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58 (); 1-9
doi:
10.1016/j.jor.2024.06.026

Mesenchymal stem cells in orthopaedics: A systematic review of applications to practice

, ,
a Kerlan Jobe Orthopedic Clinic, 6801 Park Terrace, Suite 500, Los Angeles, CA, 90045, USA
b University of Missouri Department of Orthopaedic Surgery, Columbia, MO, USA

⁎Corresponding author: Ajith Malige. Ajith.malige@gmail.com

Received: , Accepted: ,
Professor P K Surendran Memorial Education Foundation
Disclaimer:
This article was originally published by Reed Elsevier India Pvt. Ltd. and was migrated to Scientific Scholar after the change of Publisher.

Abstract

Abstract

Mesenchymal stem cells (MSCs) have alluring interest for clinical use in orthopaedics based on their therapeutic potential through directed pluripotent differentiation. While many studies and reviews have discussed the importance of this approach, few have reduced it to practice using reproducible criteria. This study was designed to systematically review and synthesize current evidence regarding clinical use of clearly defined MSCs in orthopaedics.

Studies of any level of evidence and sample size, regardless of MSC source, orthopaedic pathology, and patient population, were reviewed. In vitro and animal studies, and articles written in a language other than English, were excluded. Studies were then screened for final inclusion based on documented MSC verification using testing of the therapeutic cellular population for at least one of the following phenotypic markers: CD 73, CD 90, and CD 105. In addition, therapeutic cellular populations could not have higher percentages of CD34, CD45, CD14, HLA-DR, CD11b, or CD19 markers compared to the aforementioned markers. From each studies’ results, sample size, procedural methods, radiographic outcomes, clinical outcomes, patient-report outcomes (PROs), and adverse events were tabulated.

Overall, 43 studies were included. Twenty-three studies (53.5 %) derived their MSCs from iliac crest bone marrow while 12 (27.9 %) studied adipose-derived MSCs. Included studies explored MSC use in Osteoarthritis, Cartilage Defects, Osteonecrosis, Bone Defects and Nonunions, Spine, and Other. MSC use in all pathologies led to improvement of studied radiographic, clinical, and patient-reported outcomes.

Mesenchymal stem cells have proven to have successful and safe uses in multiple orthopaedic applications, including treating chondral defects, osteoarthritis, and osteonecrosis. A stringent and reproducible process for evaluating obtained human stem cells using CD markers for clinical use is necessary to both evaluate previous studies and continue to evaluate for future uses.

Level V.

1

1 Introduction

Mesenchymal stem cells (MSCs) have alluring interest for clinical use in orthopaedics based on their therapeutic potential through directed pluripotent differentiation into functional osteoblasts, fibroblasts, chondrocytes, myoblasts, and adipocytes,1 their immunomodulatory, anti-apoptotic, and anti-inflammatory capabilities,2 and their beneficial trophic, synthetic, and microenvironmental effects.3 Because of this, they have possible use in numerous orthopaedic pathologies that have poor intrinsic healing capabilities. MSCs are also exciting for clinical use due to their presence in many different accessible tissue sources, including bone marrow, adipose tissue, synovium, and muscle.4 However, in addition to the regulatory, financial, and logistical barriers that limit their routine clinical use in orthopaedics,5 skepticism regarding their therapeutic efficacy also remains a valid deterrent. A major contributor to this healthy skepticism is the lack of a requirement for use of a standard definition and accurate terminology regarding “stem cells” in public, academic, and even regulatory applications.

The International Society for Cellular Therapy (ISCT) defines MSCs using the following criteria: 1) plastic-adherent when maintained under standard culture conditions, 2) express CD73, CD90, and CD105 markers and should not express CD34, CD45, CD14, HLA-DR, CD11b, or CD19, and 3) contain multilineage differentiation capabilities in vitro.6 Application of the ISCT definition to accurate use of the terminology regarding “stem cells” allows for optimal interpretation and application of best current evidence to clinical use of MSCs in orthopaedics.7 While many studies and reviews have discussed the importance of this approach, few have reduced it to practice using reproducible criteria.8–10 Therefore, this study was designed to systematically review and synthesize current evidence regarding clinical use of clearly defined MSCs in orthopaedics.

