Reporting Standards in Clinical Studies Evaluating Bone Marrow Aspirate Concentrate: A Systematic Review

doi:10.1016/j.arthro.2017.11.036

Arthroscopy: The Journal of Arthroscopic & Related Surgery

Volume 34, Issue 4, April 2018, Pages 1366-1375

https://doi.org/10.1016/j.arthro.2017.11.036 Get rights and content

Purpose

To perform a systematic review of clinical studies evaluating bone marrow aspirate concentrate (BMAC) in the treatment of musculoskeletal pathology to compare levels of reporting with recently published minimum standards.

Methods

A systematic review of the clinical literature from August 2002 to August 2017 was performed. Human clinical studies published in English and involving the administration of BMAC for musculoskeletal applications were included. Studies evaluating non-concentrated preparations of bone marrow aspirate or preparations of laboratory cultured cells were excluded. Studies evaluating the treatment of dental or maxillofacial conditions were excluded. Similarly, in vitro studies, editorials, letters to the editor, and reviews were excluded. Levels of reporting were compared with previously published minimum standards agreed on through an international Delphi consensus process.

Results

Of 1,580 studies identified on the initial search, 46 satisfied the criteria for inclusion. Considerable deficiencies in reporting of key variables including the details of BMAC preparation and composition were noted. Studies reported information on only 42% (range, 25%-60%) of the variables included within established minimum reporting standards. No study provided adequate information to enable the precise replication of preparation protocols and accurate characterization of the BMAC formulation delivered.

Conclusions

We found that all existing clinical studies in the literature evaluating BMAC for orthopaedic or sports medicine applications are limited by inadequate reporting of both preparation protocols and composition. Deficient reporting of the variables that may critically influence outcomes precludes interpretation, prevents other researchers from reproducing experimental conditions, and makes comparisons across studies difficult. We encourage the adoption of emerging minimum reporting standards for clinical studies evaluating the use of mesenchymal stem cells in orthopaedics.

Level of Evidence

Level IV, systematic review of Level I through IV studies.

Section snippets

Literature Search and Selection of Clinical Studies

This study was performed in line with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines¹⁴ and was registered using the International Prospective Register of Systematic Reviews (PROSPERO) International prospective register of systematic reviews. Three databases (PubMed, Embase, and Cochrane Central Register of Controlled Trials) were used to search for relevant clinical studies published between August 2002 and August 2017. The search terms included were as

Literature Search and Selection of Clinical Studies

Figure 1 summarizes the process of article selection. The initial PubMed, Embase, and Cochrane Library search identified 1,580 individual studies. After screening of titles and abstracts for relevance and removal of duplicates, 1,493 studies were eliminated based on application of the inclusion and exclusion criteria. The full texts of the remaining 87 studies were assessed, resulting in the exclusion of 41 studies that did not fulfill the inclusion criteria. These studies delivered

Discussion

The most important finding of this systematic review was a considerable deficiency in the reporting of variables that may critically influence the outcome of clinical studies evaluating BMAC for orthopaedic applications. We identified 46 clinical studies evaluating the use of BMAC to treat a range of musculoskeletal conditions including bone-, cartilage-, and tendon-related pathology. Within these studies, the authors included information relating to only 42% of variables considered essential

Conclusions

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Cartilage

(2015)

Cited by (37)

