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0Goldberg et al. Journal of Orthopaedic Surgery and Research (2017) 12:39 DOI 10.1186/s13018-017-0534-y
Journal of Orthopaedic Surgery and Research
REVIEW Open Access
The use of mesenchymal stem cells for cartilage repair and regeneration: a systematic review
Andy Goldberg1, Katrina Mitchell1, Julian Soans1, Louise Kim2 and Razi Zaidi1*©
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 [2-5], bone marrow
* Correspondence: razizaidi@doctors.net.uk
institute of Orthopaedics and MusculoskeletalScience, RoyalNational Orthopaedic Hospital(RNOH), Brockley HillStanmore, London HA7 4LP, UK Fulllist of author information is available at the end of the article
(3 BioMed Central
stimulation techniques [6-8], chondrocyte implantation [9-13], osteochondral autografts (mosaicplasty) [2, 14, 15], osteochondral allograft [16-18] 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 [6-8]. However, the resulting tissue has shown to be a mixed fibrocartilage tissue [20-22] with varying amounts of type II collagen [8, 21, 23, 24] and inferior to native hyaline cartilage. Fibrocartilage is
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vulnerable to shear stresses and prone to breaking down over time [20]. Subchondral osseous overgrowth has also been reported after microfracture [25, 26]. Osteochon-dral 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. Pluri-potent 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).
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.
Many published reviews on cartilage repair only list human clinical trials [13, 36-46], underestimating the wealth of basic sciences and animal studies that are precursors to future research and may be relevant in clinical
Table 1 Table describing the three main properties of stem cells Stem cellproperties
• They are unspecialized ("blank slates" that can become specific types of cells).
• They can develop into specialized celltypes (cells that do specific work in the body).
• They are capable of surviving over long periods and divide to make additional stem cells.
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 smallgroup 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 ClinicalTrials. 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 willallow 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.
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.
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].
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).
Growth factors The commonest used growth factors were TGF-P and the bone morphogenetic protein (BMP)
family. A list of growth factors used can be seen in Table 5.
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 x 106 cells/ scaffold, and found that scaffolds seeded with 5 x 106 cells per scaffold induced the highest chondrogenesis; however, other groups [51-53] 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 chondro-genesis 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.
Method of assessment A range of techniques was used to assess chondrogenesis within the in vitro studies. These techniques consisted of histology, immunohisto-chemistry, qPCR, biochemical analysis, imagery and mechanical testing. The techniques used are summarised in Table 7.
Animal studies (pre-clinical)
One hundred eleven animal studies were included of which 109 were controlled laboratory studies, one was a
Fig. 1 Flow chart of literature search used for the review
Table 3 Cell species and cell sources
Cellspecies No. of studies References Cell Source No. of studiesa References
Human 73 [48, 50, 52, 53, 168-236] Bone marrow 62 [48, 50-53, 164, 168, 170-173, 177-180, 182-185, 187, 188, 192, 195-197, 203, 206-210, 212, 216, 217, 219, 221, 223, 227, 230, 232-235, 237-255]
Rabbit 17 [240-242, 246, 249, 252, 255-265] Adipose 36 [66, 169, 175, 176, 181, 186, 189, 193, 194, 199, 201, 202, 211, 214, 216, 218-220, 224, 228, 229, 231, 235, 242, 256, 257, 260-269]
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] Commercialcellline 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
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.
Defect The size of the defect varied from 2 to 25 mm2 in the smaller animals and from 1 to 64 mm 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, 58-69], six (5%) used synovia [70-75] and three (2%) used periostium-derived MSCs [76-78]. Three studies (3%) used embryonic stem cell-derived MSCs [79-81] 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 chondroprogeni-tor 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 x 103 - 1 x 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, 89-97] used a mixture of solutions prepared from hyaluronic acid [65, 92, 94-97], 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).
Growth factors Thirty-two studies (29%) assessed the effect of growth factors on MSC chondrogenesis. Seventeen out of 38 (44%) used TGF-^1/3 (Table 10), the majority of which show a positive effect on chondrogenesis.
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, 100-102].
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 4 Types of scaffolds
Number of studies using types of scaffold
Natural Synthetic Hybrid
Scaffold
No. of studies
Types of scaffolds used Natural scaffolds Type I collagen hydrogel
Agarose hydrogel Alginate bead Fibrin hydrogel Silk fibroin
Chitosan microspheres Hyaluronic acid Cartilage-derived matrix K-carrageenan Chitosan
Hyaluronic acid hydrogel
Gelatin-based scaffold
Devitalised cartilage ECM
Bead in bead alginate polysaccharide capsules
Atelocollagen gel
Fibrin disk
Methacrylated hyaluronic acid Gelatin microspheres Decellularised cell matrix Collagen type I microspheres Alginate microbeads Alginate disks Platelet rich plasma
Free oligosaccharide chondroitin sulphate C Collagen type I sponge 3D printed chitosan Synthetic scaffolds Polycaprolactone PLGA
Polylactic acid
Poly-DL-lactide-co-glycolide
Polylactide-co-caprolactone
GFOGER modified PEG hydrogel
OPF hydrogel
Hybrid scaffolds
Fibrin-polurethane hydrogel
Esterified hyaluronan and gelatin polymer
TruFit CB (PLGA, calcium sulphate and polycolide)
Growth factor None combined used
References
[185, 190,211,226, 241, 251]
[53, 247, 248, 268]
[223, 231, 271]
[208,211,263]
[198, 216, 256]
[260, 262]
[195, 237]
[193, 238]
[169, 199]
[168, 216]
[164, 245]
[176, 233]
[197, 207, 209]
[194, 204, 257]
[230, 232]
[50, 188, 192, 267] [212, 255] [187]
Table 4 Types of scaffolds (Continued)
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-^1-loaded microspheres with chitosan 1 [262]
microspheres
TGF-^1 releasing chitosan-collagen hydrogel 1 [174]
PEOT/PBT TGF-P1 loaded scaffolds 1 [173]
TGF-^1-activated chitosan/gelatin 1 [249]
PLGA nanospheres with TGF-^1 1 [172]
TGF-^1 loaded Gelatin Microspheres 1 [175]
Human studies (clinical)
Thirty-one published studies by 15 different groups looked at clinical applications of MSCs. One used allo-genic stem cells [103] and the rest autologous stem cells. The types of studies can be seen in Tables 13 and 14.
