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Similar Short-term Results Between Scaffold Implanted Mesenchymal Stem Cells versus Acellular Scaffolds with Concentrated Bone Marrow Aspirate Augmentation for the Repair of Chondral Defects of the Knee: Evidence from a Meta-Analysis
Corresponding Author: Keng Lin WONG, Department of Orthopaedic Surgery, Sengkang General Hospital, Musculoskeletal Sciences ACP, Singhealth-DukeNUS Graduate Medical School, Sengkang General Hospital, 110 Sengkang East Way Singapore 544886, DID: (65) 6930 5365 ,Mobile: (65) 97116395
Yong Loo Lin School of Medicine, National University of Singapore, Singapore, SingaporeMusculoskeletal Sciences Academic Clinical Programme, Duke-NUS Graduate Medical School, SingaporeDepartment of Orthopaedic Surgery, Sengkang General Hospital, Singapore
Scaffold-implanted mesenchymal stem cells (MSCs) are gaining popularity for the treatment of cartilage defects. However, there is little evidence comparing its efficacy against the currently well-established technique of utilizing acellular scaffolds (ACs) with concentrated bone marrow aspirate (cBMA) for treating knee chondral defects.
Objectives
To compare scaffold-implanted MSCs against ACs with cBMA for the repair of knee cartilage lesions.
Data Sources
MEDLINE and Embase
Study Eligibility Criteria, Participants, and Interventions
Inclusion: (1) Studies involving patients with high grade chondral lesions on the tibiofemoral or patellofemoral articular surfaces, (2) Studies involving patients that received either scaffold-implanted MSCs or ACs for treatment, and (3) Studies with postoperative patient follow-up of at least two years.
Study Appraisal and Synthesis Methods
Single-arm meta-analysis of studies reporting patient-reported outcome measures (PROMs), reoperation and incomplete filling rates was performed.
Results
Degree of postoperative IKDC score improvement in patients receiving ACs augmented with cBMA was significantly higher compared to those receiving scaffold-implanted MSCs (p<0.01). Additionally, patients receiving ACs with cBMA augmentation were at significantly lower risk of incomplete defect filling when compared to patients receiving either scaffold-implanted MSCs (p<0.01), or patients receiving non-cBMA augmented ACs (p<0.01).
Conclusion
This meta-analysis demonstrates that cartilage repair with ACs with cBMA augmentation yields marginally better short-term outcomes when compared to scaffold-implanted MSCs. This suggests that even with the advent of MSCs increasing in availability as a treatment modality, ACs with cBMA augmentation remains as a competitive, cost-effective option for cartilage repair.
Intraarticular injuries associated with anterior cruciate ligament tear: findings at ligament reconstruction in high school and recreational athletes. An analysis of sex-based differences.
. However, articular cartilage injuries are a spectrum of disease comprising of a range of patients, from asymptomatic individuals with small, focal lesions, to patients with large, degenerative defects and end staged osteoarthritis
), symptomatic cartilage defects truly warrant intervention. Treatment of such defects is challenging due to the aneural, avascular and alymphatic nature of cartilage, resulting in a poor native environment for healing
. Consequently, the current paradigm of cartilage defect treatment is directed towards regenerative therapy, of which two prominent modalities are that of acellular scaffolds (ACs) and scaffold-implanted mesenchymal stem cells (MSC). ACs is a single-surgery, non-cell-based therapy that involves the marrow stimulation of blood rich in growth factors, which then migrates and clots at the site of cartilage defect, maturing and differentiating into fibrocartilage tissue
. Conversely, MSC-based therapy is a staged cell-based therapy that involves stem-cells sourced from mesenchymal tissue, which are harvested and cultured prior to implantation at the lesion site. Ultimately, the aim of this treatment modality is to induce endogenous growth and activate self-proliferation of progenitor cells to promote cartilage regeneration
Although both methods have shown therapeutic potential, the relative efficacy of MSC-based therapy compared to ACs is still uncertain, and there remains a lack of consensus as to which cartilage repair procedure results in the best patient outcomes. Moreover, cost effectiveness remains the most prominent barrier to routine adoption of MSC-based therapy
. Hence, strong evidence is required to truly justify the cost-effective adoption of MSC-based therapy, particularly with recent evidence displaying that ACs with cBMA augmentation result in good clinical and radiological outcomes for patients with focal chondral defects of the knee
Does the Choice of Acellular Scaffold and Augmentation With Bone Marrow Aspirate Concentrate Affect Short-term Outcomes in Cartilage Repair? A Systematic Review and Meta-analysis.
The American Journal of Sports Medicine.2022; 03635465211069565
. The biological component of acellular scaffold cartilage repair, provided by cBMA, may provide a lower cost yet clinically efficacious alternative to MSCs.
OBJECTIVES
This study aims to, through the use of a systematic-review and meta-analysis of existing literature, compare the clinical outcomes of acellular scaffolds (ACs) augmented with bone marrow aspirate concentrate (cBMA) against scaffold-implanted MSC-based procedures in the treatment of critically sized chondral defects of the knee.
DATA SOURCES
This review was synthesized with reference to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines
. Medline and Embase electronic databases were systematically searched on the 23rd of Nov 2022 using keywords and terms synonymous with the knee, articular cartilage, matrix-induced chondrogenesis and stem cells. Additionally, references from included studies and pertinent review articles were manually trawled to identify other potential studies meeting the selection criteria. The search was limited to articles written in the English language. An example of the search strategy can be found within the supplementary material.
STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTIONS
Studies describing the post-operative outcomes of patients undergoing cartilage repair procedures were included in this review. Criteria for inclusion were met if studies had all of the following characteristics.
(1)
Patients with chondral lesions on the tibiofemoral or patellofemoral articular surfaces of Outerbridge or International Cartilage Restoration and Joint Preservation Society (ICRS) grade III and above
(2)
Patients undergoing either autologous matrix-induced chondrogenesis (ACs), with or without concomitant concentrated bone marrow aspirate (cBMA) augmentation, or mesenchymal stem-cell (MSC) derived cartilage repair procedures.
(3)
Studies with a minimum mean postoperative follow-up period duration of two years.
Studies were excluded if they did not meet all of the inclusion criteria or met any of the following exclusion criteria.
(1)
Involved patients undergoing any form of autologous chondrocyte implantation procedures.
(2)
Failed to acceptably report the method of cartilage repair used.
(3)
Published in a non-English language without interpretable translations.
(4)
Were letters to the editor, review articles or editorials.
(5)
Involved patient data from glaringly overlapping datasets with other included studies.
However, different studies involving patients belonging to the same database were considered for inclusion provided each study reported different patient outcomes. No outcomes extracted from the included studies were of overlapping patient datasets.
STUDY APPRAISAL AND SYNTHESIS METHODS
Study Selection
The inclusion of an article was evaluated by an independent blinded pair of authors (ZGWO and KLKL), with any disagreements being resolved by obtaining the consensus of a senior author (KLW). Inter-rater agreement was quantified by use of Cohen's Kappa statistic coefficient, k. Standard agreement definition was used, with the degrees of inter-rater agreement being categorized into the following ranges: poor (k=0.00-0.20), fair (k=0.21-0.40), moderate (k=0.41-0.60), substantial (k=0.61-0.80), and almost perfect (k=0.81-1.00)
Data extraction was performed to extract study characteristics (study period, location, and follow-up times), baseline characteristics (age, gender, cartilage status, and lesion size), and postoperative outcomes (functional scores, complications, radiological findings). Means and standard deviations were extracted for the pooling of continuous outcome data, and when such forms were unavailable and instead presented as medians with ranges, we employed previously established formulae by Wan et al in the conversion of data to means with standard deviations
. Binary outcome data was extracted in the form of the number of events that occurred per sample size.
Studies were categorized primarily by the method of cartilage repair, namely stem cells and ACs. Within the ACs group, a further subgroup was introduced, namely that of cBMA and non-cBMA augmented ACs procedures.
Outcomes of Interest
Primary outcomes of interest were that of patient reported outcome measures (PROMs), namely, the ten-point visual analogue score for pain (VAS), International Knee Documentation Committee (IKDC) score, as well as the Lysholm and Tegner scores for physical function. Other additional outcomes of interest were the rates of incomplete defect filling, as reported following postoperative radiological evaluation of cartilage defects, as well as the rates of revision cartilage repair procedures and progression to total knee arthroplasty.
Statistical Analysis
Continuous and binary outcome data were analyzed in separate manners, with all data being analyzed using RStudio, version 1.3.1093 (RStudio, Boston, Massachusetts). Continuous data comprised of PROM scores, as presented by studies in a pre/post-operative comparison. Hence, such data underwent pairwise meta-analyses using the metacont function of the R meta package, with pooled continuous data comparisons being presented in the form of the weighted mean differences between pre- and post-operative PROM scores using the inverse variance model with random effects applied.