2

2 Methods

After ensuring that no duplicate systematic reviews have been published based on PROSPERO and PubMed searches, PubMed, Cochrane, and Embase databases were queried for relevant articles using PRISMA guidelines. Using the keywords (with no limits) “mesenchymal stem cells in orthopaedics” and “mesenchymal stem cells in orthopaedic surgery,” 26,782 related titles were identified and screened for inclusion. After review, 208 duplicates were removed. Studies of any level of evidence and sample size, regardless of MSC source, orthopaedic pathology, and patient population (including pediatric and adult patients), were considered eligible for initial review. Studies were then screened for final inclusion based on documented MSC verification using testing of the therapeutic cellular population for at least one of the following phenotypic markers: CD 73, CD 90, and CD 105. In addition, therapeutic cellular populations could not have higher percentages of CD34, CD45, CD14, HLA-DR, CD11b, or CD19 markers compared to the aforementioned markers for studies to be included for systematic review. In vitro and animal studies, and articles written in a language other than English, were excluded.

Each included study was analyzed for country, year of completion, cell source, tested biomarkers, and orthopaedic indication treated. From each studies’ results, sample size, procedural methods, radiographic outcomes, clinical outcomes, patient-report outcomes (PROs), and adverse events were tabulated. A bias assessment was performed11,12; however, each study was included in our study regardless of bias and reported equally.

3

3 Results

3.1

3.1 Study demographics

After databases searches, screening, and assessment by 3 reviewers, 43 studies met criteria for inclusion in this systematic review (Fig. 1). Fourteen studies (32.6 %) were randomized controlled trials, 24 (55.8 %) were prospective observational studies or case series, and 5 (11.6 %) were case reports. Two studies (4.7 %) were completed in North America, 1 (2.3 %) in South America, 15 (34.9 %) in Europe, 17 (39.5 %) in Asia, 6 (14.0 %) in Australia, and 1 (2.3 %) in multiple countries. All of the included studies were published between 2011 and 2022, with 20 (46.5 %) being published within the past five years. Twenty-three studies (53.5 %) derived their MSCs from iliac crest bone marrow while 12 (27.9 %) studied adipose-derived MSCs (Table 1). Synthesis of the literature allowed for categorization of the included studies based on therapeutic indications including Osteoarthritis, Cartilage Defects, Osteonecrosis, Bone Defects and Nonunions, Spine, and Other. The major concern for bias involved the relative paucity of randomized controlled trials (RCTs) available for inclusion (Fig. 2). Only approximately one-third of included studies were RCTs. In addition, many of the studies did not adequately control for confounding variables; follow up durations were short (≤2 years); and detection bias was prominent. However, attrition bias, performance bias, and publication bias were minimal.