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.
Defects The majority of studies (42%) used MSCs to treat knee osteoarthritis [103-115]. 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 [118-121], patella-femoral joints [122, 123], femoral condyle [113, 119-121, 123-132], trochlear [119-121] 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,
Table 5 Number of in vitro studies using different growth factors
Growth factor No. of studies (%) References Growth factor No. of studies (%) References
TGF-ß1 48 (44%) [50, 169-175, 189, 190, 192, 193, 195, 199, 202, 208, 210, 211, 213, 214, 216, 217, 220, 222-224, 228, 230-232, 234, 235, 244, 246, 249, 252-256, 258, 260-263, 266, 267, 270] SOX-5 1 (1%) [204]
TGF-ß3 32 (29%) [51, 162, 164, 168, 177, 181-184, 197, 200, 205-207, 218, 223-225, 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, 225-227, 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-ß2 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] TNFa 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]
1 (1%)
121-123, 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 [103-105, 109, 111-113, 115-118, 120, 122-128, 130-132]. Five studies (18%) used adipose-derived MSCs [106-108, 110, 114], two
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, 260-265]
2-3 weeks 36 [52, 53, 168, 169, 173, 175,179, 180, 183-186, 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]
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 [103-105, 107-113, 115, 118, 120, 122126, 129, 133], whereas 11 studies (39%) used fresh concentrated stem cells from bone marrow [116, 117, 127, 128, 130-132], 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, 130-132]. In studies using culture-expanded cells, the majority used cells from early passages, P1-P3 [103, 105, 109, 110, 112, 113, 115,
118, 120, 122-125, 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, 108-110, 112, 115,
119, 120, 122-125, 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
Table 7 Types of techniques used to assess chondrogenesis of MSCs
Type of techniques No. of studies (%) References
Histology 87 (79%) [48,50-53, 164, 168-170,173-175,177-179, 181-187,191 -195,197-201, 204-211, 213-217, 219-222, 226, 229, 230, 232-238, 240-248, 250, 252-264, 267-271]
Immunohistochemistry 78 (71%) [48, 50, 52, 53, 168-171, 173-175, 178-183, 185-191,193,194, 197, 198, 201, 203-205, 207, 212-215, 217, 218, 220, 221, 224, 226, 228-238, 241, 242, 244, 246-248, 250-259, 264, 265, 267-271]
qPCR 70 (64%) [53,168,169,173,174,176,178-186,188,190,192-194,196,199, 200, 202-205, 207-209,211,214,216-220, 222-232, 235, 236, 239, 240, 242, 246, 249-251, 256, 258, 259, 261-263, 265-267, 269-271]
Biochemicalanalysis 64 (58%) [48, 50-52,164,168,170-172,176,177,179,180,182-184,188,189,191, 192,197, 199, 200, 202, 204, 205, 209, 212, 214, 216-219, 222-224, 226, 227, 233-240, 244, 245, 247-249, 252, 254, 257, 260-266, 268-270]
Imaging (confocal, SEM, TEM) 24 (22%) [52,172, 176,180,185,187,194,198, 208, 215-217, 225, 226, 230, 232, 241, 242, 249, 252, 255, 262, 263, 265]
Mechanicaltesting 15 (14%) [51, 52, 164, 169, 175, 193, 197, 207, 220, 245, 247, 248, 256, 257, 268]
MSCs [103-105, 109, 111-113, 118, 120, 122-125, 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, 130-133], intra-articular injection [103-106, 109-112, 114, 115, 119, 121, 123] or open surgery (29%) [113, 118, 120, 122-126, 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.
Table 8 Different species of animals used to assess reparative effect of MSCs on cartilage defect
Animals No. of studies (%) References
Rabbits 57 (51%) [49,54-102,134,150-154,160,161, 207, 272-324]
Pigs 16 (14%) [61, 62, 68-72, 87, 90, 153, 273, 276, 279, 290, 308-310]
Rats 13 (12%) [60, 78-82,91, 152, 160, 278, 286,311,312]
Sheep 8 (7%) [89, 272, 282, 283, 313-316]
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]
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, 117-122, 124-127, 129131]. Six studies did not report details on postoperation rehabilitation [104-106, 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, 117-121, 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%) [103-106, 109-112, 115-117, 119, 121, 123-125, 127-134] and arthroscopic assessment (61%) [107, 108, 113, 116-122, 124-126, 130-133]. 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 mesen-chymal stem cells in cartilage repair.