Binary outcomes were analyzed in a single-arm fashion. Single-arm meta-analysis was performed to synthesize observational data for continuous and binary outcomes using the metaprop function of the R meta package. Binary outcome data was pooled in the form of proportions, using the generalized linear mixed model (GLMM), a statistical model that results in smaller biases and mean squared errors with higher coverage probabilities than traditional two-step models such as the DerSimonian and Laird random effects model, another commonly used statistical model in meta-analyses
Based on the pooled proportions of single-arm studies, the respective relative risks () of binary outcome (e.g incomplete filling, reoperation rates, progression to knee arthroplasty) occurrence were respectively calculated as the ratio of the pooled proportions of event occurrence rates
. The lower () and upper () bounds for the 95% confidence intervals were estimated using the Katz-logarithmic method, wherein n1 and n2 represent the respective number of patients in each of the treatment arms being evaluated. Additionally, the p value was calculated after a natural log transformation of the relative risk z-score
. The specific formula used to approximate the confidence intervals and p-values can be found within the supplementary material.
Investigating Heterogeneity
We assessed statistical heterogeneity amongst studies by visual inspection of forest plots, as well as I2 and Cochran's Q test values. I2 values of 0%–40% were suggestive of insignificant degrees of heterogeneity, while values of 30%–60%, 50%–90%, and 75%–100% were classified as moderate, substantial, and considerable heterogeneity, respectively
. Additionally, other potential sources of heterogeneity were explored through the use of subgroup and sensitivity analyses where appropriate. Publication bias was assessed by the asymmetry of the respective funnel plots. P-values <0.05 were considered statistically significant.
Risk of Bias and Quality Assessment
Whilst the statistical analyses were performed both in a pairwise and single-arm fashion, the results of the included studies were interpreted in a single-arm, non-comparative fashion. Hence, we employed a modified risk of bias assessment as described by Hoy et al, specifically tailored to the bias assessment of single-arm studies
. The NOS grades each article on the cohort selection, as well as the adequacy of outcomes measured, whilst the Jadad scale assesses trials on the adequacy of randomization, blinding and analysis and reporting of outcomes.
RESULTS
Summary of Included Articles
A systematic search of the literature utilizing our search strategy yielded a total of 1,003 references, with 785 remaining after removal of duplicates. These 785 references were screened as abstracts with the preliminary inclusion criteria applied, following which 677 were excluded based on failing to meet the predetermined inclusion criteria. A total of 108 full texts articles underwent review, wherein both the predetermined inclusion and exclusion criteria were applied in the selection of full texts references. Of these 108 full text references sieved, 39 articles fulfilled all inclusion and exclusion criteria satisfactorily and were subsequently included in the meta-analysis (Figure 1). In summary, 10 articles originated from Italy
Combining a novel leucocyte–platelet-concentrated membrane and an injectable collagen scaffold in a single-step AMIC procedure to treat chondral lesions of the knee: a preliminary retrospective study.
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.
One-step surgery with multipotent stem cells and Hyaluronan-based scaffold for the treatment of full-thickness chondral defects of the knee in patients older than 45 years.
Long-term Clinical Outcomes of One-Stage Cartilage Repair in the Knee With Hyaluronic Acid-Based Scaffold Embedded With Mesenchymal Stem Cells Sourced From Bone Marrow Aspirate Concentrate.
Valgus high tibial osteotomy and bone-marrow-derived cells transplantation: Clinical and radiological results after a 3-year follow-up in varus osteoarthritis of the knee.
Autologous Matrix-Induced Chondrogenesis (AMIC) and AMIC enhanced by autologous concentrated Bone Marrow Aspirate (BMAC) Allow for stable clinical and functional improvements at up to 9 years follow-up: Results from a Randomized controlled study.
Management of Patellar Chondral Defects with Autologous Matrix Induced Chondrogenesis (AMIC) Compared to Microfractures: A Four Years Follow-Up Clinical Trial.
Allogenic umbilical cord blood-derived mesenchymal stromal cell implantation was superior to bone marrow aspirate concentrate augmentation for cartilage regeneration despite similar clinical outcomes.
Comparison of Bone Marrow Aspirate Concentrate and Allogenic Human Umbilical Cord Blood Derived Mesenchymal Stem Cell Implantation on Chondral Defect of Knee: Assessment of Clinical and Magnetic Resonance Imaging Outcomes at 2-Year Follow-Up.
Orthopaedics, Traumatology Society of Western F. Treatment of large deep osteochondritis lesions of the knee by autologous matrix-induced chondrogenesis (AMIC): Preliminary results in 13 patients.
A useful combination for the treatment of patellofemoral chondral lesions: realignment procedure plus mesenchymal stem cell—retrospective analysis and clinical results at 48 months of follow-up.
The Clinical Use of Human Culture-Expanded Autologous Bone Marrow Mesenchymal Stem Cells Transplanted on Platelet-Rich Fibrin Glue in the Treatment of Articular Cartilage Defects: A Pilot Study and Preliminary Results.
Collagen-Covered Autologous Chondrocyte Implantation Versus Autologous Matrix-Induced Chondrogenesis: A Randomized Trial Comparing 2 Methods for Repair of Cartilage Defects of the Knee.
Clinical Outcomes of an All-Arthroscopic Technique for Single-Stage Autologous Matrix-Induced Chondrogenesis in the Treatment of Articular Cartilage Lesions of the Knee.
Matrix-induced autologous mesenchymal stem cell implantation versus matrix-induced autologous chondrocyte implantation in the treatment of chondral defects of the knee: a 2-year randomized study.
. In total, 19 studies had a prospective study design, 13 were retrospective in nature, and six were randomized controlled trials (RCTs). A summary of the included studies can be found in Table 1, whilst a summary of the individual risks of bias and quality assessment of the included studies can be found within the supplementary material.
A total of 965 patients underwent cartilage repair procedures utilizing either ACs, with or without cBMA augmentation, or scaffold-implanted MSC-based therapy, of which 477 (49.4%) received non-augmented ACs therapy, 251 (26.0%) received ACs augmented with cBMA, and 237 (24.6%) received MSCs implanted on bioscaffolds. Patient demographics such as age, follow-up period and lesion size were pooled as raw weighted means. The mean age of patients overall was 39.8 years (36.9 to 42.7). The mean age of patients that underwent non-augmented ACs cartilage repair procedures was 36.0 years (CI: 33.4 to 38.7), patients receiving ACs with cBMA augmentation had a mean age of 44.0 years (CI: 39.3 to 48.6), and patients that underwent MSC-based therapy had a mean age of 44.3 years (CI: 34.6 to 54.0). Mean lesion size was 3.8 cm2 (CI: 3.3 to 4.3) in the unaugmented ACs arm, 6.7 cm2 (CI: 4.8 to 8.5) in the group of patients receiving ACs with cBMA augmentation, and 4.9 cm2 (CI: 3.9 to 5.8) in the MSC arm. Mean follow-up of patients after treatment of cartilage defects was 39.6 months (CI: 31.2 to 46.9) overall, 40.1 months (CI: 28.6 to 51.6) in the non-cBMA augmented ACs arm, 50.1 months (CI: 34.2 to 65.9) in the cBMA augmented ACs arm, and 25.3 months (CI: 20.9 to 29.8) in the scaffold-implanted MSC arm. Mean body mass index (BMI) scores were 26.5 kg/m2 (CI: 25.7 to 27.2) in the non-cBMA augmented ACs arm, 25.4 kg/m2 (CI: 24.3 to 26.5) in the ACs with cBMA arm, and 25.7 kg/m2 (CI: 24.8 to 26.7) in the scaffold-implanted MSC arm. A breakdown of demographic information by relevant treatment subgroups is presented in Table 2.
Patients that received either ACs, with or without cBMA augmentation, (WMD = 38.2; CI: 33.7 to 42.6, p<0.01), or MSCs (WMD = 31.6; CI: 28.3 to 34.9, p<0.01) experienced significant postoperative improvements in IKDC scores. Those that received ACs displayed a statistically greater degree of postoperative IKDC improvement than those receiving MSCs (p=0.02), but this difference failed to reach the value of minimum clinically important difference (MCID) for the IKDC score (Figure 2). Similarly, patients receiving MSCs (WMD = -4.4; CI: -4.8 to -4.1; p<0.01) and either non- or cBMA-augmented ACs (WMD = -4.2; CI: -4.6 to -3.8; p<0.01) experienced significant postoperative improvements in VAS scores. However, this difference between the two subgroups was not significant (p=0.45). Postoperative Tegner score improvement in patients undergoing cartilage repair with ACs, either with or without cBMA augmentation (WMD = 2.1; CI: 1.2 to 2.9; p<0.01), as well as those that received MSCs (WMD = 1.7; CI: 0.8 to 2.7; p<0.01) showed significant improvements in the postoperative Tegner score. However, the differences in the degree of postoperative Tegner score changes between the two treatment groups failed to reach statistical significance (p=0.63).