Results of systematic review.
Fig. 1 Results of systematic review.
Table 1 Study demographics. MSC = Mesenchymal stem cell. RCT = Randomized controlled trial; PT/CS=Prospective trial/case series; CR=Case report; AC=Acromioclavicular; OCD=Osteochondral defect.
First Author Study Type Country of Study Completion Study Year MSC Source Orthopaedic Pathology
Akgun26 RCT Turkey 2015 Knee Synovium Chondral Defect
Al-Najar13 PT/CS Jordan 2017 Iliac Crest Knee Osteoarthritis
Aoyama34 PT/CS Japan 2019 Iliac Crest Osteonecrosis
Bastos18 RCT Portugal 2019 Iliac Crest Knee Osteoarthritis
Bastos17 RCT Portugal 2016 Iliac Crest Knee Osteoarthritis
Chen35 PT/CS China 2016 Umbilical Cord Osteonecrosis
De Windt29 PT/CS United States of America 2017 Allogenic Bone Marrow Chondral Defect
Dilogo38 CS Indonesia 2019 Iliac Crest Bony Defect
Emadedin42 PT/CS Iran 2016 Iliac Crest Nonunion
Freitag22 PT/CS Australia 2019 Abdominal Fat Knee Osteoarthritis
Freitag27 CR Australia 2020 Abdominal Fat Chondral Defect
Freitag23 CR Australia 2020 Abdominal Fat Knee Osteoarthritis
Freitag52 PT/CS Australia 2020 Abdominal Fat Elbow Tendinopathy
Freitag51 CR Australia 2019 Abdominal Fat AC Joint Osteoarthritis
Freitag53 CR Australia 2020 Abdominal Fat Ankle OCD
de Frutos50 RCT Spain 2020 Iliac Crest Axial Skeleton
Götherström54 CR Sweden, Singapore, Canada 2014 Fetal Livers Osteogenesis Imperfecta
Hart49 RCT Czech Republic 2013 Iliac Crest Axial Skeleton
Hashimoto31 RCT Japan 2019 Iliac Crest Chondral Defect
Hernigou24 RCT France 2021 Iliac Crest Knee Osteoarthritis
Hernigou37 RCT France 2018 Iliac Crest Osteonecrosis
Jo14 PT/CS Korea 2014 Abdominal Fat Knee Osteoarthritis
Koh32 PT/CS Korea 2015 Buttock Fat Chondral Defect
Kumar45 PT/CS Korea 2017 Abdominal Fat Axial Skeleton
Labibzadeh43 PT/CS Iran 2016 Iliac Crest Nonunion
Lamo-Espinosa19 RCT Spain 2020 Iliac Crest Knee Osteoarthritis
Lamo-Espinosa20 RCT Spain 2016 Iliac Crest Knee Osteoarthritis
Lee33 PT/CS Singapore 2012 Iliac Crest Chondral Defect
Liebergall44 PT/CS Israel 2013 Iliac Crest Nonunion
Matas25 RCT Chile 2018 Umbilical Cord Knee Osteoarthritis
Orozco46 PT/CS Spain 2011 Unknown Bone Marrow Axial Skeleton
Papadimitriou48 PT/CS Sweden 2022 Iliac Crest Axial Skeleton
Pers15 PT/CS France 2016 Adipose Aliquots Knee Osteoarthritis
Petri39 PT/CS Germany 2013 Iliac Crest Bony Defect
Pettine47 PT/CS United States of America 2014 Iliac Crest Axial Skeleton
Roato16 PT/CS Italy 2018 Abdominal Fat Knee Osteoarthritis
Šponer40 PT/CS Czech Republic 2016 Iliac Crest Bony Defect
Šponer41 PT/CS Czech Republic 2018 Iliac Crest Bony Defect
Turajane21 RCT Thailand 2017 Peripheral Blood Knee Osteoarthritis
Wong30 RCT Singapore 2013 Iliac Crest Chondral Defect
Zhao36 PT/CS China 2015 Iliac Crest Osteonecrosis
Zhou28 RCT China 2021 Infrapatellar Fat Pad Chondral Defect
Articlebias insystematicreview. Green=No Bias and Red=Bias. Bias determined by multiple authors.
Fig. 2 Articlebias insystematicreview. Green=No Bias and Red=Bias. Bias determined by multiple authors.
3.2

3.2 Osteoarthritis

The most commonly reported use for MSCs in orthopaedics has been for symptomatic treatment of osteoarthritis (Table 3). Four studies looked at the effect of injecting MSC in isolation into knees to treat osteoarthritis. Al-Najar et al. found that their injections improved knee cartilage thickness,13 Jo et al. found that their injections increased cartilage volume and decreased cartilage defect size (depth remained the same),14 Pers et al. found that their adipose-derived MSCs did not improve imaging appearance of their pathology,15 and Roato et al. found that their adipose-derived MSC injections resulted in new tissue formation while only 2/18 (11.1 %) of patients needed an eventual TKA.16 All four studies found improvements in their tested clinical and patient-reported outcomes.

Three studies explored the effect of MSCs with platelet rich plasma (PRP) in the treatment of osteoarthritis. Bastos et al. first compared MSC injections with or without PRP17 and then compared MSC, MSC with PRP, and corticosteroid injections.18 They found improvement in clinical and PROs in both studies (even though the second study showed no improvement in knee range of motion). Lamo-Espinosa et al. also compared bone marrow-derived MSC to MSC plus PRP, finding similar improvements in clinical and PROs.19 However, only patients who received MSC plus PRP could be classified as treatment responders (improvement greater than 20 percent on at least 2 items evaluated at 12 months and a difference greater than 10 points overall).

Two studies compared MSC use with hyaluronic acid (Turajane et al. compared MSC, PRP, HA, and colony stimulating factor vs. MSC, PRP, and HA vs. HA).20,21 MSC resulted in a halt in osteoarthritis progression leading to improved PROs and a decreased rate of needed arthroplasty. Freitag et al. performed two studies involving MSC use with abrasion arthroplasty (one case report involving a high tibial osteotomy22 and a case series23). They reported improved Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) scores in their patients, while both studies reported improved clinical and patient-reported outcomes.

