a mixed fibrocartilage tissue [2022] with varying amounts of type II collagen [8, 21, 23, 24] and inferior to native hyaline cartilage. Fibrocartilage is vulnerable to shear stresses and prone to breaking down over time [20]. Subchondral osseous overgrowth has also been reported after microfracture [25, 26]. Osteochondral grafts can lead to donor site morbidity and healing seams at the recipient site [27, 28]. Autologous chondrocyte implantation (ACI) [9, 10] and its later evolution, matrix-induced autologous chondrocyte implantation (MACI), offered great promise with 80% of patients showing good or excellent results at 10 years [29] but at best results in hyaline-like repair and has experienced complications such as graft failure, periosteal hypertrophy and delamination [30, 31]. In addition, it has also been reported that cells may lose their phenotype during expansion [32, 33].

There is therefore a growing interest in regenerative medicine, which can broadly be thought of as two main types: cell therapy, where cells are injected directly into the blood or into tissues, and tissue engineering, where cell-scaffold combinations are used to repair or regenerate tissues.

Stem cells are cells that have the ability to divide and develop into many different cell types in the body and can be categorised as pluripotent and multipotent. Pluripotent stem cells are often harvested from embryonic sources and can develop into any type of cell in the body whereas multipotent stem cells are generally taken from adults and can divide and develop into a more limited range of cell types. When stem cells divide, the new cells can either remain stem cells or develop into a new type of cell with a more specific function (Table 1).
Table 1

Table describing the three main properties of stem cells

Stem cell properties

 

• They are unspecialized (“blank slates” that can become specific types of cells).

 

• They can develop into specialized cell types (cells that do specific work in the body).

 

• They are capable of surviving over long periods and divide to make additional stem cells.

 

Mesenchymal stem cells (MSCs) are a form of multipotent cells that may offer an alternative to cartilage repair techniques not hampered by availability and donor site morbidity.

The introduction of stem cell therapies into clinical practice however is a form of translational research, which as per any “bench-to-bedside” pathway now has enormous governance issues [34, 35] and is highly regulatory across four phases (Table 2) and by the Tissues and Cells Directive (2004/23/EC) https://www.hta.gov.uk/policies/eu-tissue-and-cells-directives.
Table 2

Description of the different phases of clinical trials

Clinical trial phases (http://www.nlm.nih.gov/services/ctphases.html)

 

Phase I: Safety Studies or First-In-Man. Researchers test a new drug or treatment in a small group of people for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.

 

Phase II: Uncontrolled Efficacy Studies. The drug or treatment is given to a larger group of people to see if it is effective and to further evaluate its safety.

 

Phase III: Randomised Clinical Trials. The drug or treatment is given to large groups of people to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.

 

Phase IV: Post-Market Surveillance. Studies are done after the drug or treatment has been marketed to gather information on the drug’s effect in various populations and any side effects associated with long-term use.

 

Many published reviews on cartilage repair only list human clinical trials [13, 3646], underestimating the wealth of basic sciences and animal studies that are precursors to future research and may be relevant in clinical practice further down the line. In addition, true translation would imply that all of the clinical studies would have supporting pre-clinical data.

We therefore set out to perform a systematic review of the literature to assess the translation of stem cell therapy to explore what research had been carried out at each of the stages of translation from bench-top (in vitro), animal (pre-clinical), and human studies (clinical) and assemble an evidence-based cascade for the responsible introduction of stem cell therapy for cartilage defects. In particular, we wanted to focus on the key burning questions pertaining to cartilage repair such as cell source, dosage (how many cells should be used), requirement for scaffolds and the role for extrinsic growth factors.

Main text

Search methodology

This review was conducted in accordance to PRISMA guidelines [47] using CINHAL, MEDLINE, EMBASE, Scopus and Web of Knowledge databases from 1st January 1900 to 30th June 2015.

The keywords used in the selection were “(“mesenchymal stem cells”[All Fields] OR “mesenchymal stem cells”[MeSH Terms] OR “mesenchymal”[All Fields] OR “stem cells”[All Fields] OR “Stem Cells”[MeSH Terms] OR “MSC”[All Fields]) AND (“Articular Cartilage”[MeSH Terms] OR “articular”[All Fields] OR “cartilage”[All Fields] OR “cartilage”[MeSH Terms]) AND (“healing”[All Terms] OR “repair”[All Terms] OR “Regeneration”[MeSH Terms] OR “regeneration”[All Fields] OR “tissue engineering”[MeSH Terms] OR “tissue engineering”[All Fields]) AND (“defect”[All Terms]) AND (“chond*”[All Terms])”.

All review and non-English studies were excluded. For analysis, only original research studies were included. Any duplicates were excluded. Initially, KM and JS independently screened studies’ title and abstract. Those included had the full text reviewed. Any disparities were discussed with the senior author (AJG). The references of eligible studies were also searched and included where relevant.

Unpublished trial databases (e.g. ClinicalTrials.gov) were reviewed as the grey literature using popular search engines, including Google. The keywords used for registered clinical trials in clinical trial databases were “stem cells”, “cartilage” and “orthopaedics”.

Eligible studies were drafted into tables tabulating the key data.

Results

The initial search identified 2880 study articles, of which 239 were included for analysis. The PRISMA flow diagram is shown in Fig. 1.
Fig. 1

Flow chart of literature search used for the review

In vitro studies

MSC source

A list of cell sources used in the in vitro studies is shown in Table 3. The commonest being human MSCs (66%) followed by rabbit MSCs (15%). The majority of the studies used bone marrow-derived MSCs (63%) followed by adipose tissue (33%). Two studies used commercial cell lines [48, 49].
Table 3

Cell species and cell sources

Cell species

No. of studies

References

Cell Source

No. of studiesa

References

Human

73

[48, 50, 52, 53, 168236]

Bone marrow

62

[48, 5053, 164, 168, 170173, 177180, 182185, 187, 188, 192, 195197, 203, 206210, 212, 216, 217, 219, 221, 223, 227, 230, 232235, 237255]

Rabbit

17

[240242, 246, 249, 252, 255265]

Adipose

36

[66, 169, 175, 176, 181, 186, 189, 193, 194, 199, 201, 202, 211, 214, 216, 218220, 224, 228, 229, 231, 235, 242, 256, 257, 260269]

Bovine

5

[51, 164, 243, 245, 270]

Synovium

9

[174, 191, 200, 213, 222, 226, 258, 259, 270]

Rat/mouse

5

[239, 250, 266, 269, 271]

Umbilical cord blood

3

[205, 236, 190]

Porcine

3

[247, 248, 268]

Commercial cell line

2

[215, 271]

Equine

3

[238, 253, 254]

Placental

2

[198, 225]

Goat

1

[244]

Embryonic

1

[216]

Ovine

2

[237, 251]

Not stated

0

 

Not stated

1

[267]

   

aSome studies used cells from more than one cell source

Scaffold

Within the in vitro studies, 26 different types of natural scaffold and 9 types of synthetic scaffolds were identified with a further 18 different types of hybrids, the most popular being a fibrin-polyurethane scaffold (Table 4).
Table 4

Types of scaffolds

Number of studies using types of scaffold

Natural

Synthetic

Hybrid

Growth factor combined

None used

47

14

22

6

29

Scaffold

No. of studies

References

Types of scaffolds used

Natural scaffolds

 Type I collagen hydrogel

6

[185, 190, 211, 226, 241, 251]

 Agarose hydrogel

4

[53, 247, 248, 268]

 Alginate bead

3

[223, 231, 271]

 Fibrin hydrogel

3

[208, 211, 263]

 Silk fibroin

3

[198, 216, 256]

 Chitosan microspheres

2

[260, 262]

 Hyaluronic acid

2

[195, 237]

 Cartilage-derived matrix

2

[193, 238]

 K-carrageenan

2

[169, 199]

 Chitosan

2

[168, 216]

 Hyaluronic acid hydrogel

2

[164, 245]

 Gelatin-based scaffold

2

[176, 233]

 Devitalised cartilage ECM

1

[220]

 Bead in bead alginate polysaccharide capsules

1

[221]

 Atelocollagen gel

1

[225]

 Fibrin disk

1

[254]

 Methacrylated hyaluronic acid

1

[164]

 Gelatin microspheres

1

[260]

 Decellularised cell matrix

1

[191]

 Collagen type I microspheres

1

[52]

 Alginate microbeads

1

[266]

 Alginate disks

1

[270]

 Platelet rich plasma

1

[242]

 Free oligosaccharide chondroitin sulphate C

1

[205]

 Collagen type I sponge

1

[237]

 3D printed chitosan

1

[181]

Synthetic scaffolds

 Polycaprolactone

3

[197, 207, 209]

 PLGA

3

[194, 204, 257]

 Polylactic acid

2

[230, 232]

 PVA

1

[244]

 PGA

1

[178]

 Poly-DL-lactide-co-glycolide

1

[194]

 Polylactide-co-caprolactone

1

[214]