Figure 2Forest Plot of Postoperative International Knee Documentation Committee Score Improvement, Comparing Acellular Scaffolds versus Scaffold-Implanted Mesenchymal Stem-Cells
In terms of postoperative IKDC scores, both patients that underwent either cBMA augmented ACs procedures (WMD = 38.1; CI: 34.5 to 41.7, p<0.01), or MSC-based treatments (WMD = 31.6; CI: 28.3 to 34.9; p<0.01) experienced significant postoperative improvements. Subgroup analysis comparing the two arms displayed a statistically significant difference (p<-0.01) in the degree of postoperative IKDC improvements that failed to reach the proposed MCID value for the IKDC score (Figure 3). VAS scores were significantly improved postoperatively in both patients that underwent ACs augmented with cBMA (WMD = -4.5; CI: -5.1 to -3.8; p<0.01) as well as those that underwent cartilage repair procedures with MSCs (WMD = -4.4; CI: -4.8 to -4.1; p<0.01), with the difference between both subgroups showing no statistically significant difference in the degree of postoperative VAS improvements (p=0.98). Similarly, postoperative Tegner score improvements were significant in both the group of patients receiving ACs augmented with cBMA (WMD = 2.5; CI: 1.6 to 3.4; p<0.01), as well as those that underwent MSC-based therapies (WMD = 1.7; CI: 0.8 to 2.7, p<0.01), with the difference in degree of Tegner score improvements displaying no statistical significance (p=0.27).
Figure 3Forest Plot of Postoperative International Knee Documentation Committee Score Improvement, Comparing Acellular Scaffolds (Bone Marrow Aspirate Concentrate Augmented Subgroup) versus Scaffold-Implanted Mesenchymal Stem-Cells
Postoperative Tegner score improvement was significant in patients that underwent cartilage repair with MSCs (WMD = 1.7; CI: 0.8 to 2.7, p<0.01), but failed to reach statistical significance in patients that underwent non-cBMA augmented ACs procedures (WMD = 1.0; CI: 0.4 to 1.7; p=0.42), however, this difference in the degrees of postoperative Tegner score improvement failed to reach statistical significance (p=0.22). VAS scores in patients that received MSCs (WMD = -4.4; CI: -4.8 to -4.1; p<0.01) as well as the patients that underwent non-cBMA augmented ACs procedures (WMD = -4.1; CI: -4.5 to -3.7; p<0.01) were significantly improved postoperatively, however no statistically significant differences were found in the degree of VAS score improvements when comparing both arms (p=0.25). Similarly, Postoperative IKDC scores were significantly improved in both the MSC group (WMD = 31.6; CI: 28.3 to 34.9; p<0.01) as well as the non-cBMA augmented ACs treatment group (WMD = 38.1; CI: 28.3 to 48.0; p<0.01). However, this difference in the degree of IKDC score improvement was not statistically significant (p=0.22)
Dichotomous Outcomes
Incomplete filling
Studies that reported incomplete defect filling measured this outcome via magnetic resonance imaging (MRI) at final follow-up. The overall rate of incomplete defect filling was 28.0% (CI: 19.5 to 38.5) in patients that received ACs either with or without cBMA augmentation, whilst the rate of incomplete defect filling was 36.5% (CI: 19.1 to 58.3) in patients treated with MSCs. Patients receiving non-cBMA augmented ACs had a 35.8% (CI: 22.8 to 51.4) rate of incomplete defect filling, whilst patients that underwent cBMA-augmented ACs procedures had an incomplete defect filling rate of 18.7% (CI: 12.4 to 27.2). Patients that underwent cBMA augmented ACs procedures were observed to be at a lower relative risk of incomplete defect filling as compared to either those that received MSCs (RR = 0.5; CI: 0.3 to 0.8, p<0.01), or patients that underwent ACs without cBMA augmentation (RR = 0.5; CI: 0.3 to 0.8; p<0.01).
Progression to TKR
Progression to total knee replacement (TKR) was reported as an outcome at final follow-up timepoints by the included studies. In patients undergoing MSC-based cartilage repair procedures, the rate of progression to TKR was 2.2% (CI: 0.3 to 13.9), whilst the rate of progression to TKR in patients receiving either cBMA- or non-cBMA-augmented ACs procedures was 3.4% (CI: 1.4 to 8.0). Individually, the rates of TKR progression in the cBMA-augmented ACs treatment group was 1.8% (CI: 0.3 to 11.4), and 4.5% (CI: 1.7 to 11.4) in the non-cBMA-augmented treatment arm. No significant differences in the relative risks of progression to TKR were observed for patients undergoing any of the various cartilage repair procedures.
Revision Surgery and Postoperative Arthrofibrosis
Revision surgery was defined, by the studies reporting the outcome, as the necessity of a revision cartilage repair procedure due to persistent pain and failure of symptomatic improvement within the follow-up period. Revision surgery was reported by 10 studies involving patients undergoing ACs procedures either with or without cBMA augmentation, as well as one study involving patients that received MSCs. Akgun et al
Matrix-induced autologous mesenchymal stem cell implantation versus matrix-induced autologous chondrocyte implantation in the treatment of chondral defects of the knee: a 2-year randomized study.
reported that none of the seven patients that received MSC-based cartilage repair procedures required revision surgeries in the follow-up period. Revision surgery in patients that received cBMA-augmented ACs procedures was reported as an outcome by three studies
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.
Long-term Clinical Outcomes of One-Stage Cartilage Repair in the Knee With Hyaluronic Acid-Based Scaffold Embedded With Mesenchymal Stem Cells Sourced From Bone Marrow Aspirate Concentrate.
Autologous Matrix-Induced Chondrogenesis (AMIC) and AMIC enhanced by autologous concentrated Bone Marrow Aspirate (BMAC) Allow for stable clinical and functional improvements at up to 9 years follow-up: Results from a Randomized controlled study.
, wherein amongst a total of 57 patients that underwent cartilage repair procedures, only one patient underwent a revision surgery (1.8%). Revision surgery in patients that underwent non-cBMA-augmented ACs procedures was reported by seven studies
Management of Patellar Chondral Defects with Autologous Matrix Induced Chondrogenesis (AMIC) Compared to Microfractures: A Four Years Follow-Up Clinical Trial.
Orthopaedics, Traumatology Society of Western F. Treatment of large deep osteochondritis lesions of the knee by autologous matrix-induced chondrogenesis (AMIC): Preliminary results in 13 patients.
Collagen-Covered Autologous Chondrocyte Implantation Versus Autologous Matrix-Induced Chondrogenesis: A Randomized Trial Comparing 2 Methods for Repair of Cartilage Defects of the Knee.
Clinical Outcomes of an All-Arthroscopic Technique for Single-Stage Autologous Matrix-Induced Chondrogenesis in the Treatment of Articular Cartilage Lesions of the Knee.
, totaling 110 patients, of which five patients necessitated revision cartilage repair procedures (4.5%). Postoperative arthrofibrosis was reported by a total of seven studies across all groups. Four studies in the non-cBMA augmented ACs arm totaling 80 patients reported ten cases of arthrofibrosis (12.5%)
Comparison of Bone Marrow Aspirate Concentrate and Allogenic Human Umbilical Cord Blood Derived Mesenchymal Stem Cell Implantation on Chondral Defect of Knee: Assessment of Clinical and Magnetic Resonance Imaging Outcomes at 2-Year Follow-Up.
Matrix-induced autologous mesenchymal stem cell implantation versus matrix-induced autologous chondrocyte implantation in the treatment of chondral defects of the knee: a 2-year randomized study.
Comparison of Bone Marrow Aspirate Concentrate and Allogenic Human Umbilical Cord Blood Derived Mesenchymal Stem Cell Implantation on Chondral Defect of Knee: Assessment of Clinical and Magnetic Resonance Imaging Outcomes at 2-Year Follow-Up.
in the cBMA augmented ACs arm reported two out of 25 of the included patients that suffered from postoperative arthrofibrosis (8.0%).
LIMITATIONS
This review is the first to directly compare the effects of ACs and MSC treatments for the repair of articular cartilage defects of the knee, as well as evaluating the effect of cBMA on the efficacy of ACs procedures when compared to MSCs. However, the results and conclusions of this review should be interpreted in view of several inherent limitations. Primarily, there is a paucity of long-term evidence surrounding the ACs and MSCs in the treatment of articular cartilage defects, particularly due to the relative novelty of MSCs as a treatment modality. As such, the evidence gathered from this review should be interpreted with short-term outcome improvements in mind. Furthermore, there is a known significant difference in PROMs between chondral lesions on tibiofemoral versus patellofemoral surfaces, both of which were included in the reported data. This, along with differing mean lesion size and follow-up time between groups, serve as unavoidable confounders of the results. Additionally, due to the sparse data of the individual types of MSCs, we were unable to compare the efficacies of each MSC type, resulting in an inherent degree of study heterogeneity that could not be controlled for through conventional means. Similarly due to the small sample sizes of the included studies, the degree of statistical heterogeneity as measured by the I2 statistic was largely varied. Finally, whilst some studies had a randomized design, no formal blinding of patients to treatment was performed in any of the included studies, thus we were unable to evaluate the potential existence of a placebo effect amongst the treatment arms.