Hernigou et al. explore the best location for injection of MSCs (subchondral bone versus intra-articular).24 The subchondral injection group had less progression in Kellgren and Lawrence (KL) grade, and regression in bone marrow lesion size that led to improved PROs and a lower yearly arthroplasty incidence (1.3 % vs. 4.6 % per knee-year). Finally, Matas et al. compared single dose MSC to double dose MSC or hyaluronic acid injections for osteoarthritis.25 Even though they found similar changes in Whole-Organ Magnetic Resonance Imaging Score (WORMS) on MRI between groups, double dose MSC had higher VAS and WOMAC (total and pain) improvements.

When comparing different doses of MSC, Jo et al. noted that the high-dose group (1.0 × 108 cells) showed the most improvement in cartilage defect size, cartilage volume, and PROs when compared to low-dose (1.0 × 107 cells) and mid-dose (5.0 × 107 cells) MSC concentrations.14 Surprisingly, Pers et al. found the opposite result,15 noting that only their low-dose MSC group had significant improvements in clinical outcomes compared to medium-dose (10 × 106) and high-dose (50 × 106) MSC concentration groups. While low-dose (10 × 106) and high-dose (100 × 106) MSC groups both had improvements in outcomes in Lamo-Espinosa et al.’s study, the improvements were only sustained at 1 year in the high dose group.20

3.3

3.3 Cartilage Defects

For cartilage defects, MSC use has been aimed at functional tissue repair that mitigates symptoms, halts progression of local damage, and minimizes the need for early joint replacement (Table 2). Akgun et al. studied the efficacy of MSCs derived from knee synovia in the treatment of chondral lesions,26 finding improved functional and PROs after MSC treatment compared to chondral implantation. Freitag et al. also found improvements in radiographic and PROs after using adipose-derived MSCs to treat knee chondral defects (both medial and lateral compartment lesions),27 while Zhou et al. also found similar improvements after using fat pad-derived MSCs in the treatment of knee chondral defects.28

Table 2 Mesenchymal stem cell use in chondral defects. VAS=Visual analog scale; KOOS=Knee injury and osteoarthritis outcome score; NPRS=Numerical pain rating scale; WOMAC=Western ontario and McMaster universities arthritis index; MOCART = magnetic resonance observation of cartilage repair tissue; IKDC= international knee documentation committee.
First Author # of Patients Operative or Non-Operative Stem Cells (CD Factors) Radiographic Outcomes ClinicalOutcomes Patient Reported Outcomes
Akgun26 14 Operative 73, 90, and 105 No graft failures and good-to-excellent graft infill Improved motion deficit and straight leg raise strength Improved VAS and KOOS scores
De Windt29 35 Operative 73, 90, and 105 Complete filling of the defect, integration with the host tissue, and attachment to the subchondral bone at 12 months with high concentration of proteoglycans and type II collagen Improved VAS scores Improved KOOS scores
Freitag27 Operative 73, 90, and 105 Modified ICRS score assessment showed improvement from Grade IV to Grade 0 or 1 in all participants Improved NPRS score Improved WOMAC and KOOS scores
Wong30 56 Operative 73, 90, and 105 Better MOCART scores – Improved Tegner, Lysholm, and IKDC scores
Zhou28 60 Operative 90 and 105 Better MOCART scores – Improved total WOMAC, WOMAC function, VAS rest, and VAS motion scores (WOMAC stiffness scores were similar)
Hashimoto31 11 Operative 105 Improved cartilage coverage, border zone integration, and improved mean MOCART score – Similar KOOS and IKDC scores
Koh32 80 Operative 90 and 105 Higher percentage of lesions that exhibited normal of nearly normal repair tissue intensity as well as percentage coverage Improved VAS score Improved KOOS pain and symptom-subscore, similar activity, sports, and quality-of-life subscores
Lee33 70 Operative 90 and 105 Defect filling and reduction in bone marrow edema in the arthroscopic group Similar VAS scores Similar SF-36 physical component score. Arthroscopic group had better mean IKDC and Lysholm score improvements