 GFOGER modified PEG hydrogel

1

[183]

 OPF hydrogel

1

[240]

Hybrid scaffolds

 Fibrin–polurethane hydrogel

4

[50, 188, 192, 267]

 Esterified hyaluronan and gelatin polymer

2

[212, 255]

 TruFit CB (PLGA, calcium sulphate and polycolide)

1

[187]

 PCL–HA bilayer

1

[243]

 PEGDG–crosslinked hyaluronic acid

1

[202]

 Polylactic acid–alginate

1

[232]

 Sodium alginate–hyaluronic acid

1

[189]

 Chitosan–collagen type I

1

[258]

 Polyvinylalcohol–polycaprolactone

1

[246]

 Tricalcium phosphate-collagen-hyaluronan

1

[180]

 Poly-L-lactic acid–hydroxyapatite

1

[215]

 Collagen type I–polylactic acid

1

[217]

 Polylactic acid–polyglycolic acid with fibrin

1

[261]

 Collagen–polyglycolic acid

1

[252]

 Chondroitin sulphate C–collagen type II

1

[236]

 Fibrin hydrogel with chondroitin sulphate

1

[263]

 Chitosan-demineralised bone matrix

1

[239]

 Alginate foam-chondroitin sulphate

1

[170]

Growth factor combined with scaffolds

 TGF-β1-loaded microspheres with chitosan microspheres

1

[262]

 TGF-β1 releasing chitosan-collagen hydrogel

1

[174]

 PEOT/PBT TGF-β1 loaded scaffolds

1

[173]

 TGF-β1-activated chitosan/gelatin

1

[249]

 PLGA nanospheres with TGF-β1

1

[172]

 TGF-β1 loaded Gelatin Microspheres

1

[175]

Growth factors

The commonest used growth factors were TGF-β and the bone morphogenetic protein (BMP) family. A list of growth factors used can be seen in Table 5.
Table 5

Number of in vitro studies using different growth factors

Growth factor

No. of studies (%)

References

Growth factor

No. of studies (%)

References

TGF-β1

48 (44%)

[50, 169175, 189, 190, 192, 193, 195, 199, 202, 208, 210, 211, 213, 214, 216, 217, 220, 222224, 228, 230232, 234, 235, 244, 246, 249, 252256, 258, 260263, 266, 267, 270]

SOX-5

1 (1%)

[204]

TGF-β3

32 (29%)

[51, 162, 164, 168, 177, 181184, 197, 200, 205207, 218, 223225, 227, 237, 239, 240, 245, 247, 248, 250, 251, 257, 259, 267, 268, 270]

SOX-6

1 (1%)

[204]

BMP-2

13 (12%)

[188, 202, 213, 219, 225227, 229, 264, 265, 267, 270, 271]

WNT3A

1 (1%)

[171]

FGF

9 (8%)

[171, 183, 193, 197, 198, 213, 225, 246, 258]

IL-1

1 (1%)

[197]

IGF-1

7 (6%)

[179, 184, 192, 213, 224, 254, 265]

EGF

1(1%)

[193]

BMP-6

7 (6%)

[181, 216, 219, 224, 227, 250, 266]

OP-1

1 (1%)

[222]

TGF-β2

4 (4%)

[209, 219, 238, 270]

AA2P

1 (1%)

[266]

GDF-5

3 (3%[

[48, 186, 269]

IL-10

1 (1%)

[178]

SOX-9

2 (2%)

[204, 221]

TNFα

1 (1%)

[178]

BMP-4

2 (2%)

[227, 271]

PRP

1 (1%)

[242]

DEX

2 (2%)

[224, 266]

IWP2

1 (1%)

[171]

BMP-7

1 (1%)

[219]

None

15 (14%)

[52, 176, 180, 185, 187, 191, 194, 196, 201, 212, 215, 233, 236, 241, 243]

PDGF

1 (1%)

[202]

   

Cell seeding and passage

There was wide heterogeneity in cell seeding density and there appeared to be no standard form of measurement. Li et al. [50] examined three different seeding densities: 2, 5 and 10 × 106 cells/scaffold, and found that scaffolds seeded with 5 × 106 cells per scaffold induced the highest chondrogenesis; however, other groups [5153] found that a higher seeding density results in better chondrogenesis.

Apart from 26 studies which did not state cell passage number, most studies used MSC of an early passage, anything between uncultured fresh (passage zero (P0) and five times passaged cells (P5). One study used cells of P6 [54], and another study used cells between P4 and P7 [48]. No relationship was apparent between chondrogenesis and number of passages.

Length of study

The length of each in vitro study can be seen in Table 6. The majority of studies were short-term models; 27 studies (25%) ended between 1 and 2 weeks, 35 studies (33%) ended between 2 and 3 weeks and 15 studies (14%) ended between 3 and 4 weeks.
Table 6

Length of studies

Length of study

No. of studies

References

Up to 1 week

9

[172, 203, 210, 212, 224, 229, 239, 266, 270]

1–2 weeks

27

[50, 170, 174, 178, 182, 189, 192, 194, 198, 202, 215, 218, 220, 223, 228, 234, 235, 237, 240, 249, 254, 260265]

2–3 weeks

36

[52, 53, 168, 169, 173, 175, 179, 180, 183186, 190, 191, 195, 196, 199, 200, 204, 205, 209, 213, 217, 225, 226, 230, 232, 233, 236, 246, 250, 256, 258, 269, 271]

3–4 weeks

15

[51, 176, 181, 188, 193, 201, 211, 216, 219, 221, 241, 251, 253, 255, 257]

4–5 weeks

7

[171, 177, 206, 214, 231, 259, 267]

5–6 weeks

10

[48, 187, 208, 222, 238, 244, 247, 248, 252, 268]

6–7 weeks

1

[207]

7–8 weeks

1

[197]

8–9 weeks

3

[164, 243, 245]

Not stated

1

[242]

Method of assessment

A range of techniques was used to assess chondrogenesis within the in vitro studies. These techniques consisted of histology, immunohistochemistry, qPCR, biochemical analysis, imagery and mechanical testing. The techniques used are summarised in Table 7.
Table 7

Types of techniques used to assess chondrogenesis of MSCs

Type of techniques

No. of studies (%)

References

Histology

87 (79%)

[48, 5053, 164, 168170, 173175, 177179, 181187, 191195, 197201, 204211, 213217, 219222, 226, 229, 230, 232238, 240248, 250, 252264, 267271]

Immunohistochemistry

78 (71%)

[48, 50, 52, 53, 168171, 173175, 178183, 185191, 193, 194, 197, 198, 201, 203205, 207, 212215, 217, 218, 220, 221, 224, 226, 228238, 241, 242, 244, 246248, 250259, 264, 265, 267271]

qPCR

70 (64%)

[53, 168, 169, 173, 174, 176, 178186, 188, 190, 192194, 196, 199, 200, 202205, 207209, 211, 214, 216220, 222232, 235, 236, 239, 240, 242, 246, 249251, 256, 258, 259, 261263, 265267, 269271]

Biochemical analysis

64 (58%)

[48, 5052, 164, 168, 170172, 176, 177, 179, 180, 182184, 188, 189, 191, 192, 197, 199, 200, 202, 204, 205, 209, 212, 214, 216219, 222224, 226, 227, 233240, 244, 245, 247249, 252, 254, 257, 260266, 268270]

Imaging (confocal, SEM, TEM)

24 (22%)

[52, 172, 176, 180, 185, 187, 194, 198, 208, 215217, 225, 226, 230, 232, 241, 242, 249, 252, 255, 262, 263, 265]

Mechanical testing

15 (14%)

[51, 52, 164, 169, 175, 193, 197, 207, 220, 245, 247, 248, 256, 257, 268]

Animal studies (pre-clinical)

One hundred eleven animal studies were included of which 109 were controlled laboratory studies, one was a pilot study [49] and one was a longitudinal case study on a race horse [55]. The commonest animal studied with 59 studies was rabbit (53%). The different species of animals studied is shown in Table 8.
Table 8

Different species of animals used to assess reparative effect of MSCs on cartilage defect

Animals

No. of studies (%)

References

Rabbits

57 (51%)

[49, 54102, 134, 150154, 160, 161, 207, 272324]

Pigs

16 (14%)

[61, 62, 6872, 87, 90, 153, 273, 276, 279, 290, 308310]

Rats

13 (12%)

[60, 7882, 91, 152, 160, 278, 286, 311, 312]

Sheep

8 (7%)

[89, 272, 282, 283, 313316]

Goats

5 (5%)

[49, 95, 100, 101, 318]

Horses

4 (4%)

[55, 96, 98, 317]

Dogs

4 (4%)

[86, 97, 151, 287]

Monkeys

2 (2%)

[319, 320]

Guinea pigs

1 (<1%)

[281]

Donkeys

1 (<1%)

[57]

Defect

The size of the defect varied from 2 to 25 mm2 in the smaller animals and from 1 to 64 mm2 in the larger animals. All but two studies [56, 57] used the knee for defect creation.