CONCLUSIONS
Currently, numerous cell-based treatment options are available to surgeons for the repair of articular cartilage defects of the knee. Osteochondral allograft transfer (OAT) and autologous chondrocyte implantation or ACI have long been the mainstays of treatment, with up to two decades of evidence supporting the efficacy of such techniques
. However, OAT requires adequate non-weightbearing articular cartilage for harvest and ACI requires a delayed staged surgery due to the harvesting and expansion of autologous chondrocytes, which have long been the selection caveats for both treatment options. As such, the recent paradigm has shifted more in favour of regenerative, cell-based options such as autologous matrix-induced chondrogenesis with acellular scaffolds (ACs) and mesenchymal stem cell (MSC) implantation that do not require the harvesting of native articular cartilage. Both ACs and MSCs have proven effective in the treatment of articular cartilage defects of the knee, with evidence supporting good outcomes up to seven years
Long-term Clinical Outcomes of One-Stage Cartilage Repair in the Knee With Hyaluronic Acid-Based Scaffold Embedded With Mesenchymal Stem Cells Sourced From Bone Marrow Aspirate Concentrate.
. As both treatment options have shown efficacy, little evidence exists supporting choosing either treatment option over the other, particularly when comparing MSC treatment with ACs augmented with cBMA due to the marked similarities between the two treatment modalities.
PROMs are commonly used markers of the perceived improvements of a given procedure on a patient
. Many procedures in orthopedic sports medicine are undertaken with the intent of improving patient quality of life, physical function, and pain relief, with PROM scores being direct reflections of the degree of such perceived improvements. Overall, we found that in both ACs and MSC treatment arms, the degree of postoperative improvement in VAS, Tegner and IKDC scores, in addition to being statistically significant, reached values surpassing the MCID – a proposed threshold for gauging the measurable clinically perceivable difference to a patient undergoing a procedure
. These findings compliment the current notion that both ACs and MSC therapy are effective cell-based regenerative therapies for cartilage defects of the knee. Overall, when comparing patients that received MSCs with those that received ACs either with or without cBMA augmentation, the degree of postoperative VAS and Tegner score changes were relatively similar, however, postoperative IKDC score improvement was statistically greater in the overall ACs population as compared to those receiving MSCs. Hence, we conclude that MSCs and ACs either with or without cBMA augmentation are relatively similar in the short-term for pain relief and overall return to activity.
The use of cBMA in the augmentation of ACs procedures is founded on the theory that bone marrow contains a degree of pluripotent mesenchymal stem cells, and hence the introduction of cBMA to the site of cartilage repair aids in the process of chondrocyte differentiation, ultimately improving the degree of cartilage regeneration
Autologous Matrix-Induced Chondrogenesis (AMIC) and AMIC enhanced by autologous concentrated Bone Marrow Aspirate (BMAC) Allow for stable clinical and functional improvements at up to 9 years follow-up: Results from a Randomized controlled study.
. Similarly, the use of MSCs for cartilage regeneration furthers this concept, wherein direct implantation of MSCs results in differentiation into chondrocytes due to their innate pluripotent nature, in addition to the paracrine effects of their secreted bioactive materials
. However, whilst the use of cBMA in the augmentation of ACs procedures is well-established and familiar to many cartilage surgeons, the use of MSCs for cartilage repair is still developing. Additionally, no current recognized guidelines exist for the preparation and use of MSCs in the treatment of articular cartilage defects, which furthers the heterogeneity of the current pool of MSCs used in cartilage repair
. Hence, an amalgam of these factors is a potential explanation as to why despite the theoretical advantage that MSCs convey over simple cBMA augmentation, no measurable advantages were observed when comparing the short-term outcomes of patients treated with MSCs to cBMA-augmented ACs.
Whilst PROM scores are valuable reflections of the impact of a procedure on the functional and symptomatic improvement of a patient, clinical outcomes such as revision surgery, progression to total knee replacement (TKR) and the degree of incomplete defect filling are direct surrogate measures that allow for a clinician to determine the efficacy of a treatment. Whilst the risks of progression to TKR amongst patients receiving MSCs, as well as ACs with or without cBMA augmentation, were relatively similar, patients treated with cBMA-augmented ACs procedures were noted to have significantly lower risks of incomplete defect filling when compared to patients receiving either non-cBMA-augmented ACS (p<0.01) or MSC-based treatments (p<0.01). ACs seeks to regenerate defective articular cartilage by utilizing the acellular scaffold as a nidus for the sequestration and proliferation of autologous chondrocytes
. This process is thought to be aided by the addition of cBMA, which contains pluripotent mesenchymal stem cells and growth factors thought to hasten the process of cartilage regeneration and improve defect filling. Conversely, treatment using MSCs involves directly implanting a scaffold saturated with MSCs into a site of cartilage defect, hence not only are the baseline number of progenitor cells available for differentiation into chondrocytes at the site of defect increased significantly, it is also known that MSCs have the potential to prevent chondrocyte apoptosis through a paracrine effect
. However, despite this theoretical advantage of directly implanting cultured MSCs to a lesion site, practical heterogeneity in the harvesting, preparation, and cultivation of MSCs may be contributory factors as to why the potential benefit of using MSCs is not realized as compared to cBMA-augmented ACs for the filling and repair of cartilage defects.
The postoperative safety profile of acellular scaffolds with or without cBMA augmentation has been well established, with up to a decade of postoperative follow-up data displaying that cartilage regeneration with ACs is safe overall
. However, as the advent of MSCs in cartilage regeneration is comparatively newer, the evidence supporting the safety profile is not as well established. Primary surrogates for safety of cartilage repair procedures are the avoidance of adverse events in the postoperative period such as arthrofibrosis and revision surgeries. In our systematic review of the studies reporting such events, we observed that for the short postoperative term of up to three years, rates of revision surgery and postoperative arthrofibrosis are comparable between patients receiving either ACs or MSCs. Whilst more studies with long-term evidence are required to make a complete assessment of the safety profile of MSCs in relation to ACs, preliminary results are supportive of comparative safety profiles.
IMPLICATIONS OF KEY FINDINGS
Whilst both ACs and MSCs are effective for the treatment of critical size cartilage defects of the knee, ACs with cBMA augmentation potentially yields marginally better short-term outcomes when compared to MSCs implanted on scaffolds. This suggest that despite the increasing availability of MSCs as a treatment modality for cartilage lesions of the knee, ACs with cBMA augmentation remains a competitive and cost-effective option for cartilage repair in the present day. Ultimately, more long-term evidence on the use of MSCs is required to fully evaluate the comparability of ACs and MSCs in terms of both patient outcomes and the cost-effectiveness of both interventions. (Table 3)
Table 3Summary of Postoperative Functional Score Improvements
cBMA, concentrated bone marrow aspirate; IKDC, International Knee Documentation Committee; ACs, Acellular Scaffolds; MSC, Mesenchymal Stem Cell; VAS, visual analog scale; WMD, weighted mean difference.
This manuscript received no research funding, however, the following authors declare the following unrelated financial interests
Level of Evidence
III–Meta-Analysis of Level I-III Studies
Declaration of Competing Interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dean Wang: Hospitality payments from Arthrex, DePuy Synthes Sales, Stryker Corporation, Linvatec Corporation Consulting fees from Ipsen Biosciences Education payments from Arthrex, Smith & Nephew; Keng Lin Wong: Paid Honorarium for Lectures: 3M-KCI, Urgo Medical, Molnlycke, CellResearch Corp
Intraarticular injuries associated with anterior cruciate ligament tear: findings at ligament reconstruction in high school and recreational athletes. An analysis of sex-based differences.
Does the Choice of Acellular Scaffold and Augmentation With Bone Marrow Aspirate Concentrate Affect Short-term Outcomes in Cartilage Repair? A Systematic Review and Meta-analysis.
The American Journal of Sports Medicine.2022; 03635465211069565
Combining a novel leucocyte–platelet-concentrated membrane and an injectable collagen scaffold in a single-step AMIC procedure to treat chondral lesions of the knee: a preliminary retrospective study.
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.
One-step surgery with multipotent stem cells and Hyaluronan-based scaffold for the treatment of full-thickness chondral defects of the knee in patients older than 45 years.
Long-term Clinical Outcomes of One-Stage Cartilage Repair in the Knee With Hyaluronic Acid-Based Scaffold Embedded With Mesenchymal Stem Cells Sourced From Bone Marrow Aspirate Concentrate.