Core decompression combined with intralesional autologous bone marrow derived cell therapies for osteonecrosis of the femoral head in adults: A systematic review and meta-analysis
2023, Surgeon
Core decompression (CD) is beneficial in the early stage of osteonecrosis of the femoral head (ONFH). Adjunctive bone marrow derived cell therapies (BMDCT) have been advocated which potentially aid the regenerative process.
This study was conducted to determine potential benefit of CD + BMDCT in ONFH, in terms of disease progression, conversion to arthroplasty (primary outcomes), and functional outcomes and complication rates (secondary outcomes).
A systematic review of literature was performed on 3 databases. Studies reporting CD + BMDCT (intralesional instillation) in ONFH, with a minimum follow up of 1 year and reporting the pre-defined outcome measures were included in the review. Meta-analysis consisted of two different arms: a comparative arm, to compare CD + BMDCT to CD alone, and a non-comparative meta-analysis arm, to determine pooled rates of disease progression, conversion to arthroplasty and complication rates.
A total of 18 studies were included in the systematic review. CD + BMDCT had lower rates of disease progression (OR 0.19 [95% CI, 0.09, 0.40]) and conversion to arthroplasty (OR 0.20 [95% CI, 0.11, 0.40]) as compared to CD alone. Functional score (MD = −7.07 [95% CI, −12.28, −1.86]) and visual analog scale also showed better improvement with the use of CD + BMAC (MD = −10.39 [95% CI, −12.87, −7.90]). Increasing age and post-collapse stage at presentation were noted to have an adverse effect on the outcomes.
CD + BMDCT was found to decrease disease progression and conversion to arthroplasty, and was noted to have better functional outcome scores as compared to CD alone.
Bone Marrow Aspirate Concentrate Improves Outcomes in Adults With Osteochondral Dissecans of the Talus and Achilles Rupture
2023, Arthroscopy - Journal of Arthroscopic and Related Surgery
Citation Excerpt :
Although most studies reported significant pain reduction and functional improvement,18-21,23,25-27 in some cases, there was no statistical difference between treatments and their outcomes,21,24,25 which suggests that both BMAC and the other techniques are similarly effective. Other systematic reviews were carried out to investigate the effects of clinical applications of BMAC on bone, cartilage, tendon,31,32 knee,33 and other musculoskeletal injuries.34 Murray and colleagues34 reported that previous clinical studies in the literature evaluating BMAC for orthopedic or sports medicine applications are limited in terms of preparation and composition protocols.
The objective of this systematic literature review was to investigate the effects of the clinical application of bone marrow aspirate (BMA) and/or bone marrow aspirate concentrate (BMAC) in tendon and cartilage injuries in the foot and ankle.
A search of the Embase, MEDLINE/PubMed, CINAHL, and Cochrane databases was performed in January 2021. The risk of bias of the studies was assessed using the tool “A Cochrane Risk of Bias Assessment Tool for Non-Randomized Studies.” The outcomes analyzed included pain reduction and functional improvement with the use of BMA/BMAC in patients with tendon and cartilage injuries in the foot and ankle.
Eleven studies met the inclusion criteria for analysis, involving a total of 527 subjects with osteochondral lesions (OCLs) of the talus, cartilage lesions of the talus, and acute Achilles tendon rupture. BMAC was applied alone in 4 studies, and in 7 studies, it was compared with other techniques such as matrix-induced autologous chondrocyte implantation, particulate juvenile articular cartilage, or microfracture. Interventions demonstrated improved function and reduced foot and ankle pain and showed no serious adverse effects.
Evidence indicates that BMAC provides good clinical results, with improved function and reduced pain in adults with OCL and cartilage lesions of the talus and acute Achilles tendon rupture.
Level IV, systematic review of level II to IV studies.
Use of Injections and Biologics for the Nonoperative Treatment of Rotator Cuff Pathology
2023, Clinics in Sports Medicine
Citation Excerpt :
There are several small studies without control groups listed above that show some promise and warrant additional research, but at this time there is no evidence to support the use of stem cells in the nonoperative treatment of rotator cuff tears outside of ongoing research efforts. As discussed previously with regard to PRP, standardization of communication tools, definitions, and preparations of stem cells will help improve the quality of future research while improving the feasibility of safely adopting the techniques in clinical practice.80–82 NSAIDs are commonly used in the treatment of musculoskeletal pain and inflammation.
Arthroscopic Rotator Cuff Repair with a Fibrin Scaffold Containing Growth Factors and Autologous Progenitor Cells Derived From Humeral cBMA Improves Clinical Outcomes in High Risk Patients
2022, Arthroscopy, Sports Medicine, and Rehabilitation
Citation Excerpt :
Without a standardized method for the processing of BMA and counting CFUs, a comparison between cBMA from the humerus and ilium regarding the effect on rotator cuff healing is very limited. This was supported by a recent systematic review by Murray et al., concluding that the reported information on cBMA protocols, as well as composition is inadequate and precludes the comparison across the limited number of available studies.24 Biologically augmenting the rotator cuff during surgery with PRP is another approach that has been increasingly used in orthobiologics.25
To report the clinical outcomes after biologically augmented rotator cuff repair (RCR) with a fibrin scaffold derived from autologous whole blood and supplemented with concentrated bone marrow aspirate (cBMA) harvested at the proximal humerus.
Patients who underwent arthroscopic RCR with biologic augmentation using a fibrin clot scaffold (“Mega- Clot”) containing progenitor cells and growth factors from proximal humerus BMA and autologous whole blood between April 2015 and January 2018 were prospectively followed. Only high-risk patients in primary and revision cases that possessed relevant comorbidities or physically demanding occupation were included. Minimum follow-up for inclusion was 1 year. The visual analog score for pain (VAS), American Shoulder and Elbow Surgeons (ASES), Simple Shoulder Test (SST), Single Assessment Numerical Evaluation (SANE), and Constant-Murley scores were collected preoperatively and at final follow-up. In vitro analyses of the cBMA and fibrin clot using nucleated cell count, colony forming units, and live/dead assays were used to quantify the substrates.