Stem cell type

Bone marrow-derived stem cells were used in 84 studies (75%). Thirteen studies (11%) used adipose stem cells [54, 5869], six (5%) used synovia [7075] and three (2%) used periostium-derived MSCs [7678]. Three studies (3%) used embryonic stem cell-derived MSCs [7981] whereas 2 studies (2%) used muscle-derived MSCs [82, 83]. One group showed promising results of allogenic MSCs in a rabbit model when compared to autologous cells, although numbers were small [84, 85]. Another used compared autologous chondroprogenitor cells and allogenic chondroprogenitor cells against controls in an equine model and reported that repair tissue quality in the allogenic cell group was not superior to that in the control (fibrin only) group and also showed poorer radiographic changes in the allogenic group [23].

Cell culture, dose and delivery

There was much variation in the number of cells implanted and the number of cell passages from 3–10 or more [79, 86].

The number of cells varied from 4 × 103 – 1 × 1010. The majority of studies used between 106 and 108 cells. Some did not specify the number of cells implanted. Two studies suggested that improved chondrogenesis occurs with a higher implanted cell number [75, 87], although others suggested that the high cell numbers increase the risk of synovitis [75] and synovial proliferation [88].

The cells were transplanted into the defect both as cell therapy (injection directly into the joint) (17 studies, 15%) or by tissue engineering (cell-scaffold combinations) (94 studies, 85%). Fifteen studies [49, 65, 72, 75, 81, 86, 8997] used a mixture of solutions prepared from hyaluronic acid [65, 92, 9497], phosphate buffer solution [91], plasma [75], basal medium with chondrogenesis [89], collagen acid [93], sodium alginate [86] or a growth factor medium [90]. Two studies used MSCs only [49, 72].

Scaffold

Ninety-two studies (82%) used a scaffold. The material used was a synthetic polymer either collagen based, fibrinogen glue or a synthetic protein (e.g. rHuBMP-2) in 62 (56%) studies (Table 9).
Table 9

Table showing the types of scaffold used in animal studies

Scaffold type

No. of studies

References

No Scaffold

19 (17%)

[49, 54, 61, 70, 7275, 81, 86, 8991, 97, 100, 102, 280282, 284]

Poly (lactide-co-glycoside) PLGA

17 (16%)

[56, 59, 62, 63, 83, 88, 150, 153, 160, 277, 285, 286, 289292, 316]

Fibrin/Fribrin glue

11 (9%)

[55, 64, 7678, 152, 278, 293, 308, 317, 318]

Hydrogel

9 (8%)

[65, 69, 81, 94, 279, 288, 314, 321, 323]

Collagen

9 (8%)

[79, 80, 134, 276, 299, 301, 309, 320, 322]

Hyaluronic acid

7 (6%)

[57, 92, 95, 96, 273, 304, 324]

Alginate beads

4 (3%)

[65, 84, 101, 294]

Tissue membrane

4 (3%)

[82, 98, 303, 305]

Polyglycolic acid

3 (3%)

[99, 161, 274]

PGA/PLA

3 (3%)

[68, 290, 296]

Hylauronan crosslinked matrix

2 (2%)

[154, 297]

Poly-L-lactide-co-caprolactone

2 (2%)

[275, 300]

Polycaprolactone cartilage (PCL)

2 (2%)

[87, 272]

Animal-origin osteochondral plug scaffold

2 (2%)

[272, 298]

Chitosan microspheres and fibrin glue

1 (<1%)

[60]

Gel carries (collagen/HA/Fibrogen)

1 (<1%)

[71]

Polychoxanone/poly(vinyl alcholo) PDO/PVA

1 (<1%)

[302]

Cartilage aggregate

1 (<1%)

[306]

Collagen/glycosaminoglycan porous titanium biphasic scaffold

1 (<1%)

[151]

Articular chondrocyte seeded matrix associated autologous chondrocyte transplant (MACT)

1 (<1%)

[313]

MSC-ADM (accellulo-dermal matrix)

1 (<1%)

[319]

Hyaff-11 scaffold

1 (<1%)

[295]

Porous-gelatin-chonroitin hyaluronate

1 (<1%)

[291]

Bone protein 7 PCL

1 (<1%)

[66]

Human acellular amniotic membrane

1 (<1%)

[307]

Pluronic-F 127

1 (<1%)

[102]

Tricalcium phosphate

1 (<1%)

[315]

Agarose

1 (<1%)

[311]

GCH-GCBB

1 (<1%)

[93]

ACHMS (atelocollagen honeycomb-shaped membrane)

1 (<1%)

[58]

Magnet

1 (<1%)

[310]

Human cartilage extra cellular matrix 3D porous acellular

1 (<1%)

[67]

Growth factors

Thirty-two studies (29%) assessed the effect of growth factors on MSC chondrogenesis. Seventeen out of 38 (44%) used TGF-β1/3 (Table 10), the majority of which show a positive effect on chondrogenesis.
Table 10

Table showing growth factors used in animal studies

Growth factor

No. of studies

References

TGF-β3/1/2

17 (15%)

[56, 65, 66, 70, 76, 85, 90, 100, 280, 282, 285, 287, 290, 291, 309, 311, 323]

CDMP–1

2 (2%)

[56, 134]

FGF-2

2 (2%)

[90, 304]

Ad-hTGF-B1

1 (<1%)

[321]

AdBMP–2

1 (<1%)

[78]

chABC

1 (<1%)

[74]

PRP

1 (<1%)

[75]

Gene modified MSCs (gene modification to BcL-xL gene)

1 (<1%)

[299]

hiGF-1-DNA

1 (<1%)

[101]

AdIGF–1

1 (<1%)

[78]

rHuBMP–2

1 (<1%)

[82]

Ham-F-12

1 (<1%)

[303]

NaO11

1 (<1%)

[277]

NSC23766-Rac1 inhibitor

1 (<1%)

[60]

Associated procedures

Ten of the studies compared MSC treatment against other surgical modalities such as debridement [55], microfracture [49, 91, 96, 98, 99] and mosaicplasty [77, 100102].

Outcome measures

There were a variety of outcome measures used to analyse the results of the studies. The majority of studies (79%) used evidence of hyaline-like cartilage as being a positive outcome (Tables 11 and 12).
Table 11

Outcome measures used in animal studies (some studies used more than one outcome measure)

Outcome score

No. of studies using the score (%)

References

Histology scores

111 (100%)

[49, 54102, 134, 150154, 160, 161, 272324]

International Cartilage Repair Society Score

26 (23%)

[49, 60, 61, 63, 66, 69, 72, 74, 79, 89, 92, 94, 98, 99, 272, 282, 283, 289, 305, 306, 310, 313, 314, 316, 319, 324]

Wakitani score

21 (19%)

[58, 62, 67, 68, 72, 73, 80, 82, 97, 151, 273, 277, 279, 284, 285, 290, 299, 304, 310, 321]

O’Driscoll score

2018%

[49, 71, 81, 84, 85, 93, 100, 160, 272, 276, 290, 296298, 302, 306, 308, 313, 314, 322]

Functional scores/mechanical

11 (10%)

[55, 57, 62, 67, 69, 81, 101, 277, 287, 290, 315]

MRI scores

5 (5%)

[63, 69, 96, 101, 316]

Arthroscopy scores

5 (5%)

[72, 96, 310, 317, 318]

Macroscopic osteoarthritis score

3 (3%)

[57, 281, 295]

Pineda score

3 (3%)

[290, 293, 309]

Schreiber score

2 (2%)

[101, 300]

Britternberg score

2 (2%)

[84, 85]

Slochagg score

1 (<1%)

[300]

Moran score

1 (<1%)

[64]

Gill score

1 (<1%)

[95]

Table 12

Analysis technique used on repaired tissue

Analysis used

No. of studies (%)

References

Hyaline-like cartilage

88 (79%)

[49, 5456, 58, 59, 61, 62, 6469, 7173, 75, 76, 7889, 92, 95, 97, 98, 100, 101, 134, 150152, 154, 160, 161, 273280, 285302, 304, 305, 307, 309, 310, 312, 314324]

Collagen type II

84 (76%)

[54, 5659, 62, 6573, 7588, 90, 91, 9396, 98, 100102, 134, 150154, 160, 161, 272276, 278282, 284288, 292, 294296, 300, 302306, 308, 309, 311, 313315, 317319, 321, 323]

Cluster Chondrocytes

34 (31%)

[57, 60, 62, 63, 72, 74, 77, 78, 80, 81, 83, 84, 91, 97, 102, 151, 152, 160, 161, 273, 276, 280, 281, 283, 291, 292, 296, 297, 304, 312, 318, 319, 322, 324]

Glycosaminoglycan

40 (36%)

[49, 62, 65, 6771, 7375, 81, 85, 87, 94, 96101, 160, 272, 274, 279, 282, 286, 288, 290, 291, 296, 300, 301, 308, 309, 311, 312, 315, 319, 323]