As early as the 1950s, Pridie showed fibrocartilagi-nous repair through subchondral drilling [135-137]. Initially, Pridie drilling was reported as a treatment for osteoarthritis [135, 138] and was often associated
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, 72-75, 81, 86, 89-91, 97, 100, 102, 280-282, 284]
Poly (lactide-co-glycoside) PLGA 17 (16%) [56, 59, 62, 63, 83, 88, 150, 153, 160, 277, 285, 286, 289-292, 316]
Fibrin/Fribrin glue 11 (9%) [55, 64, 76-78, 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]
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
Table 10 Table showing growth factors used in animal studies
Growth factor No. of studies References
TGF-P3/1/2 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]
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, 54-102, 134, 150-154, 160, 161, 272-324]
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, 296-298, 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, 54-56, 58, 59, 61, 62, 64-69, 71-73, 75, 76, 78-89, 92, 95, 97, 98, 100, 101, 134, 150-152, 154, 160, 161, 273-280, 285-302, 304, 305, 307, 309, 310, 312, 314-324]
Collagen type II 84 (76%) [54, 56-59, 62, 65-73, 75-88, 90, 91, 93-96, 98, 100-102, 134, 150-154, 160, 161, 272-276, 278-282, 284-288, 292, 294-296, 300, 302-306, 308, 309, 31 1, 313-315, 317-319, 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, 67-71, 73-75, 81, 85, 87, 94, 96-101, 160, 272, 274, 279, 282, 286, 288, 290, 291, 296, 300, 301, 308, 309, 31 1, 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]
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 [143-146]. Dandy wrote an entertaining article on abrasion arthroplasty where he highlighted that at least in the treatment of osteo-arthritis, 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
Table 13 Number of publications for each study type and phase
Category No. of studies References
(total 28)
Phases of clinical studies
Pilot/feasibility study incl. case report 15 (54%) [104-108, 118, 119,
122, 124-129, 133]
Phase 1 (safety assessment) 8 (26%) [109-112, 116, 123,
130, 131]
Phase 2 (efficacy assessment) 8(26%) [103,113-115,117,
120, 121, 132]
Phase 3 (large scale efficacy assessment 0 (0%) -
through a multi-centre RCT)
Phase 4 (post-market surveillance) 0 (0%) -
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 transla-tional 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, 152-154], 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, 130-132], 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,
Table 14 Summary of the published clinical studies
Table 14 Summary of the published clinical studies (Continued)
Category No. of References Assessments
studies Radiology (MRI, X-ray) 24 (77%) [103-106,109-112,115-117, 119,121-125,127-133]
Cell source
Bone marrow 22 (71%) [103115130- 105, 18, 32] 109, 20, 111-113, 22-128, Arthroscopic assessment incl. histology 17 (54%) [107, 108, 113, 116-122, 124-126, 130-133]
Adipose 5 (16%) IKDC 10 (32%) [107, 108, 115, 121, 122,
[106- 108, 110, 114] 126, 128, 130-132]
Peripheral blood 2 (6%) [119, 121] VAS pain 12 (39%) [103-106, 109-112, 114,
Synovium 2 (6%) [129, 133] 129, 131, 132]
Cell delivery Tegner activity scale 8 (26%) [107, 108, 114, 115, 129,
131-133]
Arthroscopic implantation
Lysholm 6 (19%) [114,115,125,128,131,133]
Hyaluronic acid membrane 2 (6%) [117, 130]
KOOS 5 (16%) [126, 128-130, 132]
Hyaluronic acid with fibrin 2 (6%) [116, 128]
glue or platelet gel Function (no scoring systems 4 (13%) [104-106, 109]
or unspecified)
Polyglycolic acid/hyaluronan 2 (6%) [127, 131]
ICRS cartilage injury evaluation package Clinical symptoms/outcomes 3 (10%) [120, 123, 125]
Collagen with platelet gel 1 (3%) [116] 3 (10%) [105, 109, 124]
Fibrin glue 1 (3%) [108] (no scoring system or unspecified)
HYAFF 11 scaffold 1 (3%) [132] (Revised) Hospital for special 2 (6%) [113, 125]
Acetate Ringer solution 1 (3%) [133] surgery knee-rating scale
Unspecified 1 (3%) [107] Functional Rating Index 2 (6%) [104, 106]
Intra-articular injection WOMAC 5 (16%) [103, 109-112]
PBS only 2 (6%) [104, 110] AOFAS score 2 (6%) [112, 116, 117]
PBS with HA 2 (6%) [119, 121] Knee Society Score 1 (3%) [110]
Autologous serum 2 (6%) [115, 123] Harris Hip Score 1 (3%) [112]
Ringer lactate solution 3 (10%) [103, 111, 112] Concomitant procedures
PBS with serum albumin 1 (3%) [105] Subchondral bone marrow 11 (35%) [113,115,118,119,121-123,
stimulation (multiple perforation, 125,127,128,131]
HA and PRP 1 (3%) [106] drilling, abrasion chondroplasty)
PRP 1 (3%) [114] Debridement, synovectomy, excision 8 (26%) [107,108,114,116,117,
Commercial serum 1 (3%) [109] of degenerative tears (no subchondral 124,130,133]
bone marrow stimulation)
Transplantation by open surgery ACL reconstruction, meniscus 8 (26%) [115, 123, 126, 129-133]
Collagen 6 (21%) [103, 113, 118, 122, 124, repair, osteotomy, or patella