Thirteen patients (56.9 ± 7.7 years) were included. The mean follow-up was 26.9 ± 17.7 months (n = 13). There were significant improvements in all outcome scores from the preoperative to the postoperative state: VAS (5.6 ± 2.5 to 3.1 ± 3.2; P < .001), ASES (42.0 ± 17.1 to 65.5 ± 30.6; P < .001), SST (3.2 ± 2.8 to 6.5 ± 4.7; P = .002), SANE (11.5 ± 15.6 to 50.3 ± 36.5; P < .001), and Constant-Murley (38.9 ± 17.5 to 58.1 ± 26.3; P < .001). Six patients (46%) had retears on postoperative MRI, despite all having improvements in pain and function except one. All failures were chronic rotator cuff tears, and all were revision cases except one (1.6 ± 0.5 previous RCRs). The representative sample of harvested cBMA showed an average of 28.5 ± 9.1 × 10⁶ nucleated cells per mL.
Arthroscopic rotator cuff repairs that are biologically augmented with a fibrin scaffold containing growth factors and autologous progenitor cells derived from autologous whole blood and humeral cBMA can improve clinical outcomes in primary, as well as revision cases in high-risk patients. However, the incidence of retears remains a concern in this population, demanding further improvements in biologic augmentation.
IV, therapeutic case series.
Injection of Bone Marrow Aspirate for Glenohumeral Joint Osteoarthritis: A Pilot Randomized Control Trial
2021, Arthroscopy, Sports Medicine, and Rehabilitation
Citation Excerpt :
This is encouraging and suggests that further, larger scale research regarding the use of BMA and BMAC in this group of difficult-to-treat patients may be rewarding. There are a variety of products on the market for BMA and BMAC; 2 recent systematic reviews noted that there was inadequate reporting of both preparation protocols and composition in the literature.33,34 In this study, 10 mL of BMA were extracted from the posterior superior iliac spine using the Marrow Cellutions system and injected in the GHJ without a concentration process.35
To compare the efficacy of a single, intra-articular, nonconcentrated bone marrow aspirate (BMA) injection in comparison to cortisone for the treatment of glenohumeral joint osteoarthritis (GHJ OA).
Inclusion criteria were patients between the ages of 18 and 75 with a diagnosis of GHJ OA on radiograph. Patients were randomized to receive an ultrasound-guided, intra-articular cortisone injection or BMA injection (without concentration). The primary outcome measure was the Western Ontario Osteoarthritis of the Shoulder (WOOS) index at 12 months. Secondary outcome measures were the QuickDASH, EuroQOL 5-dimensions 5-level questionnaire (EQ-5D-5L) and visual analogue scale.
The study included 25 shoulders of 22 patients who completed baseline and 12 months’ patient-reported outcome measures (12 shoulders received cortisone, 13 shoulders received BMA) after the study was terminated early by changes in Health Canada regulations. Baseline characteristics demonstrated a significant difference in the ages of the 2 groups, with the BMA group being older (61.6 vs 53.8 mean years, P = 0.021). For the BMA group, a significant improvement was seen in the WOOS index (P = 0.002), the QuickDASH (P < 0.001), and the EQ-5D-5L pain dimension (P = 0.004) between baseline and 12 months. No significant difference was seen for any outcome in the cortisone group between baseline and 12 months. No significant difference was demonstrated between changes in the WOOS scores from baseline to 12 months when compared between groups (P = 0.07). However, a significant difference in changes in scores was seen in the QuickDASH (P = 0.006) and the EQ-5D-5L pain scores (P = 0.003) and the EQ-5D-5L health scores (P = 0.032) in favor of BMA.
The results of this study demonstrate that patients with GHJ OA treated with BMA have superior changes in the QuickDASH and EQ-5D-5L pain and health scores but not in the WOOS outcomes measures at 12 months post injection when compared to patients treated with cortisone. However, because of the limited number of patients as a result of the early termination of the study, larger randomized studies are required to confirm these findings.
Level II, randomized controlled trial.
Analysis of Time to Form Colony Units for Connective Tissue Progenitor Cells (Stem Cells) Harvested From Concentrated Bone Marrow Aspirate and Subacromial Bursa Tissue in Patients Undergoing Rotator Cuff Repair
2020, Arthroscopy, Sports Medicine, and Rehabilitation
To evaluate the time required for colonies to develop from concentrated bone marrow aspirate (cBMA) and subacromial bursal tissue samples.
Samples of cBMA and subacromial bursa tissue were harvested from patients undergoing rotator cuff repair surgery between November 2014 and December 2019. Samples were analyzed for time to form colonies and number of colonies formed. The impact of age, sex, and cellularity (cBMA only) was analyzed. Samples were cultured and evaluated daily for colony formation in accordance with the guidelines of the International Society for Cellular Therapy. Demographic factors were analyzed for impact on time to form colonies and number of colonies formed.
Samples of cBMA were obtained from 92 patients. Subacromial bursa tissue was obtained from 54 patients. For cBMA, older age was associated with more days to form colonies (P = .003), but sex (P = .955) and cellularity (P = .623) were not. For bursa, increased age was associated with longer time to form colonies (P = .002) but not sex (P = .804). Conclusions: Increased age (in cBMA and subacromial bursa tissue) and lower initial cellularity (in cBMA) are associated with longer time to form colonies in culture.
Although connective tissue progenitor cells are widely used in orthopaedic practice, there are few metrics to determine their efficacy. Time to form colonies may serve as an important measurement for determining connective tissue progenitor cell viability for augmentation of rotator cuff repair. Subacromial bursa tissue may represent a viable alternative to cBMA for augmentation of rotator cuff repair, capable of forming colonies expediently in vivo.