Genes

22 (20%)

[56, 60, 61, 63, 64, 66, 78, 80, 82, 90, 94, 96, 134, 275, 277, 283, 285, 294, 311, 316, 321, 323]

Proteoglycan

8 (7%)

[56, 63, 84, 95, 98, 287, 294, 295]

Human studies (clinical)

Thirty-one published studies by 15 different groups looked at clinical applications of MSCs. One used allogenic stem cells [103] and the rest autologous stem cells. The types of studies can be seen in Tables 13 and 14.
Table 13

Number of publications for each study type and phase

Category

No. of studies (total 28)

References

Phases of clinical studies

 Pilot/feasibility study incl. case report

15 (54%)

[104108, 118, 119, 122, 124129, 133]

 Phase 1 (safety assessment)

8 (26%)

[109112, 116, 123, 130, 131]

 Phase 2 (efficacy assessment)

8 (26%)

[103, 113115, 117, 120, 121, 132]

 Phase 3 (large scale efficacy assessment through a multi-centre RCT)

0 (0%)

 Phase 4 (post-market surveillance)

0 (0%)

Table 14

Summary of the published clinical studies

Category

No. of studies

References

Cell source

 Bone marrow

22 (71%)

[103105, 109, 111113, 115118, 120, 122128, 130132]

 Adipose

5 (16%)

[106108, 110, 114]

 Peripheral blood

2 (6%)

[119, 121]

 Synovium

2 (6%)

[129, 133]

Cell delivery

 Arthroscopic implantation

  Hyaluronic acid membrane

2 (6%)

[117, 130]

  Hyaluronic acid with fibrin glue or platelet gel

2 (6%)

[116, 128]

  Polyglycolic acid/hyaluronan

2 (6%)

[127, 131]

  Collagen with platelet gel

1 (3%)

[116]

  Fibrin glue

1 (3%)

[108]

  HYAFF 11 scaffold

1 (3%)

[132]

  Acetate Ringer solution

1 (3%)

[133]

  Unspecified

1 (3%)

[107]

Intra-articular injection

  PBS only

2 (6%)

[104, 110]

  PBS with HA

2 (6%)

[119, 121]

  Autologous serum

2 (6%)

[115, 123]

  Ringer lactate solution

3 (10%)

[103, 111, 112]

  PBS with serum albumin

1 (3%)

[105]

  HA and PRP

1 (3%)

[106]

  PRP

1 (3%)

[114]

  Commercial serum

1 (3%)

[109]

Transplantation by open surgery

  Collagen

6 (21%)

[103, 113, 118, 122, 124, 126, 129]

  Ascorbic acid-mediated sheet

2 (7%)

[120, 123]

  Fibrin glue

1 (4%)

[125]

Cell dose

 Less than 10 million

8 (26%)

[105, 107, 108, 114, 120, 122, 124, 129]

 10–20 million

5 (16%)

[113, 118, 119, 123, 125]

 Over 20 million

7 (23%)

[103, 104, 109112, 133]

 Unspecified

11 (35%)

[106, 115117, 121, 126128, 130132]

Follow-up

 Up to 6 months

4 (13%)

[104106, 110]

 Up to 12 months

6 (19%)

[103, 109, 111, 124, 125, 127]

 Up to 2 years

11 (35%)

[107, 113116, 120, 121, 128131]

 Up to 3 years

7 (23%)

[108, 112, 117, 119, 122, 126, 132]

 Over 3 years

2 (6%)

[118, 133]

Assessments

 Radiology (MRI, X-ray)

24 (77%)

[103106, 109112, 115117, 119, 121125, 127133]

 Arthroscopic assessment incl. histology

17 (54%)

[107, 108, 113, 116122, 124126, 130133]

 IKDC

10 (32%)

[107, 108, 115, 121, 122, 126, 128, 130132]

 VAS pain

12 (39%)

[103106, 109112, 114, 129, 131, 132]

 Tegner activity scale

8 (26%)

[107, 108, 114, 115, 129, 131133]

 Lysholm

6 (19%)

[114, 115, 125, 128, 131, 133]

 KOOS

5 (16%)

[126, 128130, 132]

 Function (no scoring systems or unspecified)

4 (13%)

[104106, 109]

 ICRS cartilage injury evaluation package

3 (10%)

[120, 123, 125]

 Clinical symptoms/outcomes (no scoring system or unspecified)

3 (10%)

[105, 109, 124]

 (Revised) Hospital for special surgery knee-rating scale

2 (6%)

[113, 125]

 Functional Rating Index

2 (6%)

[104, 106]

 WOMAC

5 (16%)

[103, 109112]

 AOFAS score

2 (6%)

[112, 116, 117]

 Knee Society Score

1 (3%)

[110]

 Harris Hip Score

1 (3%)

[112]

Concomitant procedures

 Subchondral bone marrow stimulation (multiple perforation, drilling, abrasion chondroplasty)

11 (35%)

[113, 115, 118, 119, 121123, 125, 127, 128, 131]

 Debridement, synovectomy, excision of degenerative tears (no subchondral bone marrow stimulation)

8 (26%)

[107, 108, 114, 116, 117, 124, 130, 133]

 ACL reconstruction, meniscus repair, osteotomy, or patella alignment, ACL calcification removal, trochlear resurfacing, osteochondral fragment fixation

8 (26%)

[115, 123, 126, 129133]

 None

6 (19%)

[103, 105, 106, 110112]

 Not specified

3 (10%)

[104, 109, 120]

Previous procedures

 Microfractures/multiple perforation/multiple drilling

6 (19%)

[104, 116, 117, 122, 125, 130]

 Menisectomy

6 (19%)

[103, 111, 124, 129, 131, 133]

 ACL reconstruction

4 (13%)

[103, 111, 131, 133]

 Multiple (microfracture, debridement)

1 (3%)

[119]

 ACI

2 (6%)

[116, 117]

 None

6 (19%)

[106108, 110, 114, 118]

 Not specified

9 (29%)

[105, 109, 112, 115, 120, 121, 126, 128, 132]

PBS phosphate-buffered saline, HA hyaluronic acid, PRP plate-rich-plasma, RCT randomised controlled study, KOOS Knee and Osteoarthritis Outcome Score, IKDC score International Knee Documentation Committee Score, WOMAC the Western Ontario and McMaster Universities Arthritis Index, AOFAS the American Orthopaedic Foot & Ankle Society

There were 52 unpublished clinical trials, majority of which are early phase studies (I–II; 63%) and only 5 trials were phase II/III. Table 15 shows a summary of these clinical trials.
Table 15

Clinical trials (unpublished/on-going) registered in ClinicalTrials.gov

Title

Cell source

Country

Clinical trial phase

Condition

Study design

Enrolment

Follow-up

Arm(s)

Cell delivery

Primary outcomes

Study status (on 8.3.2016)

ClinicalTrials.gov Identifier

Autologous cells

Mesenchymal Stem Cells in Knee Cartilage Injuries

Bone marrow

Jordan

II

Advanced knee articular cartilage injury

Non-randomized parallel assignment; double blind

13

12 months

Culture expanded MSCs alone vs. MSC with platelet lysate

Intra-articular injection

Therapeutic benefit

Completed in August 2015; no publication found

NCT02118519

Adult Stem Cell Therapy for Repairing Articular Cartilage in Gonarthrosis

Bone marrow

Spain

I/II

Gonarthrosis grade 2–3

Open label; single group assignment

15

12 months

Culture expanded MSCs (40 million cells)

Articular injection

Feasibility/safety

Completed in January 2013; no publication found

NCT01227694

Autologous Bone Marrow Mesenchymal Stem Cells Transplantation for Articular Cartilage Defects Repair

Bone marrow

UK

I/II

Knee articular cartilage defects

Randomized parallel assignment; double blind

10

12 months

MSCs (fresh or cultured unspecified)

Intra-articular injection

Change in WOMAC

Unknown

(estimated study completion date; July 2014)

NCT01895413

Mesenchymal Stem Cell for Osteonecrosis of the Femoral Head

Bone marrow

China

0

Osteochondritis of the femoral head

Open label single group assignment

15

5 years

Culture expanded MSC and bone marrow nuclear cells

Infusion through medial femoral circumflex artery, lateral femoral circumflex artery and obturator artery

Femoral head blood-supply artery angiographies; femoral head necrosis

Unknown

(estimated study completion date; August 2015)

NCT00813267

The Effects of Intra-articular Injection of Mesenchymal Stem Cells in Knee Joint Osteoarthritis

Bone marrow

Iran

II

Knee joint osteoarthritis

Single centre, randomised, placebo controlled, double blind

40

3 months

Culture-expanded MSCs vs. placebo

Intra-articular injection

Changes in WOMAC physical function and VAS pain

Completed in November 2012; no publication found

NCT01504464

Safety and Efficacy of Autologous Bone Marrow Stem Cells for Treating Osteoarthritis