Valgus high tibial osteotomy and bone-marrow-derived cells transplantation: Clinical and radiological results after a 3-year follow-up in varus osteoarthritis of the knee.
Autologous Matrix-Induced Chondrogenesis (AMIC) and AMIC enhanced by autologous concentrated Bone Marrow Aspirate (BMAC) Allow for stable clinical and functional improvements at up to 9 years follow-up: Results from a Randomized controlled study.
Management of Patellar Chondral Defects with Autologous Matrix Induced Chondrogenesis (AMIC) Compared to Microfractures: A Four Years Follow-Up Clinical Trial.
Allogenic umbilical cord blood-derived mesenchymal stromal cell implantation was superior to bone marrow aspirate concentrate augmentation for cartilage regeneration despite similar clinical outcomes.
Comparison of Bone Marrow Aspirate Concentrate and Allogenic Human Umbilical Cord Blood Derived Mesenchymal Stem Cell Implantation on Chondral Defect of Knee: Assessment of Clinical and Magnetic Resonance Imaging Outcomes at 2-Year Follow-Up.
Orthopaedics, Traumatology Society of Western F. Treatment of large deep osteochondritis lesions of the knee by autologous matrix-induced chondrogenesis (AMIC): Preliminary results in 13 patients.
A useful combination for the treatment of patellofemoral chondral lesions: realignment procedure plus mesenchymal stem cell—retrospective analysis and clinical results at 48 months of follow-up.
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Collagen-Covered Autologous Chondrocyte Implantation Versus Autologous Matrix-Induced Chondrogenesis: A Randomized Trial Comparing 2 Methods for Repair of Cartilage Defects of the Knee.
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Matrix-induced autologous mesenchymal stem cell implantation versus matrix-induced autologous chondrocyte implantation in the treatment of chondral defects of the knee: a 2-year randomized study.
Similar Short-term Results Between Scaffold Implanted Mesenchymal Stem Cells versus Acellular Scaffolds with Concentrated Bone Marrow Aspirate Augmentation for the Repair of Chondral Defects of the Knee: Evidence from a Meta-Analysis
Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
Musculoskeletal Sciences Academic Clinical Programme, Duke-NUS Graduate Medical School, Singapore
Department of Orthopaedic Surgery, Sengkang General Hospital, Singapore
Correspondence
Corresponding Author: Keng Lin WONG, Department of Orthopaedic Surgery, Sengkang General Hospital, Musculoskeletal Sciences ACP, Singhealth-DukeNUS Graduate Medical School, Sengkang General Hospital, 110 Sengkang East Way Singapore 544886, DID: (65) 6930 5365 ,Mobile: (65) 97116395
Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
Musculoskeletal Sciences Academic Clinical Programme, Duke-NUS Graduate Medical School, Singapore
Department of Orthopaedic Surgery, Sengkang General Hospital, Singapore
Correspondence
Corresponding Author: Keng Lin WONG, Department of Orthopaedic Surgery, Sengkang General Hospital, Musculoskeletal Sciences ACP, Singhealth-DukeNUS Graduate Medical School, Sengkang General Hospital, 110 Sengkang East Way Singapore 544886, DID: (65) 6930 5365 ,Mobile: (65) 97116395
Scaffold-implanted mesenchymal stem cells (MSCs) are gaining popularity for the treatment of cartilage defects. However, there is little evidence comparing its efficacy against the currently well-established technique of utilizing acellular scaffolds (ACs) with concentrated bone marrow aspirate (cBMA) for treating knee chondral defects.
Objectives
To compare scaffold-implanted MSCs against ACs with cBMA for the repair of knee cartilage lesions.
Data Sources
MEDLINE and Embase
Study Eligibility Criteria, Participants, and Interventions
Inclusion: (1) Studies involving patients with high grade chondral lesions on the tibiofemoral or patellofemoral articular surfaces, (2) Studies involving patients that received either scaffold-implanted MSCs or ACs for treatment, and (3) Studies with postoperative patient follow-up of at least two years.
Study Appraisal and Synthesis Methods
Single-arm meta-analysis of studies reporting patient-reported outcome measures (PROMs), reoperation and incomplete filling rates was performed.
Results
Degree of postoperative IKDC score improvement in patients receiving ACs augmented with cBMA was significantly higher compared to those receiving scaffold-implanted MSCs (p<0.01). Additionally, patients receiving ACs with cBMA augmentation were at significantly lower risk of incomplete defect filling when compared to patients receiving either scaffold-implanted MSCs (p<0.01), or patients receiving non-cBMA augmented ACs (p<0.01).
Conclusion
This meta-analysis demonstrates that cartilage repair with ACs with cBMA augmentation yields marginally better short-term outcomes when compared to scaffold-implanted MSCs. This suggests that even with the advent of MSCs increasing in availability as a treatment modality, ACs with cBMA augmentation remains as a competitive, cost-effective option for cartilage repair.
Articular cartilage injuries of the knee are common, with many defects detected incidentally in otherwise asymptomatic individuals1x1Piasecki, DP, Spindler, KP, Warren, TA, Andrish, JT, and Parker, RD. Intraarticular injuries associated with anterior cruciate ligament tear: findings at ligament reconstruction in high school and recreational athletes. An analysis of sex-based differences. Am J Sports Med. 2003;
31: 601–605 Crossref | PubMed | Scopus (145) | Google ScholarSee all References. However, articular cartilage injuries are a spectrum of disease comprising of a range of patients, from asymptomatic individuals with small, focal lesions, to patients with large, degenerative defects and end staged osteoarthritis2x2Merkely, G, Ackermann, J, and Lattermann, C. Articular Cartilage Defects: Incidence, Diagnosis, and Natural History. Operative Techniques in Sports Medicine. 2018;
26: 156–161 Crossref | Scopus (19) | Google ScholarSee all References. Despite the prevalence of such injuries, only critically sized (>1.5cm2x2Merkely, G, Ackermann, J, and Lattermann, C. Articular Cartilage Defects: Incidence, Diagnosis, and Natural History. Operative Techniques in Sports Medicine. 2018;
26: 156–161 Crossref | Scopus (19) | Google ScholarSee all References), symptomatic cartilage defects truly warrant intervention. Treatment of such defects is challenging due to the aneural, avascular and alymphatic nature of cartilage, resulting in a poor native environment for healing3x3Benedek, TG. A history of the understanding of cartilage. Osteoarthritis Cartilage. 2006;
14: 203–209 Abstract | Full Text | Full Text PDF | PubMed | Scopus (29) | Google ScholarSee all References. Consequently, the current paradigm of cartilage defect treatment is directed towards regenerative therapy, of which two prominent modalities are that of acellular scaffolds (ACs) and scaffold-implanted mesenchymal stem cells (MSC). ACs is a single-surgery, non-cell-based therapy that involves the marrow stimulation of blood rich in growth factors, which then migrates and clots at the site of cartilage defect, maturing and differentiating into fibrocartilage tissue4x4Calcei, JG, Ray, T, Sherman, SL, and Farr, J. Management of Large Focal Chondral and Osteochondral Defects in the Knee. J Knee Surg. 2020;
33: 1187–1200 Crossref | PubMed | Scopus (7) | Google ScholarSee all References. Conversely, MSC-based therapy is a staged cell-based therapy that involves stem-cells sourced from mesenchymal tissue, which are harvested and cultured prior to implantation at the lesion site. Ultimately, the aim of this treatment modality is to induce endogenous growth and activate self-proliferation of progenitor cells to promote cartilage regeneration5x5Debnath, UK. Mesenchymal Stem Cell Therapy in Chondral Defects of Knee: Current Concept Review. Indian J Orthop. 2020;
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Although both methods have shown therapeutic potential, the relative efficacy of MSC-based therapy compared to ACs is still uncertain, and there remains a lack of consensus as to which cartilage repair procedure results in the best patient outcomes. Moreover, cost effectiveness remains the most prominent barrier to routine adoption of MSC-based therapy6x6Davies, BM, Rikabi, S, French, A et al. Quantitative assessment of barriers to the clinical development and adoption of cellular therapies: A pilot study. J Tissue Eng. 2014;
5: 2041731414551764 Crossref | PubMed | Scopus (17) | Google ScholarSee all References. Hence, strong evidence is required to truly justify the cost-effective adoption of MSC-based therapy, particularly with recent evidence displaying that ACs with cBMA augmentation result in good clinical and radiological outcomes for patients with focal chondral defects of the knee7x7Ow, ZGW, Cheang, HLX, Koh, JH et al. Does the Choice of Acellular Scaffold and Augmentation With Bone Marrow Aspirate Concentrate Affect Short-term Outcomes in Cartilage Repair? A Systematic Review and Meta-analysis. The American Journal of Sports Medicine. 2022;
: 03635465211069565 Crossref | Scopus (1) | Google ScholarSee all References. The biological component of acellular scaffold cartilage repair, provided by cBMA, may provide a lower cost yet clinically efficacious alternative to MSCs.