126, 29] alignment, ACL calcification
removal, trochlear resurfacing,
Ascorbic acid-mediated sheet 2 (7%) [120, 123] osteochondral fragment fixation
Fibrin glue 1 (4%) [125] None 6 (19%) [103, 105, 106, 110-112]
Cell dose Not specified 3 (10%) [104, 109, 120]
Less than 10 million 8 (26%) [105, 107, 108, 114, 120, Previous procedures
122, 24, 1 29]
Microfractures/multiple 6 (19%) [104,116,117,122,125,130]
10-20 million 5 (16%) [113, 118, 119, 123, 125] perforation/multiple drilling
Over 20 million 7 (23%) [103,104,109-1 12,133] Menisectomy 6 (19%) [103,111,124,129,131,133]
Unspecified 11 (35%) [106, 115- 117, 121, ACL reconstruction 4 (13%) [103, 1 1 1, 131, 133]
126- 28, 1 30- 32]
Multiple (microfracture, debridement) 1 (3%) [119]
Follow-up
ACI 2 (6%) [116, 117]
Up to 6 months 4 (13%) [104- 106, 110]
None 6 (19%) [106-108,110, 114,118]
Up to 12 months 6 (19%) [103,109,1 1,124,125,127]
Up to 2 years Up to 3 years Over 3 years
11 (35%) 7 (23%) 2 (6%)
[107, 113-116, 120, 121, 128-131]
[108, 112, 117, 119, 122, 126, 132]
[118, 133]
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
Cell source
Country
Autologous cells
Mesenchymal Stem Cells in Knee Cartilage Injuries Bone marrow
Adult Stem Cell Therapy for Repairing Articular Bone marrow Cartilage in Gonarthrose
Autologous Bone Marrow Mesenchymal Stem Bone marrow Cells Transplantation for Articular Cartilage Defects Repair
Mesenchymal Stem Cell for Osteonecrosis of the Bone marrow Femoral Head
The Effects of Intra-articular Injection of Bone marrow
Mesenchymal Stem Cells in Knee Joint
Osteoarthritis
Safety and Efficacy of Autologous Bone Marrow Bone marrow Stem Cells for Treating Osteoarthritis
Treatment of Knee Osteoarthritis by Intra-articular Bone marrow njection of Bone Marrow Mesenchymal Stem Cells
ntra-Articular Autologous Bone Marrow Bone marrow
Mesenchymal Stem Cells Transplantation to Treat Mild to Moderate Osteoarthritis
Treatment of Osteoarthritis by Intra-articular Bone marrow
njection of Bone Marrow Mesenchymal Stem Cells With Platelet Rich Plasma (CMM-PRGF/ART)
Mesenchymal Stem Cells Enhanced With PRP Bone marrow
Versus PRP In OA Knee (MSCPRPOAK)
Side Effects of Autologous Mesenchymal Stem Bone marrow Cell Transplantation in Ankle Joint Osteoarthritis
Human Autologous MSCs for the Treatment of Bone marrow Mid to Late Stage Knee OA
A Controlled Surveillance of the Osteoarthritic Bone marrow
Knee Microenvironment With Regenexx® SD
Treatment
The Effect of Platelet-rich Plasma in Patients With Bone marrow Osteoarthritis of the Knee
Outcomes Data of Bone Marrow Stem Cells to Bone marrow Treat Hip and Knee Osteoarthritis
Use of Autologous Bone Marrow Aspirate Bone marrow
Concentrate in Painful Knee Osteoarthritis (BMAC)
Jordan
China ran
ndia Spain Malaysia
ndia ran
Canada USA
ran USA USA
Autologous Stem Cells in Osteoarthritis
Bone marrow
Mexico
al Condition
Study design
Enrolment
Advanced knee articular cartilage injury
Gonarthrosis grade 2-3
Knee articular cartilage defects
Osteochondritis of the femoral head Knee joint osteoarthritis
Knee OA Kellgren and Lawrence classification 3-4
Knee OA
Mild to moderate OA based on Kellgren-Lawrence radiographic classification
Knee OA
Knee OA grade 1-2 Ahlbacks radiographic staging
Severe ankle OA
Mid- to late-stage knee OA
Knee OA Kellgren-Lawrence grade 2 or greater
Knee OA grade 2 and above (radiographic)
Hip and knee OA
Bilateral knee OA Kellgren-Lawrence grade 1-3
Knee OA Kellgren-Lawrence radiographic scale grade 2-3
Non-randomized parallel assignment; 13 double blind
Open label; single group assignment 15
Randomized parallel assignment; 10 double blind
Open label single group assignment 15
Single centre, randomised, placebo 40 controlled, double blind
Open label single group assignment; 10 multi-centre
Randomised parallel assignment; 30 open label
Randomised parallel assignment; 50 open label
Randomised parallel assignment; 38 open label; multi-centre
Randomised parallel assignment 24 double blinded
Single group assignment open label 6
Single group assignment, open label 12
Observational cohort study 20
Randomised, parallel assignment, 50 placebo controlled, double blinded
Observational cohort study 12
Randomised, parallel assignment, 25 placebo controlled, single blinded
Randomised parallel assignment, 61 open label
The Use of Autologous Bone Marrow Mesenchymal Bone marrow
Stem Cells in the Treatment of Articular Cartilage
Defects
Autologous Transplantation of Mesenchymal Stem Bone marrow
Cells (MSCs) and Scaffold in Full-thickness Articular
Cartilage
"One-step" Bone Marrow Mononuclear Cell Bone marrow
Transplantation in Talar Osteochondral Lesions
(BMDC)
Transplantation of Bone Marrow Stem Cells Bone marrow
Stimulated by Proteins Scaffold to Heal Defects Articular Cartilage of the Knee
NSTRUCT for Repair of Knee Cartilage Defects Bone marrow