Bone marrow

India

I/II

Knee OA Kellgren and Lawrence classification 3–4

Open label single group assignment; multi-centre

10

1 year

MSCs (fresh or culture-expanded unspecified)

Unknown

WOMAC pain score and safety

On-going

(estimated study completion date; January 2012)

NCT01152125

Treatment of Knee Osteoarthritis by Intra-articular Injection of Bone Marrow Mesenchymal Stem Cells

Bone marrow

Spain

I/II

Knee OA

Randomised parallel assignment; open label

30

12 months

Culture-expanded MSCs (10 million or 100 million cells) and hyaluronic acid (HyalOne®) vs. HyalOne®

Intra-articular injection

Pain and function (VAS, WOMAC, KOOS, EuroQol, SF-16, Lequesne), radiographic

On-going

(estimated study completion date; February 2015)

NCT02123368

Intra-Articular Autologous Bone Marrow Mesenchymal Stem Cells Transplantation to Treat Mild to Moderate Osteoarthritis

Bone marrow

Malaysia

II

Mild to moderate OA based on Kellgren-Lawrence radiographic classification

Randomised parallel assignment; open label

50

12 months

MSCs (fresh or culture-expanded unspecified) in hyaluronic acid “Orthovisc” vs. hyaluronic acid

Intra-articular implantation

Changes in cartilage thickness (MRI)

Unknown (estimated study completion date; March 2014)

NCT01459640

Treatment of Osteoarthritis by Intra-articular Injection of Bone Marrow Mesenchymal Stem Cells With Platelet Rich Plasma (CMM-PRGF/ART)

Bone marrow

Spain

I/II

Knee OA

Randomised parallel assignment; open label; multi-centre

38

12 months

Culture-expanded MSCs with PRP (PRGF®) vs. PRGF® only

Intra-articular injection

Pain and function (VAS, WOMAC, KOOS, EuroQol, SF-16, Lequesne), radiographic

On-going (estimated study completion date; June 2017)

NCT02365142

Mesenchymal Stem Cells Enhanced With PRP Versus PRP In OA Knee (MSCPRPOAK)

Bone marrow

India

I/II

Knee OA grade 1–2 Ahlbacks radiographic staging

Randomised parallel assignment double blinded

24

6 months

Culture-expanded MSCs (10 million cells) with autologous PRP vs. PRP only

Injected by lateral approach

VAS pain

Unknown

(estimated study completion date; June 2014)

NCT01985633

Side Effects of Autologous Mesenchymal Stem Cell Transplantation in Ankle Joint Osteoarthritis

Bone marrow

Iran

I

Severe ankle OA

Single group assignment open label

6

6 months

Culture-expanded MSCs

Intra-articular injection

Safety

Completed in September 2011; no publication found

NCT01436058

Human Autologous MSCs for the Treatment of Mid to Late Stage Knee OA

Bone marrow

Canada

I/II

Mid- to late-stage knee OA

Single group assignment, open label

12

1 year

Culture-expanded MSCs (1 million, 10 million or 50 million cells)

Injection

Safety

On-going

(estimated study completion date; February 2021)

NCT02351011

A Controlled Surveillance of the Osteoarthritic Knee Microenvironment With Regenexx® SD Treatment

Bone marrow

USA

NA

Knee OA Kellgren-Lawrence grade 2 or greater

Observational cohort study

20

6 weeks

Regenexx® SD (bone marrow concentrate)

Injection

Temporal median change in protein concentration or percentage of cellular subpopulations

On-going

(estimated study completion date; March 2016)

NCT02370823

The Effect of Platelet-rich Plasma in Patients With Osteoarthritis of the Knee

Bone marrow

Iran

III

Knee OA grade 2 and above (radiographic)

Randomised, parallel assignment, placebo controlled, double blinded

50

2 year

Bone marrow aspirate vs. placebo (saline)

Intra-articular injection

VAS pain, WOMAC physical activity, cartilage repair (MRI)

Completed in April 2014; no publication found

NCT02582489

Outcomes Data of Bone Marrow Stem Cells to Treat Hip and Knee Osteoarthritis

Bone marrow

USA

NA

Hip and knee OA

Observational cohort study

12

1 year

Bone marrow concentrate

Injection

VAS pain, Harris Hip Score or Knee Society Score, Physician Global Assessment

Completed in March 2014; no publication found

NCT01601951

Use of Autologous Bone Marrow Aspirate Concentrate in Painful Knee Osteoarthritis (BMAC)

Bone marrow

USA

II

Bilateral knee OA Kellgren-Lawrence grade 1–3

Randomised, parallel assignment, placebo controlled, single blinded

25

12 months

Bone marrow concentrate vs. placebo (saline)

Injection

Safety

On-going

(estimated study completion date; December 2016)

NCT01931007

Autologous Stem Cells in Osteoarthritis

Bone marrow

Mexico

I

Knee OA Kellgren-Lawrence radiographic scale grade 2–3

Randomised parallel assignment, open label

61

6 months

Hematopoietic stem cells (fresh) vs. acetaminophen (750 mg orally TID)

Infusion

Safety

Completed in May 2014; no publication found

NCT01485198

The Use of Autologous Bone Marrow Mesenchymal Stem Cells in the Treatment of Articular Cartilage Defects

Bone marrow

Egypt

Not given

An isolated osteochondral defect with no more than grade 1 or 2 Outerbridge

Single group assignment, open label

25

12 months

Culture-expanded MSCs

Open surgery or arthroscopy

Clinical scores and radiological images

Unknown

(estimated study completion date; December 2014)

NCT00891501

Autologous Transplantation of Mesenchymal Stem Cells (MSCs) and Scaffold in Full-thickness Articular Cartilage

Bone marrow

Iran

I

Full-thickness chondral defects

Single group assignment, open label

6

12 months

Culture-expanded MSCs mixed with collagen I scaffold

Unspecified

Knee cartilage defects

Completed in December 2010; no publication found

NCT00850187

“One-step” Bone Marrow Mononuclear Cell Transplantation in Talar Osteochondral Lesions (BMDC)

Bone marrow

USA

III

ICRS grade 3–4 Osteochondral lesions of the talar dome

Single group assignment, open label

140

24 months

Bone marrow concentrate

Arthroscopy

American Orthopaedic Foot and Ankle Society hindfoot score

On-going (estimated completion date; June 2016)

NCT02005861

Transplantation of Bone Marrow Stem Cells Stimulated by Proteins Scaffold to Heal Defects Articular Cartilage of the Knee

Bone marrow

France

0

Knee OA ICRS classification grade 4

Single group assignment, open label

50

1 year

Freshly isolated bone marrow mononuclear cells mixed with protein scaffold

Arthroscopy (one step procedure)

IKS

Unknown

(estimated completion date; December 2014))

NCT01159899

INSTRUCT for Repair of Knee Cartilage Defects

Bone marrow

The Netherlands

Not given

Knee articular cartilage defect

Single group assignment, open label; multi-centre

40

1 year

INSTRUCT scaffold (biodegradable scaffold seeded with autologous primary chondrocytes and bone marrow cells)

Arthrotomy

Safety and lesion filling

Completed in June 2014; no publication found

NCT01041885

HyaloFAST Trial for Repair of Articular Cartilage in the Knee (FastTRACK)

Bone marrow

Hungary

Not given

Knee articular cartilage defect

Randomised, parallel assignment, placebo controlled, single blinded, multi-centre

200

2 years

Hyalofast® scaffold with bone marrow aspirate concentrate vs. microfracture

One-step arthroscopic procedure

Changes in KOOS

On-going (estimated study completion date; June 2020)

NCT02659215

Autologous Adipose Stem Cells and Platelet Rich Plasma Therapy for Patients With Knee Osteoarthritis

Adipose

Vietnam

I/II

Idiopathic or secondary knee OA grade 2–3 radiographic severity

non-randomised unblinded

16

12 months

Stromal vascular fraction (10–50 million cells) and platelet rich plasma (PRP)

Injection

Safety

Completed in December 2015; no publication found

NCT02142842

Effectiveness and Safety of Autologous ADRC for Treatment of Degenerative Damage of Knee Articular Cartilage

Adipose

Russia

I/II

Knee OA (degenerative damage of knee articular cartilage)

Single group assignment, open label

12

24 weeks

Adipose-derived regenerative cells (ADRC) extracted using Celution 800/CRS System (Cytori Therapeutics, Inc.)