OBJECTIVES
This study aims to, through the use of a systematic-review and meta-analysis of existing literature, compare the clinical outcomes of acellular scaffolds (ACs) augmented with bone marrow aspirate concentrate (cBMA) against scaffold-implanted MSC-based procedures in the treatment of critically sized chondral defects of the knee.
DATA SOURCES
This review was synthesized with reference to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines8x8Page, MJ, McKenzie, JE, Bossuyt, PM et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;
372: n71 Crossref | PubMed | Scopus (12118) | Google ScholarSee all References. Medline and Embase electronic databases were systematically searched on the 23rd of Nov 2022 using keywords and terms synonymous with the knee, articular cartilage, matrix-induced chondrogenesis and stem cells. Additionally, references from included studies and pertinent review articles were manually trawled to identify other potential studies meeting the selection criteria. The search was limited to articles written in the English language. An example of the search strategy can be found within the supplementary material.
STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTIONS
Studies describing the post-operative outcomes of patients undergoing cartilage repair procedures were included in this review. Criteria for inclusion were met if studies had all of the following characteristics.
(1)
Patients with chondral lesions on the tibiofemoral or patellofemoral articular surfaces of Outerbridge or International Cartilage Restoration and Joint Preservation Society (ICRS) grade III and above
(2)
Patients undergoing either autologous matrix-induced chondrogenesis (ACs), with or without concomitant concentrated bone marrow aspirate (cBMA) augmentation, or mesenchymal stem-cell (MSC) derived cartilage repair procedures.
(3)
Studies with a minimum mean postoperative follow-up period duration of two years.
Studies were excluded if they did not meet all of the inclusion criteria or met any of the following exclusion criteria.
(1)
Involved patients undergoing any form of autologous chondrocyte implantation procedures.
(2)
Failed to acceptably report the method of cartilage repair used.
(3)
Published in a non-English language without interpretable translations.
(4)
Were letters to the editor, review articles or editorials.
(5)
Involved patient data from glaringly overlapping datasets with other included studies.
However, different studies involving patients belonging to the same database were considered for inclusion provided each study reported different patient outcomes. No outcomes extracted from the included studies were of overlapping patient datasets.
STUDY APPRAISAL AND SYNTHESIS METHODS
Study Selection
The inclusion of an article was evaluated by an independent blinded pair of authors (ZGWO and KLKL), with any disagreements being resolved by obtaining the consensus of a senior author (KLW). Inter-rater agreement was quantified by use of Cohen's Kappa statistic coefficient, k. Standard agreement definition was used, with the degrees of inter-rater agreement being categorized into the following ranges: poor (k=0.00-0.20), fair (k=0.21-0.40), moderate (k=0.41-0.60), substantial (k=0.61-0.80), and almost perfect (k=0.81-1.00)9x9McHugh, ML. Interrater reliability: the kappa statistic. Biochem Med (Zagreb). 2012;
22: 276–282 Crossref | PubMed | Google ScholarSee all References.
Data Extraction
Data extraction was performed to extract study characteristics (study period, location, and follow-up times), baseline characteristics (age, gender, cartilage status, and lesion size), and postoperative outcomes (functional scores, complications, radiological findings). Means and standard deviations were extracted for the pooling of continuous outcome data, and when such forms were unavailable and instead presented as medians with ranges, we employed previously established formulae by Wan et al in the conversion of data to means with standard deviations10x10Wan, X, Wang, W, Liu, J, and Tong, T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Medical Research Methodology. 2014;
14: 135 Crossref | PubMed | Scopus (3977) | Google ScholarSee all References. Binary outcome data was extracted in the form of the number of events that occurred per sample size.
Studies were categorized primarily by the method of cartilage repair, namely stem cells and ACs. Within the ACs group, a further subgroup was introduced, namely that of cBMA and non-cBMA augmented ACs procedures.
Outcomes of Interest
Primary outcomes of interest were that of patient reported outcome measures (PROMs), namely, the ten-point visual analogue score for pain (VAS), International Knee Documentation Committee (IKDC) score, as well as the Lysholm and Tegner scores for physical function. Other additional outcomes of interest were the rates of incomplete defect filling, as reported following postoperative radiological evaluation of cartilage defects, as well as the rates of revision cartilage repair procedures and progression to total knee arthroplasty.
Statistical Analysis
Continuous and binary outcome data were analyzed in separate manners, with all data being analyzed using RStudio, version 1.3.1093 (RStudio, Boston, Massachusetts). Continuous data comprised of PROM scores, as presented by studies in a pre/post-operative comparison. Hence, such data underwent pairwise meta-analyses using the metacont function of the R meta package, with pooled continuous data comparisons being presented in the form of the weighted mean differences between pre- and post-operative PROM scores using the inverse variance model with random effects applied.
Binary outcomes were analyzed in a single-arm fashion. Single-arm meta-analysis was performed to synthesize observational data for continuous and binary outcomes using the metaprop function of the R meta package. Binary outcome data was pooled in the form of proportions, using the generalized linear mixed model (GLMM), a statistical model that results in smaller biases and mean squared errors with higher coverage probabilities than traditional two-step models such as the DerSimonian and Laird random effects model, another commonly used statistical model in meta-analyses11x11Lin, L and Chu, H. Meta-analysis of Proportions Using Generalized Linear Mixed Models. Epidemiology. 2020;
31: 713–717 Crossref | PubMed | Scopus (65) | Google ScholarSee all References.
Based on the pooled proportions of single-arm studies, the respective relative risks () of binary outcome (e.g incomplete filling, reoperation rates, progression to knee arthroplasty) occurrence were respectively calculated as the ratio of the pooled proportions of event occurrence rates12x12Koo, CH, Chang, JHE, Syn, NL, Wee, IJY, and Mathew, R. Systematic Review and Meta-analysis on Colorectal Cancer Findings on Colonic Evaluation After CT-Confirmed Acute Diverticulitis. Dis Colon Rectum. 2020;
63: 701–709 Crossref | PubMed | Scopus (19) | Google ScholarSee all References. The lower () and upper () bounds for the 95% confidence intervals were estimated using the Katz-logarithmic method, wherein n1 and n2 represent the respective number of patients in each of the treatment arms being evaluated. Additionally, the p value was calculated after a natural log transformation of the relative risk z-score13x13Katz, D, Baptista, J, Azen, SP, and Pike, MC. Obtaining Confidence Intervals for the Risk Ratio in Cohort Studies. Biometrics. 1978;
34: 469–474 Crossref | Scopus (303) | Google ScholarSee all References. The specific formula used to approximate the confidence intervals and p-values can be found within the supplementary material.
Investigating Heterogeneity
We assessed statistical heterogeneity amongst studies by visual inspection of forest plots, as well as I2 and Cochran's Q test values. I2 values of 0%–40% were suggestive of insignificant degrees of heterogeneity, while values of 30%–60%, 50%–90%, and 75%–100% were classified as moderate, substantial, and considerable heterogeneity, respectively14x14Deeks, JJ, Higgins, JP, and Altman, DG. Analysing Data and Undertaking Meta-Analyses. Cochrane Handbook for Systematic Reviews of Interventions. 2008;
: 243–296 Crossref | Scopus (3868) | Google ScholarSee all References. Additionally, other potential sources of heterogeneity were explored through the use of subgroup and sensitivity analyses where appropriate. Publication bias was assessed by the asymmetry of the respective funnel plots. P-values <0.05 were considered statistically significant.
Risk of Bias and Quality Assessment
Whilst the statistical analyses were performed both in a pairwise and single-arm fashion, the results of the included studies were interpreted in a single-arm, non-comparative fashion. Hence, we employed a modified risk of bias assessment as described by Hoy et al, specifically tailored to the bias assessment of single-arm studies15x15Hoy, D, Brooks, P, Woolf, A et al. Assessing risk of bias in prevalence studies: modification of an existing tool and evidence of interrater agreement. J Clin Epidemiol. 2012;
65: 934–939 Abstract | Full Text | Full Text PDF | PubMed | Scopus (1296) | Google ScholarSee all References. Quality assessment of included articles was performed using the Newcastle-Ottawa Scale (NOS) for cohort studies16x16Wells, G, Shea, B, and O'Connell, J. The Newcastle-Ottawa Scale (NOS) for Assessing The Quality of Nonrandomised Studies in Meta-analyses. Ottawa Health Research Institute Web site. 2014;
7 Google ScholarSee all References and the Jadad scale for randomized controlled trials17x17Jadad, AR, Moore, RA, Carroll, D et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary?. Control Clin Trials. 1996;
17: 1–12 Abstract | Full Text PDF | PubMed | Scopus (13638) | Google ScholarSee all References. The NOS grades each article on the cohort selection, as well as the adequacy of outcomes measured, whilst the Jadad scale assesses trials on the adequacy of randomization, blinding and analysis and reporting of outcomes.