HyaloFAST Trial for Repair of Articular Cartilage Bone marrow in the Knee (FastTRACK)
France
The Netherlands Not given Hungary Not given
Autologous Adipose Stem Cells and Platelet Rich Adipose
Plasma Therapy for Patients With Knee
Osteoarthritis
Effectiveness and Safety of Autologous ADRC for Adipose Treatment of Degenerative Damage of Knee Articular Cartilage
Autologous Adipose-Derived Stromal Cells Adipose
Delivered Intra-articularly in Patients With
Osteoarthritis
Mesenchymal Stem Cell Treatment for Primary Adipose Osteoarthritis Knee
Vietnam
Russia
Taiwan
Autologous Adipose Tissue-Derived Mesenchymal Adipose Progenitor Cells Therapy for Patients With Knee Osteoarthritis
Clinical Trial of Autologous Adipose Tissue-Derived Adipose Mesenchymal Progenitor Cells (MPCs) Therapy for Knee Osteoarthritis
Outcomes Data of Adipose Stem Cells to Treat Osteoarthritis
Clinical Trial to Evaluate Efficacy and Safety of JOINTSTEM in Patients With Degenerative Arthritis
ADIPOA-Clinica Study
Safety and Clinical Effectiveness of A3 SVF in Osteoarthritis
Adipose Adipose Adipose Adipose
USA Korea France USA
An isolated osteochondral defect with Single group assignment, open label 25 no more than grade 1 or 2 Outerbridge
Full-thickness chondral defects
ICRS grade 3-4 Osteochondral lesions of the talar dome
Knee OA ICRS classification grade 4
Knee articular cartilage defect Knee articular cartilage defect
Idiopathic or secondary knee OA grade 2-3 radiographic severity
Knee OA (degenerative damage of knee articular cartilage)
Bilateral primary OA Kellgren and Lawrence grade 2-3 as determined by X-ray
Knee OA
Knee OA
Knee OA Knee OA
Moderate or severe knee OA OA
Single group assignment, open label 6
Single group assignment, open label 140
Single group assignment, open label 50
Single group assignment, open label; 40 multi-centre
Randomised, parallel assignment, 200 placebo controlled, single blinded, multi-centre
non-randomised unblinded 16
Single group assignment, open label 12
Single group assignment, open label, 500 multi-centre
Single group assignment, open label, 10
Single group assignment, double 48 blinded
Randomised, parallel assignment, 48 placebo controlled, single blinded
Observational cohort study 50
Randomised parallel assignment, 120 double blinded
Non-randomised parallel assignment, 12 open label
Single group assignment, open label 30
Safety and Clinical Outcomes Study: SVF Adipose USA Not given
Deployment for Orthopaedic, Neurologic, Urologie, and Cardiopulmonary Conditions
Microfracture Versus Adipose-Derived Stem Cells for the Treatment of Articular Cartilage Defects
Autologous Mesenchymal Stem Cells vs. Chondrocytes for the Repair of Chondral Knee Defects (ASCROD)
A Phase 2 Study to Evaluate the Efficacy and Safety of JointStem in Treatment of Osteoarthritis
Allogenic cells
Treatment of Knee Osteoarthritis With Allogenic Mesenchymal Stem Cells (MSV_allo)
Clinical Trial of Allogenic Adipose Tissue-Derived Mesenchymal Progenitor Cells Therapy for Knee Osteoarthritis
Clinical Study of Umbilical Cord Tissue Mesenchymal Stem Cells (UC-MSC) for Treatment of Osteoarthritis
Safety and Feasibility Study of Mesenchymal Trophic Factor (MTF) for Treatment of Osteoarthritis
A Study to Assess Safety and Efficacy of Umbilica Cord-derived Mesenchymal Stromal Cells in Knee Osteoarthritis
Human Umbilical Cord Mesenchymal Stem Cell Transplantation in Articular Cartilage Defect
Evaluation of Safety and Exploratory Efficacy of CARTISTEM®, a Cell Therapy Product for Articular Cartilage Defects
Study to Compare the Efficacy and Safety of Cartistem® and Microfracture in Patients With Knee Articular Cartilage Injury or Defect
Follow-Up Study of CARTISTEM® vs. Microfracture for the Treatment of Knee Articular Cartilage Injury or Defect
njections of FloGraft Therapy, Autologous Stem Cells, or Platelet Rich Plasma for the Treatment of Degenerative Joint Pain
Adipose USA
Adipose Spain
Adipose
Bone marrow Spain
Adipose China
Umbilical Cord Panama
Umbilical Cord Panama
Umbilical Cord Chile
Umbilical Cord China
Umbilical cord blood Korea
Umbilical cord blood Korea
Umbilical cord blood Korea
Amniotic fluid USA
Neurodegenerative diseases, OA, erectile dysfunction, autoimmune diseases, cardiomyopathies or emphysema
Knee OA
Articular cartil; condyle
Single group assignment, open label 3000
Randomised, parallel assignment, double blind
1 lesion of the femoral
Randomised, parallel assignment, open label
Knee OA
Randomised, parallel assignment, double blinded
Knee OA grade 2-4 of Kellgren and Lawrence
Degenerative arthritis by radiographic criteria of Kellgren Lawrence
Randomised, parallel assignment, 30 double blinded
Randomised, parallel assignment, 18 double blind
Modified Kellgren-Lawrence classification grade 2-4 radiographic OA severity.
Modified Kellgren-Lawrence classification grade 2-4 radiographic OA severity.