Intra-articular injection

Safety

On-going (estimated study completion date; December 2016)

NCT02219113

Autologous Adipose-Derived Stromal Cells Delivered Intra-articularly in Patients With Osteoarthritis

Adipose

USA

I/II

OA

Single group assignment, open label, multi-centre

500

6 months

MSCs in PRP

Intra-articular injection

Pain score, functional rating index, visual analogue scale (VAS), physical therapy (PT) and range of motion (53), quality of life scores, reduction in analgesics, adverse events

On-going (estimated study completion date; December 2016)

NCT01739504

Mesenchymal Stem Cell Treatment for Primary Osteoarthritis Knee

Adipose

Taiwan

I

Bilateral primary OA Kellgren and Lawrence grade 2–3 as determined by X-ray

Single group assignment, open label,

10

12 months

MSCs (8–10 million cells)

Intra-articular injections

Safety

On-going (estimated study completion date; December 2016)

NCT02544802

Autologous Adipose Tissue-Derived Mesenchymal Progenitor Cells Therapy for Patients With Knee Osteoarthritis

Adipose

China

II

Knee OA

Single group assignment, double blinded

48

6 months

Fresh MSCs (10 million, 20 million, 50 million cells twice) vs. placebo (PBS)

Intra-articular injection

WOMAC score

Completed in December 2013; no publication found

NCT01809769

Clinical Trial of Autologous Adipose Tissue-Derived Mesenchymal Progenitor Cells (MPCs) Therapy for Knee Osteoarthritis

Adipose

China

II

Knee OA

Randomised, parallel assignment, placebo controlled, single blinded

48

12 months

Culture-expanded MSCs vs. sodium hyaluronate

Intra-articular injection

WOMAC

On-going (estimated study completion date; July 2016)

NCT02162693

Outcomes Data of Adipose Stem Cells to Treat Osteoarthritis

Adipose

USA

NA

Knee OA

Observational cohort study

50

12 months

Cellular concentrate

Unknown

KOOS, HOOS

On-going (estimated study completion date; September 2017)

NCT02241408

Clinical Trial to Evaluate Efficacy and Safety of JOINTSTEM in Patients With Degenerative Arthritis

Adipose

Korea

II/III

Knee OA

Randomised parallel assignment, double blinded

120

24 weeks

MSCs (100 million cells) vs. sodium chloride

Injection

WOMAC

On-going (estimated study completion date; July 2017)

NCT02658344

ADIPOA–Clinical Study

Adipose

France

I

Moderate or severe knee OA

Non-randomised parallel assignment, open label

12

1 year

MSCs (2 million, 10 million, 50 million cells)

Intra-articular injection

Safety

Completed in December 2014; no publication found

NCT01585857

Safety and Clinical Effectiveness of A3 SVF in Osteoarthritis

Adipose

USA

Not given

OA

Single group assignment, open label

30

1 year

Stromal vascular fraction with activated platelet

Injection

Pain and inflammation–WOMAC scores, comprehensive inflammation blood panel

On-going

(estimated study completion date; September 2015)

NCT01947348

Safety and Clinical Outcomes Study: SVF Deployment for Orthopaedic, Neurologic, Urologic, and Cardio-pulmonary Conditions

Adipose

USA

Not given

Neurodegenerative diseases, OA, erectile dysfunction, autoimmune diseases, cardiomyopathies or emphysema

Single group assignment, open label

3000

36 months

Stromal vascular fraction

Intra-venous, intra-articular, and soft tissue injection

Safety

On-going

(estimated study completion date; March 2018)

NCT01953523

Microfracture Versus Adipose-Derived Stem Cells for the Treatment of Articular Cartilage Defects

Adipose

USA

Not given

Knee OA

Randomised, parallel assignment, double blind

90

24 months

Fibrin glue + acellular collagen dermal matrix + DSCs, + additional layer of fibrin glue vs. microfracture

Arthroscopy

KOOS

On-going (estimated study completion date; December 2020)

NCT02090140

Autologous Mesenchymal Stem Cells vs. Chondrocytes for the Repair of Chondral Knee Defects (ASCROD)

Adipose

Spain

I/II

Articular cartilage lesion of the femoral condyle

Randomised, parallel assignment, open label

30

18 months

Cultured stem cells vs. cultured autologous chondrocytes

Unknown

Hyaline cartilage production for chondral knee lesions repair

Unknown (estimated study completion date; June 2012)

NCT01399749

A Phase 2 Study to Evaluate the Efficacy and Safety of JointStem in Treatment of Osteoarthritis

Adipose

USA

II

Knee OA

Randomised, parallel assignment, double blinded

45

6 months

Joint stem adipose-derived (MSCs) vs. Synvisc-One (hyaluronic acid)

 

Cartilage volume, cartilage articular surface area, cartilage thickness, subchondral bone surface curvature (MRI)

On-going (estimated study completion date; September 2017)

NCT02674399

Allogenic cells

Treatment of Knee Osteoarthritis With Allogenic Mesenchymal Stem Cells (MSV_allo)

Bone marrow

Spain

I/II

Knee OA grade 2–4 of Kellgren and Lawrence

Randomised, parallel assignment, double blinded

30

1 years

Culture-expanded MSCs (40 million cells) vs. hyaluronic acid

Intra-articular transplantation

Safety

Completed in June 2014; published in August 2015

NCT01586312

(Linked to study NCT01183728)

Clinical Trial of Allogenic Adipose Tissue-Derived Mesenchymal Progenitor Cells Therapy for Knee Osteoarthritis

Adipose

China

I

Degenerative arthritis by radiographic criteria of Kellgren Lawrence

Randomised, parallel assignment, double blind

18

48 weeks

10 million MSCs vs. 20 million MSCs

Intra-articular injection

WOMAC

On-going (estimated study completion date; July 2017)

NCT02641860

Clinical Study of Umbilical Cord Tissue Mesenchymal Stem Cells (UC-MSC) for Treatment of Osteoarthritis

Umbilical Cord

Panama

I/II

Modified Kellgren-Lawrence classification grade 2–4 radiographic OA severity.

Randomised, parallel assignment, open label

40

12 months

Single intra-articular injection of MSCs vs.

IV injections of MSC for 3 days

Intra-articular injection; IV

Safety

On-going (estimated study completion date; March 2017)

NCT02237846

Safety and Feasibility Study of Mesenchymal Trophic Factor (MTF) for Treatment of Osteoarthritis

Umbilical Cord

Panama

I/II

Modified Kellgren-Lawrence classification grade 2–4 radiographic OA severity.

Non-Randomised, single group assignment,

open label

40

12 months

Intra-articular injection of allogeneic MTF from UC-MSC vs. 12 subcutaneous MTF injections, once per week

Intra-articular injection; subcutaneous injection

Safety

On-going (estimated study completion date; June 2017)

NCT02003131

A Study to Assess Safety and Efficacy of Umbilical Cord-derived Mesenchymal Stromal Cells in Knee Osteoarthritis

Umbilical Cord

Chile

I/II

Kellgren-Lawrence classification grade 1–3 radiographic OA severity

Randomised, parallel assignment, double blind

30

12 months

MSCs (single dose of 20 million MSCs or double dose at 6 month interval) vs. hyaluronic acid

Intra-articular injection

Safety

On-going (estimated study completion date; December 2016)

NCT02580695

Human Umbilical Cord Mesenchymal Stem Cell Transplantation in Articular Cartilage Defect

Umbilical Cord

China

I

Kellgren-Lawrence classification grade 2–4 radiographic OA severity

Single group assignment, open label

20

12 months

20 million cells every month for 4 months

Intra-articular injection

Safety

On-going (estimated study completion date; December 2016)

NCT02291926

Evaluation of Safety and Exploratory Efficacy of CARTISTEM®, a Cell Therapy Product for Articular Cartilage Defects

Umbilical cord blood

Korea

I/II

Focal, full-thickness grade 3–4 articular cartilage defects

Single group assignment, open label

12

12 months

CARTISTEM® (cultured UC MSCs mixed with sodium hyaluronate)

Unknown

Safety

On-going (estimated study completion date; May 2017)

NCT01733186

Study to Compare the Efficacy and Safety of Cartistem® and Microfracture in Patients With Knee Articular Cartilage Injury or Defect

Umbilical cord blood

Korea

III

Knee Articular Cartilage Injury or Defect

Randomised, parallel assignment, open label

104

48 weeks

CARTISTEM® (cultured UC MSCs mixed with sodium hyaluronate) vs. Microfracture

Surgery

CRS cartilage repair assessment

Completed in January 2011; no publication found

NCT01041001

Follow-Up Study of CARTISTEM® vs. Microfracture for the Treatment of Knee Articular Cartilage Injury or Defect

Umbilical cord blood

Korea

III

Knee articular cartilage injury or defect

Randomised, parallel assignment, open label

103

60 months

CARTISTEM® (cultured UC MSCs mixed with sodium hyaluronate) vs. microfracture

Unknown

IKDC, VAS pain, WOMAC

On-going (estimated study completion date; May 2015)

NCT01626677

Injections of FloGraft Therapy, Autologous Stem Cells, or Platelet Rich Plasma for the Treatment of Degenerative Joint Pain

Amniotic fluid

USA

NA

Pain associated with one of the following conditions: lumbar facet degeneration, degenerative condition causing upper extremity joint pain or degenerative condition causing lower extremity joint pain

Cohort observational study

300

24 weeks

FloGraftTM (allogenic amniotic fluid-derived allograft) vs. autologous BMMSCs vs. platelet rich plasma

Injection

Pain

On-going (estimated study completion date; June 2016)