RESULTS
Summary of Included Articles
A systematic search of the literature utilizing our search strategy yielded a total of 1,003 references, with 785 remaining after removal of duplicates. These 785 references were screened as abstracts with the preliminary inclusion criteria applied, following which 677 were excluded based on failing to meet the predetermined inclusion criteria. A total of 108 full texts articles underwent review, wherein both the predetermined inclusion and exclusion criteria were applied in the selection of full texts references. Of these 108 full text references sieved, 39 articles fulfilled all inclusion and exclusion criteria satisfactorily and were subsequently included in the meta-analysis (Figure 1Figure 1). In summary, 10 articles originated from Italy18x18D'Antimo, C, Biggi, F., Borean, A., Di Fabio, S., and Pirola, I. Combining a novel leucocyte–platelet-concentrated membrane and an injectable collagen scaffold in a single-step AMIC procedure to treat chondral lesions of the knee: a preliminary retrospective study. Eur J Orthop Surg Traumatol. 2017;
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135: 251–263 Crossref | PubMed | Scopus (108) | Google ScholarSee all References. In total, 19 studies had a prospective study design, 13 were retrospective in nature, and six were randomized controlled trials (RCTs). A summary of the included studies can be found in Table 1Table 1, whilst a summary of the individual risks of bias and quality assessment of the included studies can be found within the supplementary material.
cBMA: Concentrated Bone Marrow Aspirate; SD: Standard Deviation; NR: Not Reported; TS: Tachosil; PB: Peripheral Blood
Patient Demographics
A total of 965 patients underwent cartilage repair procedures utilizing either ACs, with or without cBMA augmentation, or scaffold-implanted MSC-based therapy, of which 477 (49.4%) received non-augmented ACs therapy, 251 (26.0%) received ACs augmented with cBMA, and 237 (24.6%) received MSCs implanted on bioscaffolds. Patient demographics such as age, follow-up period and lesion size were pooled as raw weighted means. The mean age of patients overall was 39.8 years (36.9 to 42.7). The mean age of patients that underwent non-augmented ACs cartilage repair procedures was 36.0 years (CI: 33.4 to 38.7), patients receiving ACs with cBMA augmentation had a mean age of 44.0 years (CI: 39.3 to 48.6), and patients that underwent MSC-based therapy had a mean age of 44.3 years (CI: 34.6 to 54.0). Mean lesion size was 3.8 cm2 (CI: 3.3 to 4.3) in the unaugmented ACs arm, 6.7 cm2 (CI: 4.8 to 8.5) in the group of patients receiving ACs with cBMA augmentation, and 4.9 cm2 (CI: 3.9 to 5.8) in the MSC arm. Mean follow-up of patients after treatment of cartilage defects was 39.6 months (CI: 31.2 to 46.9) overall, 40.1 months (CI: 28.6 to 51.6) in the non-cBMA augmented ACs arm, 50.1 months (CI: 34.2 to 65.9) in the cBMA augmented ACs arm, and 25.3 months (CI: 20.9 to 29.8) in the scaffold-implanted MSC arm. Mean body mass index (BMI) scores were 26.5 kg/m2 (CI: 25.7 to 27.2) in the non-cBMA augmented ACs arm, 25.4 kg/m2 (CI: 24.3 to 26.5) in the ACs with cBMA arm, and 25.7 kg/m2 (CI: 24.8 to 26.7) in the scaffold-implanted MSC arm. A breakdown of demographic information by relevant treatment subgroups is presented in Table 2Table 2.
Patients that received either ACs, with or without cBMA augmentation, (WMD = 38.2; CI: 33.7 to 42.6, p<0.01), or MSCs (WMD = 31.6; CI: 28.3 to 34.9, p<0.01) experienced significant postoperative improvements in IKDC scores. Those that received ACs displayed a statistically greater degree of postoperative IKDC improvement than those receiving MSCs (p=0.02), but this difference failed to reach the value of minimum clinically important difference (MCID) for the IKDC score (Figure 2Figure 2). Similarly, patients receiving MSCs (WMD = -4.4; CI: -4.8 to -4.1; p<0.01) and either non- or cBMA-augmented ACs (WMD = -4.2; CI: -4.6 to -3.8; p<0.01) experienced significant postoperative improvements in VAS scores. However, this difference between the two subgroups was not significant (p=0.45). Postoperative Tegner score improvement in patients undergoing cartilage repair with ACs, either with or without cBMA augmentation (WMD = 2.1; CI: 1.2 to 2.9; p<0.01), as well as those that received MSCs (WMD = 1.7; CI: 0.8 to 2.7; p<0.01) showed significant improvements in the postoperative Tegner score. However, the differences in the degree of postoperative Tegner score changes between the two treatment groups failed to reach statistical significance (p=0.63).
Figure 2
Forest Plot of Postoperative International Knee Documentation Committee Score Improvement, Comparing Acellular Scaffolds versus Scaffold-Implanted Mesenchymal Stem-Cells
In terms of postoperative IKDC scores, both patients that underwent either cBMA augmented ACs procedures (WMD = 38.1; CI: 34.5 to 41.7, p<0.01), or MSC-based treatments (WMD = 31.6; CI: 28.3 to 34.9; p<0.01) experienced significant postoperative improvements. Subgroup analysis comparing the two arms displayed a statistically significant difference (p<-0.01) in the degree of postoperative IKDC improvements that failed to reach the proposed MCID value for the IKDC score (Figure 3Figure 3). VAS scores were significantly improved postoperatively in both patients that underwent ACs augmented with cBMA (WMD = -4.5; CI: -5.1 to -3.8; p<0.01) as well as those that underwent cartilage repair procedures with MSCs (WMD = -4.4; CI: -4.8 to -4.1; p<0.01), with the difference between both subgroups showing no statistically significant difference in the degree of postoperative VAS improvements (p=0.98). Similarly, postoperative Tegner score improvements were significant in both the group of patients receiving ACs augmented with cBMA (WMD = 2.5; CI: 1.6 to 3.4; p<0.01), as well as those that underwent MSC-based therapies (WMD = 1.7; CI: 0.8 to 2.7, p<0.01), with the difference in degree of Tegner score improvements displaying no statistical significance (p=0.27).
Figure 3
Forest Plot of Postoperative International Knee Documentation Committee Score Improvement, Comparing Acellular Scaffolds (Bone Marrow Aspirate Concentrate Augmented Subgroup) versus Scaffold-Implanted Mesenchymal Stem-Cells
Postoperative Tegner score improvement was significant in patients that underwent cartilage repair with MSCs (WMD = 1.7; CI: 0.8 to 2.7, p<0.01), but failed to reach statistical significance in patients that underwent non-cBMA augmented ACs procedures (WMD = 1.0; CI: 0.4 to 1.7; p=0.42), however, this difference in the degrees of postoperative Tegner score improvement failed to reach statistical significance (p=0.22). VAS scores in patients that received MSCs (WMD = -4.4; CI: -4.8 to -4.1; p<0.01) as well as the patients that underwent non-cBMA augmented ACs procedures (WMD = -4.1; CI: -4.5 to -3.7; p<0.01) were significantly improved postoperatively, however no statistically significant differences were found in the degree of VAS score improvements when comparing both arms (p=0.25). Similarly, Postoperative IKDC scores were significantly improved in both the MSC group (WMD = 31.6; CI: 28.3 to 34.9; p<0.01) as well as the non-cBMA augmented ACs treatment group (WMD = 38.1; CI: 28.3 to 48.0; p<0.01). However, this difference in the degree of IKDC score improvement was not statistically significant (p=0.22)
Dichotomous Outcomes
Incomplete filling
Studies that reported incomplete defect filling measured this outcome via magnetic resonance imaging (MRI) at final follow-up. The overall rate of incomplete defect filling was 28.0% (CI: 19.5 to 38.5) in patients that received ACs either with or without cBMA augmentation, whilst the rate of incomplete defect filling was 36.5% (CI: 19.1 to 58.3) in patients treated with MSCs. Patients receiving non-cBMA augmented ACs had a 35.8% (CI: 22.8 to 51.4) rate of incomplete defect filling, whilst patients that underwent cBMA-augmented ACs procedures had an incomplete defect filling rate of 18.7% (CI: 12.4 to 27.2). Patients that underwent cBMA augmented ACs procedures were observed to be at a lower relative risk of incomplete defect filling as compared to either those that received MSCs (RR = 0.5; CI: 0.3 to 0.8, p<0.01), or patients that underwent ACs without cBMA augmentation (RR = 0.5; CI: 0.3 to 0.8; p<0.01).