De Windt et al. studied the role of allogenic MSCs combined with recycled autologous chondrocytes in the role of treating chondral defects (medial femoral condyle [n = 17], lateral femoral condyle [n = 12], and trochlea [n = 6]).29 They found complete filling of the defect, integration with the host tissue, and attachment to the subchondral bone at 12 months with high concentration of proteoglycans and type II collagen in the MSC group that led to improved PROs. Wong et al. reported on outcomes after injecting bone marrow-derived MSC in varus knees with cartilage defects undergoing high tibial osteotomy and microfracture.30 The MSC group achieved significantly better improved mean MOCART scores at 1 year leading to improved clinical outcomes and PROs.Table 3

Table 3 Mesenchymal Stem Cell Use in Osteoarthritis. VAS=Visual Analog Scale; KOOS=Knee Injury and Osteoarthritis Outcome Score; KSS=Knee Society Score; WOMAC=Western Ontario and McMaster Universities Arthritis Index; SAS, Short Arthritis Assessment Scale; SF-36, short-form 36 (quality of life); WORMS=Whole-Organ Magnetic Resonance Imaging Score; KL=Kellgren and Lawrence; NPRS=Numerical Pain Rating Scale; ICRS = international Cartilage Repair Society; MOCART = Magnetic Resonance Observation of Cartilage Repair Tissue.
First Author # of Patients Operative or Non-Operative Stem Cells (CD Factors) Radiographic Outcomes ClinicalOutcomes Patient Reported Outcomes
Al-Najar13 13 Non-operative 73, 90, and 105 Improved femoral and tibial cartilage thickness – Improved KOOS scores
Jo14 18 Operative 73 and 90 Cartilage defect size decrease and cartilage volume increase. Cartilage depth the same Improved VAS scores Improved WOMAC and KSS scores
Pers15 18 Operative 73, 90, and 105 No changes Improved VAS scores while only 1 needed a TKA Improved WOMAC, KOOS, SAS, and SF-36 scores
Roato16 18 Operative 73, 90, and 105 Evidence of new tissue formation Improved VAS scores, and 2 patients needed TKA Improved WOMAC scores
Bastos17 18 Non-operative 73 and 90 – – Similar KOOS improvement
Bastos18 47 Non-operative 73 and 90 – No difference in final knee hyperextension, flexion, and total flexion Higher KOOS Improvement
Lamo-Espinosa19 32 Non-operative 73 and 90 No changes Similar VAS improvements Similar WOMAC improvements
Lamo-Espinosa20 30 Non-operative 73 and 90 Halt in progression on joint space loss on radiographs and improved WORMS score on MRI Improved VAS scores Higher WOMAC improvement
Turajane21 60 Operative 105 0 vs 15 % needing TKA Higher WOMAC improvement
Freitag22 1 Operative 73, 90, and 105 Modified ICRS improvement Higher NPRS improvement Higher WOMAC improvement
Freitag23 27 Operative 73, 90, and 105 Improved MOCART score Improved NPRS scores and 92.5 % satisfaction rate Improved WOMAC and KOOS scores
Hernigou24 120 Operative 73, 90, and 105 subchondral injection group had less progression in KL grade, regression in bone marrow lesion size and synovitis volume, and cartilage volume increase Subchondral injection group had higher VAS improvements and yearly arthroplasty incidence Subchondral injection group had higher KSS improvements
Matas25 29 Non-operative 73, 90, and 105 Similar WORMS score Double dose MSC had higher VAS improvements Double dose MSC had higher WOMAC (total and pain) improvements

Multiple studies explored the role of MSCs when used with microfracture procedures. Hashimoto et al. compared microfracture with microfracture combined with injection of bone marrow-derived MSCs.31 Koh et al. also studied the effect of microfracture alone versus adipose-derived MSC with microfracture,32 and Lee et al. compared the use of arthroscopic microfracture with MSC and HA injections versus an open procedure using a sutured periosteal patch with MSCs embedded underneath it.33 The first two studies detailed improved lesion repair leading to better PROs after MSC use, while Lee et al. noted improvements after both their arthroscopic and open techniques. Finally, when comparing different doses of MSC, de Windt et al. found no difference in KOOS and VAS pain scores between the standard yield 10:90 MSC to chondron ratio) and high yield groups (20:80 ratio).29