NCT01978639

IMPACT: Safety and Feasibility of a Single-stage Procedure for Focal Cartilage Lesions of the Knee

Unspecified

The Netherlands

I/II

Full-thickness articular cartilage lesion on the femoral condyle or trochlea

Single-group assignment, open label

35

18 months

Autologous chondrons (chondrocytes with their pericellular matrix) and allogeneic MSCs in the fibrin glue carrier

Unspecified (single stage surgery)

Safety

On-going (Estimated Study Completion Date: August 2015)

NCT02037204

Allogeneic Mesenchymal Stem Cells in Osteoarthritis

Unspecified

India

II

Kellgren and Lawrence classification grade 2–3 radiographic OA severity

Randomised, double blind, multi-centre

60

2 years

Culture-expanded MSCs in 2 ml plasmalyte + 2 ml, hyaluronan vs. 2 ml, plasmalyte + 2 ml, hyaluronan

Intra-articular

Safety and tolerability

Unknown (estimated study completion date; July 2014

NCT01453738

Allogeneic Mesenchymal Stem Cells for Osteoarthritis

Unspecified

Malaysia

II

Kellgren and Lawrence classification grade 2–3 OA

Randomised, double blind, multi-centre

72

1 year

Culture-expanded MSCs in 2 ml plasmalyte + 2 ml, hyaluronan vs. 2 ml, plasmalyte + 2 ml, hyaluronan

Intra-articular

Safety and tolerability

Unknown (estimated study completion date; February 2013)

NCT01448434

Autologous or allogenic unspecified

Transplantation of Bone Marrow Derived Mesenchymal Stem Cells in Affected Knee Osteoarthritis by Rheumatoid Arthritis

Bone marrow

II/III

Iran

Rheumatoid arthritis

Randomised, parallel assignment, open label

60

6 months

MSCs vs. saline

Intra-articular injection

Pain

Completed in December 2011; no publication found

NCT01873625

Safety and Efficacy Study of MSB-CAR001 in Subjects 6 Weeks Post an Anterior Cruciate Ligament Reconstruction

Unknown

I/II

Australia

Anterior cruciate ligament injury

Randomised, parallel assignment, double blind

24

2 year

MSB-CAR001 (a preparation of MSCs) with hyaluronan vs. hyaluronan alone

Injection

Safety

Unknown

NCT01088191

Defects

The majority of studies (42%) used MSCs to treat knee osteoarthritis [103115]. The rest of the studies looked at knee cartilage defects except for two which studied the ankle talar dome [116, 117]. One study used MSCs to treat knee osteoarthritis (OA), knee OA and ankle OA [112].

Of the knee cartilage defects, the patients were heterogeneous with varying defect sizes and locations, including the patellae [118121], patella-femoral joints [122, 123], femoral condyle [113, 119121, 123132], trochlear [119121] and tibial plateau [121]; and several had multiple defect sites [105, 120, 123, 128].

Previous treatment and associated procedures

The majority of patients who received MSC treatment had undergone previous arthroscopy [103, 104, 118, 119, 122, 124, 130], failed debridement [113, 118, 119, 121123, 125, 127, 131] or bone marrow stimulation [114, 116, 117, 126].

Cell harvest source

Twenty-one studies (68%) used bone marrow-derived MSCs from the anterior or posterior superior iliac spine [103105, 109, 111113, 115118, 120, 122128, 130132]. Five studies (18%) used adipose-derived MSCs [106108, 110, 114], two studies (7%) used synovium-derived MSCs [129, 133] and two studies (7%) used peripheral blood progenitor cells collected by apheresis [119, 121].

Cell stage

Twenty studies (61%) culture-expanded their cells [103105, 107113, 115, 118, 120, 122126, 129, 133], whereas 11 studies (39%) used fresh concentrated stem cells from bone marrow [116, 117, 127, 128, 130132], fat tissues [106, 114] or peripheral blood [119, 121] in a one stage-procedure. In studies using bone marrow concentrate, approximately 60 ml of bone marrow aspirate was harvested and concentrated down to a volume of 2–4 ml before use [116, 117, 127, 130132]. In studies using culture-expanded cells, the majority used cells from early passages, P1–P3 [103, 105, 109, 110, 112, 113, 115, 118, 120, 122125, 129]. One study reported the use of cells at a late passage (P5) [104] ,and five studies did not specify a passage number [107, 108, 111, 126, 133].

Thirteen studies (42%) confirmed the phenotype of cells before clinical application [105, 108110, 112, 115, 119, 120, 122125, 129]. Commonly used surface markers to select MSCs were CD29, CD44, CD73, CD90 and CD105. Also CD14, CD34 and HLA-DR were used to eliminate non-MSCs.

Cell dose and delivery

The number of cells applied (dose) varied from 2–57 million for bone marrow-derived MSCs [103105, 109, 111113, 118, 120, 122125, 129] and from 1.2–100 million for adipose-derived MSCs [107, 108, 110, 114]. For synovial MSCs, 8–77 million cells were used [129, 133], and for peripheral blood progenitor cells, 20 million cells were used [119]. Also, the methods for implantation varied from arthroscopic implantation (35%) [107, 108, 116, 117, 127, 128, 130133], intra-articular injection [103106, 109112, 114, 115, 119, 121, 123] or open surgery (29%) [113, 118, 120, 122126, 129].

In the cell therapy studies, the cells were suspended with a variety of different co-stimulators, including hydroxyapatite (HA) [106, 119, 121, 123], platelet rich plasma (PRP) [106, 114] and platelet lysate [104]. Some studies also administered multiple injections of stem cells [119, 121] and/or further injection of HA [115, 119, 121, 123], PRP [106, 114] or nucleated cells [104] following a stem cell injection.

The most frequently used scaffolds were type I collagen of porcine or bovine origin [113, 118, 122, 124, 126, 129], followed by ascorbic acid sheet [120, 123] and platelet-rich fibrin glue mixture [108, 125].

Rehabilitation

Early continuous passive motion was employed in 14 studies [113, 117122, 124127, 129131]. Six studies did not report details on post-operation rehabilitation [104106, 109, 116, 132]. Three studies aimed for full weight bearing very early by week 4 [107, 108, 122] whereas 11 studies (40%) aimed for full weight bearing by the 6th–8th week [113, 117121, 124, 125, 127, 131, 133]. No study addressed the effect of rehabilitation on the quality of the repair.

Outcomes

Most commonly used outcome measures for treatment efficacy were radiological (77%) [103106, 109112, 115117, 119, 121, 123125, 127134] and arthroscopic assessment (61%) [107, 108, 113, 116122, 124126, 130133]. Most commonly used patient-reported outcomes are International Knee Documentation Committee (IKDC) score (36%), followed by a visual analogue scale (VAS) pain (39%) and Tegner activity scale (29%).

Adverse effects

None of the studies reported any severe adverse effects related to the MSC treatment. Two group reported minor adverse events including mild pain and effusion after the injections, which persisted for no more than 7 days [103, 114].

Conclusions

There is a growing fascination with the role of mesenchymal stem cells in cartilage repair.

As early as the 1950s, Pridie showed fibrocartilaginous repair through subchondral drilling [135137]. Initially, Pridie drilling was reported as a treatment for osteoarthritis [135, 138] and was often associated with many additional procedures such as synovectomy and trimming of osteophytes.

Since Pridie’s initial experiments, the process of marrow stimulation techniques or exposure of mesenchymal stem cells from cancellous bone has changed its guise on several occasions.

Ficat in 1979 described “Spongialization” in which the cancellous bed was exposed in 85 patients with chondral lesions of the patella with encouraging results [139]. Johnson et al. [140] described abrasion arthroplasty and encouraged its use especially in younger patients [141, 142]. Other authors had less positive outcomes [143146]. Dandy wrote an entertaining article on abrasion arthroplasty where he highlighted that at least in the treatment of osteoarthritis, its effects could relate to the arthroscopic washout, rest or even the placebo effects of the charismatic surgeon [147]. The final evolution of marrow stimulation was the term “Microfracture” enabled by commercially manufactured bone picks used to breach the subchondral bone [8]. Marrow-stimulating technique procedures, in particular microfracture, are now considered the first-line treatment for full-thickness cartilage lesions and have demonstrated good to excellent results in 60–80% of patients [148, 149].

Cartilage repair has evolved from marrow stimulation techniques through to chondrocyte transplant and now stem cells at rapid pace. An ideal translational pipeline would demonstrate how in vitro data was used to inform a pre-clinical model, which would later form a phase I/IIa first-in-man study and subsequently a phase III clinical trial. This would of course be the safe and responsible method by which novel therapies are brought to the market.

This systematic review is the first of its kind to explore the full spectrum of evidence from in vitro studies, through animal studies to human clinical trials, and yet, we found little evidence of connectivity between in vitro, animal and then human work. In fact, we did not find a single group that had carried out and reported studies in all three categories.