Kellgren-Lawrence classification grade 1-3 radiographic OA severity
Randomised, parallel assignment, 40 open label
Non-Randomised, single group 40
assignment,
open label
Randomised, parallel assignment, 30 double blind
Kellgren-Lawrence classification Single group assignment, open label 20
grade 2-4 radiographic OA severity
Focal, full-thickness grade 3-4 articular Single group assignment, open label 12 cartilage defects
Knee Articular Cartilage Injury or Defect Randomised, parallel assignment, 104
open label
Knee articular cartilage injury or defect Randomised, parallel assignment, 103
open label
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
MPACT: Safety and Feasibility of a Single-stage Unspecified Procedure for Focal Cartilage Lesions of the Knee
Allogeneic Mesenchymal Stem Cells in Unspecified
Osteoarthritis
Allogeneic Mesenchymal Stem Cells for Unspecified
Osteoarthritis
Autologous or allogenic unspecified
Transplantation of Bone Marrow Derived Bone marrow
Mesenchymal Stem Cells in Affected Knee Osteoarthritis by Rheumatoid Arthritis
Safety and Efficacy Study of MSB-CAR001 in Unknown
Subjects 6 Weeks Post an Anterior Cruciate Ligament Reconstruction
The Netherlands ndia
Malaysia
Australia
Full-thickness articular cartilage lesion on the femoral condyle or trochlea
Kellgren and Lawrence classification grade 2-3 radiographic OA severity
Kellgren and Lawrence classification grade 2-3 OA
Single-group assignment, open label 35
Randomised, double blind, 60
multi-centre
Randomised, double blind, 72
multi-centre
Rheumatoid arthritis Randomised, parallel assignment, 60
open label
Anterior cruciate ligament injury Randomised, parallel assignment, 24
double blind
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 12 months Culture expanded MSCs
alone vs. MSC with platelet lysate
12 months Culture expanded MSCs (40 million cells)
Adult Stem Cell Therapy for Cartilage in Gonarthrose
ring Articular
Autologous Bone Marrow Mesenchymal Stem Cells Transplantation for Articular Cartilage Defects Repair
12 months MSCs (fresh or cultured unspecified)
Mesenchymal Stem Cell for Osteonecrosis of the 5 years Femoral Head
Culture expanded MSC and bone marrow nuclear cells
The Effects of Intra-articular Injection of Mesenchymal Stem Cells in Knee Joint Osteoarthritis
Safety and Efficacy of Autologous Bone Marrow Stem Cells for Treating Osteoarthritis
Treatment of Knee Osteoarthritis by Intra-articular njection of Bone Marrow Mesenchymal Stem Cells
ntra-Articular Autologous Bone Marrow Mesenchymal Stem Cells Transplantation to Treat Mild to Moderate Osteoarthritis
Treatment of Osteoarthritis by Intra-articular njection of Bone Marrow Mesenchymal Stem Cells With Platelet Rich Plasma (CMM-PRGF/ART)
3 months Culture-expanded MSCs vs. placebo
year MSCs (fresh or culture-expanded unspecified)
12 months Culture-expanded MSCs (10 million or 100 million cells) and hyaluronic acid (HyalOne®) vs. HyalOne®
12 months MSCs (fresh or culture-expanded unspecified) in hyaluronic acid "Orthovisc" vs. hyaluronic acid
12 months Culture-expanded MSCs with PRP (PRGF®) vs. PRGF® only
Mesenchymal Stem Cells Enhanced With PRP Versus PRP In OA Knee (MSCPRPOAK)
Side Effects of Autologous Mesenchymal Stem Cell Transplantation in Ankle Joint Osteoarthritis
6 months Culture-expanded MSCs (10 million cells) with autologous PRP vs. PRP only
6 months Culture-expanded MSCs
Intra-articular injection Therapeutic benefit
Articular injection
Feasibility/safety
Intra-articular injection Change in WOMAC
Infusion through medial Femoral head blood-supply femoral circumflex artery, artery angiographies;
lateral femoral circumflex femoral head necrosis artery and obturator
artery
Intra-articular injection
Unknown
Intra-articular injection
Intra-articular implantation
Intra-articular injection
njected by latera approach
Changes in WOMAC physical function and VAS pain
WOMAC pain score and safety
Pain and function (VAS, WOMAC, KOOS, EuroQol, SF-16, Lequesne), radiographic
Changes in cartilage thickness (MRI)
Pain and function (VAS, WOMAC, KOOS, EuroQol, SF-16, Lequesne), radiographic
VAS pain
Intra-articular injection Safety
Completed in August 2015; no publication found
Completed in January 2013; no publication found
Unknown (estimated study completion date; July 2014)
Unknown (estimated study completion date; August 2015)
Completed in November 2012; no publication found
On-going (estimated study completion date; January 2012)
On-going (estimated study completion date; February 2015)
Unknown (estimated study completion date; March 2014)
On-going (estimated study completion date; June 2017)
Unknown (estimated study completion date; June 2014)
Completed in September 2011; no publication found
NCT02118519
NCT01227694
NCT01895413
NCT00813267
NCT01504464
NCT01152125
NCT02123368
NCT01459640
NCT02365142
NCT01985633
NCT01436058
Human Autologous MSCs for the Treatment of Mid to Late Stage Knee OA
year Culture-expanded MSCs (1 million, 10 million or 50 million cells)
A Controlled Surveillance of the Osteoarthritic Knee Microenvironment With Regenexx® SD Treatment
6 weeks Regenexx® SD (bone marrow concentrate)
The Effect of Platelet-rich Plasma in Patients With 2 year Osteoarthritis of the Knee
Outcomes Data of Bone Marrow Stem Cells to Treat Hip and Knee Osteoarthritis
Bone marrow aspirate vs. placebo (saline)
Bone marrow concentrate
Use of Autologous Bone Marrow Aspirate Concentrate in Painful Knee Osteoarthritis (BMAC)
12 months Bone marrow concentrate vs. placebo (saline)
Autologous Stem Cells in Osteoarthritis
The Use of Autologous Bone Marrow Mesenchymal Stem Cells in the Treatment of Articular Cartilage Defects
6 months Hematopoietic stem cells (fresh) vs. acetaminophen (750 mg orally TID)
12 months Culture-expanded MSCs
Autologous Transplantation of Mesenchymal Stem Cells (MSCs) and Scaffold in Full-thickness Articular Cartilage
"One-step" Bone Marrow Mononuclear Cell Transplantation in Talar Osteochondral Lesions (BMDC)