3.4

3.4 Osteonecrosis

MSC use in osteonecrosis has centered on improving local blood flow and enhancing bone repair and regeneration (Table 4). Aoyama et al. explored the use of MSC augmented with vascularized iliac bone grafts to treat idiopathic osteonecrosis of the femoral head.34 Chen et al. then studied the efficacy of umbilical cord-derived MSC in the treatment of femoral head osteonecrosis.35 Zhao et al. then studied the use of MSC with tantalum rod insertion and vascularized iliac bone grafting in the treatment of femoral head osteonecrosis.36 Finally, Hernigou et al. studied the efficacy of MSCs compared to decompression in the treatment of osteonecrosis in a large randomized controlled trial.37 All four studies detailed an improvement in necrotic lesion volume (improved lesion repair) or high rates of joint preservation success (halting of the osteonecrotic pathologic process).

Table 4 Mesenchymal stem cell use in osteonecrosis. ARCO= association research circulation osseous; JOA = Japanese orthopaedic association; ODI=Oxygen delivery index. THA = Total hip arthroplasty.
First Author # of Patients Operative or Non-Operative Stem Cells (CD Factors) Radiographic Outcomes ClinicalOutcomes Patient Reported Outcomes
Aoyama34 9 Operative 73, 90, and 105 Improvement in bony volume and 7/9 patients stayed in ARCO Stage 3 – Improved JOA Scores
Chen35 9 Operative 90 Decreased necrotic volume and improved ODI – –
Zhao36 31 Operative 105 Joint-preserving success rate of the entire group was 89.47 % for ARCO stage IIIc and 75 % for ARCO stage IV Significantly improved Harris hip score in 31 hips and only 5 (16.1 %) hips that needed THA. –
Hernigou37 125 Operative 73, 90, and 105 Improved necrotic lesion repair and larger amount of red marrow, bone formation, and blood vessels Improved VAS scores, decreased number of hips that progressed to collapse, number of hips that needed primary total hip arthroplasty, revision arthroplasty, and re-revision arthroplasty Improved Harris hip scores
3.5

3.5 Bone Defects and Nonunions

MSCs have been used to treat bone defects and nonunions by beneficially altering the micro-environment to foster osteogenesis (Table 5). Dilogo et al. studied the efficacy of MSCs when combined with bone morphogenic protein-2, hydroxyapatite, and internal fixation to treat bony defects,38 while Petri et al. studied the use of MSC derived from bone marrow aspirate concentrate (BMAC) seeded onto a bovine xenogenous scaffold.39 They both found improvement in bony healing (decrease in defect size and improved cortical bone density, respectively) that led to improved outcomes. Šponer et al. performed two studies looking at treating femoral bony defects, first looking at the use of β-Tricalcium Phosphate Scaffold with and without MSC,40 and second, by adding cancellous allograft to the control group from above .41 Both showed improved trabecular remodeling and incorporation (the first study also showed decreased radiolucency and re-revision rates since their defects were addressed during revision total hip arthroplasty), but only the second had improved cortical defect healing that led to improved pain and Harris hip scores.

Table 5 Mesenchymal stem cell use in bony defects and nonunions. VAS=Visual analog scale; LEFS = lower extremity functional scale; DASH = disabilities of the arm, shoulder, and hand; SF-12 = Short Form-12.
First Author # of Patients Operative or Non-Operative Stem Cells (CD Factors) Radiographic Outcomes Clinical Outcomes Patient Reported Outcomes
Dilogo38 6 Operative 73 and 105 Improved Tiedemann score and decreased defect size Improved VAS score Improved LEFS, and DASH scores
Petri39 5 Operative 73, 90, and 105 Increased fluoride uptake and cortical bone density 75 % of contralateral side Full weight bearing by 11.3 weeks –
Šponer40 18 Operative 73, 90, and 105 Improved trabecular remodeling and decreased radiolucency Similar pain scores, 0 re-revisions Similar Harris hip scores
Šponer41 37 Operative 73, 90, and 105 Improved trabecular incorporation and remodeling and cortical bony repair Improved pain scores Improved Harris hip scores
Emadedin42 5 Non-operative 73, 90, and 105 60 % of patients achieved union 60 % of patients achieved union –
Labibzadeh43 7 Non-operative 73,90 and 105 57.1 % of patients achieved union 57.1 % of patients achieved union –
Liebergall44 24 Operative 105 Decrease in fusion time Eventual union in all fractures and similar improvements in VAS Similar improvements in SF-12