Indeed, even from groups, which showed a seemingly hierarchical approach to translation, discrepancies became apparent. For example, Saw et al. from Korea used a pre-clinical goat model to repair cartilage defects using HA plus bone marrow-derived cells [150] and then moved into a first-in-man study, but in doing so, elected to change from bone marrow aspirate to peripheral blood and justified this change because it was easier to harvest peripheral blood than marrow [151].

There are several sources of cells that have been used in cartilage repair including bone marrow, peripheral blood, synovium, adipose tissue and umbilicus (Table 14) without any clear evidence of superiority of one over the other.

One stage vs. two stages

As two stage procedures involving cell culture are expensive and cumbersome, there is an increasing push towards a single stage stem cell treatment. In this situation there is some supportive pre-clinical data [91, 95, 98, 152154], but there does not appear to be a pre-clinical study that directly compares bone marrow concentrates against cultured MSCs.

Several groups have reported the use of bone marrow concentrates in clinical practice [116, 117, 127, 128, 130132], in which the buffy coat is used containing the nucleated cells, of which a few will be stem cells.

Briefly, the patient has approximately 60 mL of bone marrow harvested from the iliac crest which is then spun down in a cell centrifuge (SmartPrep, Harvest Technologies Corp., USA, or IOR-G1, Novagenit, Mezzolombardo, TN, Italy) to provide 6 mL of concentrate containing nucleated cells. A small amount of the nucleated cells are then placed onto a hyaluronic acid membrane (Hyalofast, Fidia Advanced Biopolymers, Italy) or collagen membrane (IOR-G1, Novagenit, Mezzolombardo, TN, Italy) as a scaffold, which is then arthroscopically placed into the cartilage defect which had been pre-prepared using a burr or drill. The construct is then held with a platelet gel obtained from a harvest of 120 mL of patient’s venous blood taken the day before surgery (Vivostat system, (Vivolution, Denmark)) [118]. The results of the first 30 patients have been reported as showing improvements in MRI and arthroscopic appearance as well as clinical scores at 3 years follow-up [118].

This new technique is of course an evolution of the autologous matrix-enhanced chondrogenesis (AMIC) which used the stem cells from the adjacent marrow (and not pre-harvested bone marrow concentrates) within either collagen patches [155157] or polyglycolic acid–hyaluronan-based scaffolds [158, 159].

There has also been a further step taken to avoid bone marrow harvest in which peripheral blood has been used in knee chondral lesions. In an RCT, arthroscopic subchondral drilling was followed by postoperative intra-articular injections of hyaluronic acid (HA) with and without peripheral blood stem cells (PBSC). Fifty patients were studied and randomised 1 week after surgery to receive either 8 injections of HA or 8 injections of HA plus PBSC. Those that underwent PBSC received stimulation with filgrastim, which contains recombinant human granulocyte colony-stimulating factor prior to harvest [106, 151]. At 18 month follow-up, they reported no adverse effects and improved MRI findings in the PBSC group compared to HA alone, took biopsies of 16 of the 25 patients in each group and claimed better tissue morphology in the PBSC group, as graded by the International Cartilage Repair Society Visual Assessment Scale II. Interestingly, however, the same group’s pre-clinical used bone marrow aspirates and not peripheral blood [150].

Autologous vs. allogenic

There is an increasing interest in allogenic cells to avoid donor site morbidity and to reduce cost. The pre-clinical data with regards to allogenic cells is conflicting. One group showed promising results of allogenic MSCs in a rabbit model when compared to autologous cells, although numbers were small [160, 161]. Another group compared autologous chondroprogenitor cells and allogenic chondroprogenitor cells against controls in an equine model and reported inferior repair in the allogenic cell group [23]. Despite conflicting pre-clinical data, human studies using allogenic cells began in Korea in 2009. A phase I/IIa study to assess safety and efficacy of a combination of human umbilical cord blood-derived mesenchymal stem cells and sodium hyaluronate (CARTISTEM® (MEDIPOST Co., Ltd., Korea)) was performed in knee chondral defects (NCT01041001). A parallel phase 3, open-label, multi-centre RCT comparing CARTISTEM® and microfracture in knee chondral defects was carried out in Korea and the USA (NCT01733186). Results are still pending.

Another area of huge controversy is the actual dose of cells that should be used. In vitro between 50,000 cells/mL and 100 billion cells/ml have been studied. In pre-clinical animal studies, this ranged from 1000 to 1 billion cells/mL, and in human studies, the reported range has been 1.2 million cells/mL–24 million cells/mL.

It remains unclear what the most appropriate cell dose should be, with some groups reporting that a higher cell number leads to a better repair [52, 71, 87, 95, 162164], but Zhao et al. [99] highlighted the limitation to cell saturation and survival, and thus, there may be a top limit to cell number that can be used to aid repair.

A multitude of methods for cell delivery have also been adopted, from direct joint injection or embedded in a plethora of scaffolds, such as type I collagen gels of porcine or bovine origin, ascorbic acid sheets or fibrin glues (Table 14).

In vitro and in pre-clinical studies, a plethora of growth factors have been studied including TGF-β1 and TGF-β2 and BMP-7 but none of these have been included in human clinical trials (Table 5).

It is clear that the relationship between cell passage, cell dose, the use of scaffolds and growth factors and the efficacy of MSC treatment is still to be established.

Future

There is no question that the field of cartilage repair accelerates at rapid pace, and it is clear that the single stage procedures are likely to win over two stage procedures to save costs and reduce the burden on both provider and the patient. The reduction of donor site morbidity is a further driver helping direct progress.

The concept of cell banks of allogenic cells clearly meets all of the above criteria, but the lack of good supporting pre-clinical and long-term safety and efficacy data does little to pacify potential pitfalls of this direction. The fact that the phase 3 RCT of allogenic umbilical stem cells was allowed to be registered (NCT01041001) before the same group registered their phase I/IIa safety study (NCT01733186) intimates that sometimes clinical pace exceeds that of the regulators to lay down new ground.

Tools are likely to be introduced to the operating theatre that might improve the efficacy of treatment, such as fluorescence-activated cell sorting (FACS) machines which can isolate MSCs from the buffy coat of bone marrow aspirate by their cell surface markers. At present, this technology is expensive and complicated and ways to reduce cost and make the process simple are required before they could enter the operating theatre.

Induced pluripotent stem cells (iPSCs) are adult somatic cells that have been genetically reprogrammed to an embryonic stem cell-like state by being forced to express genes and factors important for maintaining the defining properties of embryonic stem cells [165].

These cells show unlimited self-renewal, and some in vitro studies have shown chondrogenic differentiation by iPSCs from human chondrocytes biopsied from osteoarthritic knees [166] and cartilage formation from human neural stem cells [167]. However, this work is at a very early stage, and aside from the ethical considerations, much research into control of cell phenotype and cell fate to alleviate concerns for cancer risk are required before this technology is ready to move into the pre-clinical and clinical realms.

In conclusion, this review is a comprehensive assessment of the evidence base to date behind the translation of basic science to the clinical practice of cartilage repair. We have revealed a lack of connectivity between the in vitro, pre-clinical and human data and a patchwork quilt of synergistic evidence. It appears that the drivers for progress in this space are largely driven by patient demand, surgeon inquisition, and a regulatory framework that is learning at the same pace as new developments take place. We strongly recommend funding body commission studies that have a clear translational purpose in order to drive the science towards patient benefit.

Abbreviations

ACI: 

Autologous chondrocyte implantation

AMIC: 

Autologous matrix-enhanced chondrogenesis

AOFAS: 

American Orthopaedic Foot & Ankle Society

FACS: 

Fluorescence-activated cell sorting

HA: 

Hydroxyapatite

IKDC: 

International Knee Documentation Committee

iPSCs: 

Induced pluripotent stem cells

KOOS: 

Knee and Osteoarthritis Outcome Score

MACI: 

Matrix-induced autologous chondrocyte implantation

MeSH: 

Medical Subject Headings

MSC: 

Mesenchymal stem cells

OA: 

Osteoarthritis

PBS: 

Phosphate-buffered saline

PBSC: 

Peripheral blood stem cells

PRP: 

Platelet rich plasma

qPCR: 

Real-time polymerase chain reaction

RCT: 

Randomised controlled trial

VAS: 

Visual analogue scale

WOMAC: 

Western Ontario and McMaster Universities Arthritis Index

Declarations

Acknowledgements

None

Funding

There was no external funding for this work.

Availability of data and materials

Not applicable

Authors’ contributions

All authors were involved in the conception and design of the study or acquisition of the data or analysis and interpretation of the data and contributed to drafting the article or revising it critically for important intellectual content. All authors read and approved the final manuscript.

Competing interests

The authors declare that they have no competing interests.

Consent for publication

Not applicable

Ethics approval and consent to participate

Not applicable

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)
Institute of Orthopaedics and Musculoskeletal Science, Royal National Orthopaedic Hospital (RNOH)
(2)
Joint Research and Enterprise Office, St George’s University of London and St George’s University Hospitals NHS Foundation Trust

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