Transplantation of Bone Marrow Stem Cells Stimulated by Proteins Scaffold to Heal Defects Articular Cartilage of the Knee
NSTRUCT for Repair of Knee Cartilage Defects
HyaloFAST Trial for Repair of Articular Cartilage in the Knee (FastTRACK)
12 months Culture-expanded MSCs mixed with collagen scaffold
24 months Bone marrow concentrate
1 year Freshly isolated bone marrow mononuclear cells mixed with protein scaffold
1 year INSTRUCT scaffold
(biodegradable scaffold seeded with autologous primary chondrocytes and bone marrow cells)
2 years Hyalofast® scaffold with
bone marrow aspirate concentrate vs. microfracture
njection
njection
ntra-articular injection njection
njection Infusion
Open surgery or arthroscopy
Unspecified
Arthroscopy
Arthroscopy (one step procedure)
Arthrotomy
One-step arthroscopic procedure
Safety
Temporal median change in protein concentration or percentage of cellular subpopulations
VAS pain, WOMAC physical activity, cartilage repair (MRI)
VAS pain, Harris Hip Score or Knee Society Score, Physician Global Assessment
Safety
Safety
On-going (estimated study completion date; February 2021)
On-going (estimated study completion date; March 2016)
Completed in April 2014; no publication found
Completed in March 2014; no publication found
On-going (estimated study completion date; December 2016)
Completed in May 2014; no publication found
Clinical scores and radiological images
Knee cartilage defects
American Orthopaedic Foot and Ankle Society hindfoot score
Unknown (estimated study completion date; December 2014)
Completed in December 2010; no publication found
On-going (estimated completion date; June 2016)
Unknown
(estimated completion date; December 2014))
Safety and lesion filling Completed in June 2014;
no publication found
Changes in KOOS On-going (estimated
study completion date; June 2020)
NCT02351011
NCT02370823
NCT02582489 NCT01601951
NCT01931007
NCT01485198 NCT00891501
NCT00850187 NCT02005861 NCT01159899
NCT01041885 NCT02659215
Autologous Adipose Stem Cells and Platelet Rich Plasma Therapy for Patients With Knee Osteoarthritis
Effectiveness and Safety of Autologous ADRC for Treatment of Degenerative Damage of Knee Articular Cartilage
Autologous Adipose-Derived Stromal Cells Delivered Intra-articularly in Patients With Osteoarthritis
12 months Stromal vascular fraction (10-50 million cells) and platelet rich plasma (PRP)
24 weeks Adipose-derived
regenerative cells (ADRC) extracted using Celution 800/CRS System (Cytori Therapeutics, Inc.)
6 months MSCs in PRP
njection
ntra-articular injection
ntra-articular injection
Mesenchymal Stem Cell Treatment for Primary Osteoarthritis Knee
12 months MSCs (8-10 million cells)
ntra-articular injections
Autologous Adipose Tissue-Derived Mesenchymal 6 months Fresh MSCs (10 million,
Progenitor Cells Therapy for Patients With Knee 20 million, 50 million
Osteoarthritis cells twice) vs. placebo
Clinical Trial of Autologous Adipose Tissue-Derived 12 months Culture-expanded MSCs
Mesenchymal Progenitor Cells (MPCs) Therapy vs. sodium hyaluronate for Knee Osteoarthritis
Outcomes Data of Adipose Stem Cells to Treat Osteoarthritis
12 months Cellular concentrate
ntra-articular injection
ntra-articular injection
Unknown
Clinical Trial to Evaluate Efficacy and Safety of 24 weeks MSCs (100 million cells) Injection
JOINTSTEM in Patients With Degenerative Arthritis vs. sodium chloride
ADIPOA-Clinica Study
Safety and Clinical Effectiveness of A3 SVF in Osteoarthritis
year MSCs (2 million,
10 million, 50 million cells)
year Stromal vascular fraction with activated platelet
ntra-articular injection
njection
Safety and Clinical Outcomes Study: SVF Deployment for Orthopaedic, Neurologic, Urologic, and Cardiopulmonary Conditions
36 months Stromal vascular fraction
ntra-venous, ¡ntra-articular, and soft tissue injection
Safety
Safety
Completed in December 2015; no publication found
On-going (estimated study completion date; December 2016)
NCT02142842
NCT02219113
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
Safety
WOMAC score
On-going (estimated study completion date; December 2016)
On-going (estimated study completion date; December 2016)
Completed in December 2013; no publication found
NCT01739504
NCT02544802
NCT01809769
KOOS, HOOS
Safety
Pain and inflammation-WOMAC scores, comprehensive inflammation blood panel
Safety
On-going (estimated study completion date; July 2016)
On-going (estimated study completion date; September 2017)
On-going (estimated study completion date; July 2017)
Completed in December 2014; no publication found
On-going (estimated study completion date; September 2015)
On-going (estimated study completion date; March 2018)
NCT02162693
NCT02241408
NCT02658344
NCT01585857
NCT01947348
NCT01953523
Microfracture Versus Adipose-Derived Stem Cells for the Treatment of Articular Cartilage Defects
Autologous Mesenchymal Stem Cells vs. Chondrocytes for the Repair of Chondral Knee Defects (ASCROD)
A Phase 2 Study to Evaluate the Efficacy and Safety of JointStem in Treatment of Osteoarthritis
24 months Fibrin glue + acellular
collagen dermal matrix + DSCs, + additional layer of fibrin glue vs. microfracture
18 months Cultured stem cells vs.
cultured autologous chondrocytes
6 months Joint stem adipose-derived (MSCs) vs. Synvisc-One (hyaluronic acid)
Arthroscopy
Unknown
Allogenic cells
Treatment of Knee Osteoarthritis With Allogenic Mesenchymal Stem Cells (MSV_allo)
Clinical Trial of Allogenic Adipose Tissue-Derived Mesenchymal Progenitor Cells Therapy for Knee Osteoarthritis
Clinical Study of Umbilical Cord Tissue Mesenchymal Stem Cells (UC-MSC) for Treatment of Osteoarthritis
Safety and Feasibility Study of Mesenchymal Trophic Factor (MTF) for Treatment of Osteoarthritis
A Study to Assess Safety and Efficacy of Umbilica Cord-derived Mesenchymal Stromal Cells in Knee Osteoarthritis
Human Umbilical Cord Mesenchymal Stem Cell Transplantation in Articular Cartilage Defect
1 years Culture-expanded MSCs (40 million cells) vs. hyaluronic acid
48 weeks 10 million MSCs vs.