Emadedin et al. performed a prospective trial, percutaneously introducing bone marrow derived MSC into sites of long bone atrophic nonunion.42 They found that 60 % of their patients went on to radiographic and clinical union, while one femur and one tibial nonunion did not. Labibzadeh et al. found a similar rate of union when they combined MSC with platelet lysate product when treating long bone nonunions.43 Finally, Liebergall et al. found that a combination of MSC, platelet-rich plasma (PRP), and demineralized bone matrix (DBM) helped shorten time to union by 1.5 months in distal tibia fractures.44

3.6

3.6 Spine

MSC use in the spine has been studied for non-operative and operative indications (Table 6). Three studies looking at the non-operative treatment of spinal pathology45–47 noted improvements in radiographic findings (halt in loss of disc height, improved disc water content, and improved modified Pfirrmann grades, respectively) that led to improved clinical outcomes. Papadimitriou was the only study that published negative results on MSC use in the treatment of non-operative low back pain.48 They reported on MSC use for patients scheduled for surgical intervention for their low back pain. No statistically significant improvement was seen for PROMs on a group level up to 2 years post-injection. Three of 10 patients opted to proceed with the initially planned surgery within the first year and 2 more within 3 years post-injection. The efficacy of MSC in improving spine fusion rates when used with allograft has also yielded positive results, with both studies noting an improvement in fusion rates.49,50

Table 6 Mesenchymal Stem Cell Use in Axial Skeleton Pathology. VAS=Visual Analog Scale; SF-36 = Short Form 36; EQ-5D = European quality of life-5; NRS = numerical rating scale.
First Author # of Patients Operative or Non-Operative Stem Cells (CD Factors) Radiographic Outcomes Clinical Outcomes Patient Reported Outcomes
Kumar45 10 Non-operative 73 No decrease in disc height VAS showed improvement ODI showed improvement
Orozco46 10 Non-operative 90 and 105 No change in disc height but increase in disc water content Improved pain, disability, and VAS Improved SF-36 Physical and ODI
Pettine47 26 Non-operative 90 and 105 1 modified Pfirrmann grade improvement Improved pain and VAS scores Improved ODI scores
Papadimitriou48 10 Non-operative 90 and 105 – 50 % underwent surgery within 3 years, NRS showed no improvement EQ-5D, NRS, and ODI showed no improvement
Hart49 80 Operative 90 and 105 Higher fusion rate in allograft + MSC vs. allograft – –
Garcia de Frutos50 65 Operative 73, 90, and 105 Higher fusion rate in allograft + MSC vs. autograft Similar VAS improvements between groups Similar ODI and SF-36 improvements between groups

When comparing different doses of MSC use, Kumar et al. found no difference in VAS or ODI scores between patients receiving a low dose of MSC (2 × 107 cells/disc) and those receiving a high dose (4 × 107 cells/disc).45 However, Pettine et al. found the opposite in their study exploring lumbar discogenic pain.47 They noted that patients greater than 40 years of age receiving greater than 2000 CFU-F/ml of bone marrow aspirate containing MSCs had improved VAS and ODI scores than those patients receiving less than that.

3.7

3.7 Other

Freitag et al. published multiple case reports on the use of MSCs in the treatment of various pathologies (Supplemental File 1). They explored the effect of using adipose-derived MSCs in treating acromioclavicular (AC) joint arthritis,51 an elbow extensor tendinopathy,52 and an ankle osteochondral lesion.53 They found improved clinical outcomes in all three patients (the patient with ankle pathology still had severe functional limitation), while their patient with AC joint arthritis also had improved imaging findings. Finally, Götherström et al. transplanted MSCs from fetal livers in two infants with osteogenesis imperfecta (one got two infusions).54 They found that MSC infusion resulted in bone low-level engraftment and improved linear growth, mobility, and fracture incidence.

3.8

3.8 Adverse events

Adverse events in this review were mostly minor and unrelated to MSC use (Supplemental File 2). Pain, swelling, and effusion were the most commonly cited adverse events, while studies involving spinal procedures also commonly had wound dehiscence or superficial infections. Most adverse events were self-limiting with or without medication use. Overall rates of adverse events ranged from 0 to 100 % (83.3 % in non-case reports).