View all citing articles on Scopus

: See commentary on page 1376

: The authors report the following potential conflict of interest or source of funding: R.F.L. receives support from Arthrex; Smith & Nephew; Ossur; Health East, Norway; NIH R-13 grant for biologics. Institution provided support by Arthrex, Ossur, Siemens, and Smith & Nephew. Full ICMJE author disclosure forms are available for this article online, as supplementary material.

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Systematic ReviewReporting Standards in Clinical Studies Evaluating Bone Marrow Aspirate Concentrate: A Systematic Review

Purpose

Methods

Results

Conclusions

Level of Evidence

Section snippets

Literature Search and Selection of Clinical Studies

Literature Search and Selection of Clinical Studies

Discussion

Conclusions

Exp Cell Res

Bone

Knee

Knee

Bone

Arthroscopy

Spine J

J Arthroplasty

J Orthop Res

Recent insights into the identity of mesenchymal stem cells: Implications for orthopaedic applications

J Bone Joint Br

Mesenchymal stem cells

J Orthop Res

Pharmaceutical manufacturing handbook: Regulations and quality

Genetic and epigenetic instability of human bone marrow mesenchymal stem cells expanded in autologous serum or fetal bovine serum

Int J Dev Biol

AAOS research symposium updates and consensus: Biologic treatment of orthopaedic injuries

J Am Acad Orthop Surg

One-stage cartilage repair using a hyaluronic acid-based scaffold with activated bone marrow-derived mesenchymal stem cells compared with microfracture: Five-year follow-up

Am J Sports Med

A prospective, single-blind, placebo-controlled trial of bone marrow aspirate concentrate for knee osteoarthritis

Am J Sports Med

A prospective comparison of 3 approved systems for autologous bone marrow concentration demonstrated nonequivalency in progenitor cell number and concentration

J Orthop Trauma

Minimum information for studies evaluating biologics in orthopaedics (MIBO): Platelet-rich plasma and mesenchymal stem cells

J Bone Joint Surg Am

Natural history of mesenchymal stem cells, from vessel walls to culture vessels

Cell Mol Life Sci

Autologous, allogeneic, induced pluripotent stem cell or a combination stem cell therapy? Where are we headed in cartilage repair and why: A concise review

Stem Cell Res Ther

Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement

BMJ

One-step arthroscopic technique for the treatment of osteochondral lesions of the knee with bone-marrow-derived cells: Three years results

Musculoskelet Surg

Efficacy of autologous bone marrow concentrate for knee osteoarthritis with and without adipose graft

Biomed Res Int

Osteogenic progenitors in bone marrow aspirates have clinical potential for tibial non-unions healing in diabetic patients

Int Orthop

One-step bone marrow-derived cell transplantation in talar osteochondral lesions

Clin Orthop Relat Res

Use of collagen scaffold and autologous bone marrow concentrate as a one-step cartilage repair in the knee: Histological results of second-look biopsies at 1 year follow-up

Int J Immunopathol Pharmacol

One-step cartilage repair with bone marrow aspirate concentrated cells and collagen matrix in full-thickness knee cartilage lesions: Results at 2-year follow-up

Cartilage

One-step surgery with multipotent stem cells for the treatment of large full-thickness chondral defects of the knee

Am J Sports Med

Matrix-induced autologous chondrocyte implantation versus multipotent stem cells for the treatment of large patellofemoral chondral lesions: A nonrandomized prospective trial

Cartilage

Systematic Review
Reporting Standards in Clinical Studies Evaluating Bone Marrow Aspirate Concentrate: A Systematic Review