20 million MSCs
12 months Single intra-articular injection of MSCs vs. IV injections of MSC for 3 days
12 months Intra-articular injection of allogeneic MTF from UC-MSC vs. 12 subcutaneous MTF injections, once per week
12 months MSCs (single dose of 20 million MSCs or double dose at 6 month interval) vs. hyaluronic acid
12 months 20 million cells every month for 4 months
Intra-articular transplantation
Intra-articular injection
Intra-articular injection; IV
Intra-articular injection; subcutaneous injection
Intra-articular injection
Intra-articular injection
Evaluation of Safety and Exploratory Efficacy of CARTISTEM®, a Cell Therapy Product for Articular Cartilage Defects
Study to Compare the Efficacy and Safety of Cartistem® and Microfracture in Patients With Knee Articular Cartilage Injury or Defect
12 months CARTISTEM® (cultured Unknown
UC MSCs mixed with sodium hyaluronate)
48 weeks CARTISTEM® (cultured Surgery
UC MSCs mixed with sodium hyaluronate) vs. Microfracture
KOOS On-going (estimated NCT02090140
study completion date; December 2020)
Hyaline cartilage production Unknown (estimated NCT01399749
for chondral knee lesions study completion date;
repair June 2012)
Cartilage volume, cartilage On-going (estimated NCT02674399
articular surface area, study completion date;
cartilage thickness, September 2017)
subchondral bone surface
curvature (MRI)
Completed in June 2014; NCT01586312 published in August 2015 (Linked to study NCT01183728)
On-going (estimated NCT02641860 study completion date; July 2017)
On-going (estimated study completion date; March 2017)
NCT02237846
On-going (estimated study completion date; June 2017)
NCT02003131
On-going (estimated study completion date; December 2016)
NCT02580695
CRS cartilage repair assessment
On-going (estimated study completion date; December 2016)
On-going (estimated study completion date; May 2017)
Completed in January 2011; no publication found
NCT02291926
NCT01733186
NCT01041001
Follow-Up Study of CARTISTEM® vs. Microfracture 60 months for the Treatment of Knee Articular Cartilage Injury or Defect
njections of FloGraft Therapy, Autologous Stem Cells, or Platelet Rich Plasma for the Treatment of Degenerative Joint Pain
MPACT: Safety and Feasibility of a Single-stage Procedure for Focal Cartilage Lesions of the Knee
Allogeneic Mesenchymal Stem Cells in Osteoarthritis
Allogeneic Mesenchymal Stem Cells for Osteoarthritis
Autologous or allogenic unspecified
Transplantation of Bone Marrow Derived Mesenchymal Stem Cells in Affected Knee Osteoarthritis by Rheumatoid Arthritis
Safety and Efficacy Study of MSB-CAR001 in Subjects 6 Weeks Post an Anterior Cruciate Ligament Reconstruction
24 weeks
CARTISTEM® (cultured Unknown
UC MSCs mixed with sodium hyaluronate) vs. microfracture
FloGraft™ (allogenic Injection
amniotic fluid-derived allograft) vs. autologous BMMSCs vs. platelet rich plasma
18 months Autologous chondrons (chondrocytes with their pericellular matrix) and allogeneic MSCs in the fibrin glue carrier
2 years Culture-expanded MSCs in 2 ml plasmalyte + 2 ml, hyaluronan vs. 2 ml, plasmalyte + 2 ml, hyaluronan
1 year Culture-expanded MSCs in 2 ml plasmalyte + 2 ml, hyaluronan vs. 2 ml, plasmalyte + 2 ml, hyaluronan
6 months MSCs vs. saline
IKDC, VAS pain, WOMAC
Unspecified (single stage Safety surgery)
ntra-articular
ntra-articular
Safety and tolerablllty
Safety and tolerablllty
ntra-articular injection Pain
2 year MSB-CAR001 (a preparation Injection of MSCs) with hyaluronan vs. hyaluronan alone
Safety
On-going (estimated NCT01626677 study completion date; May 2015)
On-going (estimated NCT01978639 study completion date; lune 2016)
On-going (Estimated Study Completion Date: August 2015)
Unknown (estimated study completion date; February 2013)
NCT02037204
Unknown (estimated NCT01453738 study completion date; July 2014
NCT01448434
Completed in December NCT01873625
2011; no publication
Unknown
NCT01088191
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 [155-157] 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 sub-chondral 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 allo-genic chondroprogenitor cells against controls in an equine model and reported inferior repair in the allo-genic 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 preclinical 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-|31 and TGF-|32 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 osteo-arthritic 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 assess -ment 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 transla-tional 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
Acknowledgements
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
Author details
11nstitute of Orthopaedics and Musculoskeletal Science, Royal National Orthopaedic Hospital (RNOH), Brockley Hill Stanmore, London HA7 4LP, UK. 2Joint Research and Enterprise Office, St George's University of London and St George's University Hospitals NHS Foundation Trust, Hunter Wing, Cranmer Terrace, London SW17 0RE, UK.
Received: 2 January 2017 Accepted: 13 February 2017 Published online: 09 March 2017
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