4

4 Discussion

In order to more accurately delineate the effects of MSCs for treatment of orthopaedic disorders, we conducted this systematic review using International Society for Cellular Therapy (ISCT) criteria for study inclusion.6 In an attempt to balance comprehensive review of the literature with accurate use of the terminology regarding “stem cells” and allow for optimal interpretation and application of best current evidence to clinical use of MSCs in orthopaedics, articles were included only with documented MSC verification using testing of the therapeutic cellular population for at least one of the following phenotypic markers: CD 73, CD 90, and CD 105. This more stringent approach has been recommended and produced unique results when compared to previous systematic reviews focused on MSC use in orthopaedics.8,55

Our results support the use of “true MSCs” for safe and effective symptomatic and/or adjunctive treatment of isolated chondral defects, knee osteoarthritis, osteonecrosis, bony defects, long bone nonunion, and spinal fusion.56–58 However, this systematic review did not provide evidence for stand-alone treatment using MSCs (or the appropriate MSC dosage) for the orthopaedic disorders studied. In addition, differences in patient populations, pathology severity, previous and concurrent treatments, comparison cohorts and controls, outcome measures, and study durations limited pooling, comparative effectiveness, and meta-analyses. Furthermore, many studies do not appropriately control for pathology-specific confounding factors for successful results, making results difficult to interpret. This includes meniscal injuries or other chondral lesions in studies treating chondral defects and osteoarthritis. Body mass index (BMI) should be controlled for in all chondral defects and osteoarthritis studies, while smoking should be controlled for in bony defect,59 nonunion, and spinal fusion studies. As such, the available evidence did not allow for conclusions regarding patient selection, MSC source and preparation methods, dose effects, or duration of effects.

It would also not be accurate to pool or compare results from difference MSC sources. However, posterior iliac crest bone marrow has been shown to be the most fruitful source of MSCs.60 Furthermore, because only two studies used allogenic sources of MSCs,29,54 a comparison between allogenic and autogenic sources could not be completed. However, it would be interesting to compare the safety and efficacy of both uses in the future, as allogenic sources could potentially decrease the increased morbidity associated with the additional procedure.

Overall, most studies do a good job at specifically detailing their adverse events as well as their connection to their studied MSC treatments. This review does point to the overall safety of MSC use in multiple pathologies, as total adverse event percentage (0–100 % overall and 83.3 % in non-case reports), and specifically those associated with direct MSC use, is low. There were very few serious adverse events (including 2 deaths), all of which were not directly associated with MSC use, while all MSC-related adverse events were presumed and not directly proven to be secondary to MSC utilization procedures. Pain, swelling, and effusion were the most commonly reported adverse events.

Limitations of this study stem from the limitations of each individual study. Every study used different rehabilitation protocols, which could affect post-operative outcomes (especially in post-operative settings). Each specific pathology included patients at different corresponding stages of pathology severity (both intra and inter-study variability existed), making pooling results together difficult. The stringent inclusion criteria of this review led to a lack of inclusion of any articles exploring rotator cuff healing, a major area of MSC use and exploration. Additionally, there are a wide variety of clinical and patient reported outcomes used to define treatment success in this review. While most studies point to the successful use of MSC in orthopaedic surgery, this variability makes comparing studies difficult. Finally, it should be noted that many articles (including randomized controlled trials) were excluded due to the inclusion criteria. While some of these may actually have high levels of identifiable stem cells and highly successful results, their lack of cell identification makes their procedures and results hard to reproduce. The authors believe that characterization of their stem cell concentration should become standard research practice for all future studies.

5

5 Conclusion

Mesenchymal stem cells have proven to have successful and safe uses in multiple orthopaedic applications, including treating chondral defects, osteoarthritis, and osteonecrosis. A stringent and reproducible process for evaluating obtained human stem cells using CD markers for clinical use is necessary to both evaluate previous studies and continue to evaluate for future uses.

Ethical statement

IRB Approval was not needed for this systematic review. There was no direct patient information or HPI included in this study.

Funding sources

None.

Patient consent

Not Applicable.

CRediT authorship contribution statement

Ajith Malige: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. Carson Gates: Data curation, Investigation, Methodology, Project administration, Resources, Software, Validation, Visualization, Writing – original draft, Writing – review & editing. James L. Cook: Conceptualization, Data curation, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – review & editing.

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