Progression to TKR
Progression to total knee replacement (TKR) was reported as an outcome at final follow-up timepoints by the included studies. In patients undergoing MSC-based cartilage repair procedures, the rate of progression to TKR was 2.2% (CI: 0.3 to 13.9), whilst the rate of progression to TKR in patients receiving either cBMA- or non-cBMA-augmented ACs procedures was 3.4% (CI: 1.4 to 8.0). Individually, the rates of TKR progression in the cBMA-augmented ACs treatment group was 1.8% (CI: 0.3 to 11.4), and 4.5% (CI: 1.7 to 11.4) in the non-cBMA-augmented treatment arm. No significant differences in the relative risks of progression to TKR were observed for patients undergoing any of the various cartilage repair procedures.
Revision Surgery and Postoperative Arthrofibrosis
Revision surgery was defined, by the studies reporting the outcome, as the necessity of a revision cartilage repair procedure due to persistent pain and failure of symptomatic improvement within the follow-up period. Revision surgery was reported by 10 studies involving patients undergoing ACs procedures either with or without cBMA augmentation, as well as one study involving patients that received MSCs. Akgun et al56x56Akgun, I, Unlu, M.C., Erdal, O.A., Ogut, T., Erturk, M., Ovali, E., Kantarci, F., Caliskan, G., and Akgun, Y. Matrix-induced autologous mesenchymal stem cell implantation versus matrix-induced autologous chondrocyte implantation in the treatment of chondral defects of the knee: a 2-year randomized study. Arch Orthop Trauma Surg. 2015;
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LIMITATIONS
This review is the first to directly compare the effects of ACs and MSC treatments for the repair of articular cartilage defects of the knee, as well as evaluating the effect of cBMA on the efficacy of ACs procedures when compared to MSCs. However, the results and conclusions of this review should be interpreted in view of several inherent limitations. Primarily, there is a paucity of long-term evidence surrounding the ACs and MSCs in the treatment of articular cartilage defects, particularly due to the relative novelty of MSCs as a treatment modality. As such, the evidence gathered from this review should be interpreted with short-term outcome improvements in mind. Furthermore, there is a known significant difference in PROMs between chondral lesions on tibiofemoral versus patellofemoral surfaces, both of which were included in the reported data. This, along with differing mean lesion size and follow-up time between groups, serve as unavoidable confounders of the results. Additionally, due to the sparse data of the individual types of MSCs, we were unable to compare the efficacies of each MSC type, resulting in an inherent degree of study heterogeneity that could not be controlled for through conventional means. Similarly due to the small sample sizes of the included studies, the degree of statistical heterogeneity as measured by the I2 statistic was largely varied. Finally, whilst some studies had a randomized design, no formal blinding of patients to treatment was performed in any of the included studies, thus we were unable to evaluate the potential existence of a placebo effect amongst the treatment arms.
CONCLUSIONS
Currently, numerous cell-based treatment options are available to surgeons for the repair of articular cartilage defects of the knee. Osteochondral allograft transfer (OAT) and autologous chondrocyte implantation or ACI have long been the mainstays of treatment, with up to two decades of evidence supporting the efficacy of such techniques57x57Ogura, T, Mosier, BA, Bryant, T, and Minas, T. A 20-Year Follow-up After First-Generation Autologous Chondrocyte Implantation. Am J Sports Med. 2017;
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32: 2160–2168 Abstract | Full Text | Full Text PDF | PubMed | Scopus (103) | Google ScholarSee all References. However, OAT requires adequate non-weightbearing articular cartilage for harvest and ACI requires a delayed staged surgery due to the harvesting and expansion of autologous chondrocytes, which have long been the selection caveats for both treatment options. As such, the recent paradigm has shifted more in favour of regenerative, cell-based options such as autologous matrix-induced chondrogenesis with acellular scaffolds (ACs) and mesenchymal stem cell (MSC) implantation that do not require the harvesting of native articular cartilage. Both ACs and MSCs have proven effective in the treatment of articular cartilage defects of the knee, with evidence supporting good outcomes up to seven years25x25Gobbi, A and Whyte, G.P. Long-term Clinical Outcomes of One-Stage Cartilage Repair in the Knee With Hyaluronic Acid-Based Scaffold Embedded With Mesenchymal Stem Cells Sourced From Bone Marrow Aspirate Concentrate. Am J Sports Med. 2019;
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PROMs are commonly used markers of the perceived improvements of a given procedure on a patient60x60Ow, ZGW, Cheong, CK, Hai, HH et al. Securing Transplanted Meniscal Allografts Using Bone Plugs Results in Lower Risks of Graft Failure and Reoperations: A Meta-analysis. Am J Sports Med. 2021;
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6: e2 Crossref | PubMed | Scopus (67) | Google ScholarSee all References. These findings compliment the current notion that both ACs and MSC therapy are effective cell-based regenerative therapies for cartilage defects of the knee. Overall, when comparing patients that received MSCs with those that received ACs either with or without cBMA augmentation, the degree of postoperative VAS and Tegner score changes were relatively similar, however, postoperative IKDC score improvement was statistically greater in the overall ACs population as compared to those receiving MSCs. Hence, we conclude that MSCs and ACs either with or without cBMA augmentation are relatively similar in the short-term for pain relief and overall return to activity.
The use of cBMA in the augmentation of ACs procedures is founded on the theory that bone marrow contains a degree of pluripotent mesenchymal stem cells, and hence the introduction of cBMA to the site of cartilage repair aids in the process of chondrocyte differentiation, ultimately improving the degree of cartilage regeneration27x27De Girolamo, L, Schönhuber, H, Viganò, M et al. Autologous Matrix-Induced Chondrogenesis (AMIC) and AMIC enhanced by autologous concentrated Bone Marrow Aspirate (BMAC) Allow for stable clinical and functional improvements at up to 9 years follow-up: Results from a Randomized controlled study. Journal of Clinical Medicine. 2019;
8 Crossref | Scopus (33) | Google ScholarSee all References. Similarly, the use of MSCs for cartilage regeneration furthers this concept, wherein direct implantation of MSCs results in differentiation into chondrocytes due to their innate pluripotent nature, in addition to the paracrine effects of their secreted bioactive materials62x62Barry, F and Murphy, M. Mesenchymal stem cells in joint disease and repair. Nat Rev Rheumatol. 2013;
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1: 169–178 Crossref | PubMed | Scopus (187) | Google ScholarSee all References. However, whilst the use of cBMA in the augmentation of ACs procedures is well-established and familiar to many cartilage surgeons, the use of MSCs for cartilage repair is still developing. Additionally, no current recognized guidelines exist for the preparation and use of MSCs in the treatment of articular cartilage defects, which furthers the heterogeneity of the current pool of MSCs used in cartilage repair65x65Wang, Y-H, Tao, Y-C, Wu, D-B, Wang, M-L, Tang, H, and Chen, E-Q. Cell heterogeneity, rather than the cell storage solution, affects the behavior of mesenchymal stem cells in vitro and in vivo. Stem Cell Res Ther. 2021;
12: 391 Crossref | PubMed | Scopus (5) | Google ScholarSee all References. Hence, an amalgam of these factors is a potential explanation as to why despite the theoretical advantage that MSCs convey over simple cBMA augmentation, no measurable advantages were observed when comparing the short-term outcomes of patients treated with MSCs to cBMA-augmented ACs.
Whilst PROM scores are valuable reflections of the impact of a procedure on the functional and symptomatic improvement of a patient, clinical outcomes such as revision surgery, progression to total knee replacement (TKR) and the degree of incomplete defect filling are direct surrogate measures that allow for a clinician to determine the efficacy of a treatment. Whilst the risks of progression to TKR amongst patients receiving MSCs, as well as ACs with or without cBMA augmentation, were relatively similar, patients treated with cBMA-augmented ACs procedures were noted to have significantly lower risks of incomplete defect filling when compared to patients receiving either non-cBMA-augmented ACS (p<0.01) or MSC-based treatments (p<0.01). ACs seeks to regenerate defective articular cartilage by utilizing the acellular scaffold as a nidus for the sequestration and proliferation of autologous chondrocytes66x66Benthien, JP and Behrens, P. Autologous Matrix-Induced Chondrogenesis (AMIC): Combining Microfracturing and a Collagen I/III Matrix for Articular Cartilage Resurfacing. Cartilage. 2010;
1: 65–68 Crossref | PubMed | Scopus (86) | Google ScholarSee all References. This process is thought to be aided by the addition of cBMA, which contains pluripotent mesenchymal stem cells and growth factors thought to hasten the process of cartilage regeneration and improve defect filling. Conversely, treatment using MSCs involves directly implanting a scaffold saturated with MSCs into a site of cartilage defect, hence not only are the baseline number of progenitor cells available for differentiation into chondrocytes at the site of defect increased significantly, it is also known that MSCs have the potential to prevent chondrocyte apoptosis through a paracrine effect67x67Le, H, Xu, W, Zhuang, X, Chang, F, Wang, Y, and Ding, J. Mesenchymal stem cells for cartilage regeneration. Journal of tissue engineering. 2020;
11: 2041731420943839 (-2041731420943839) Crossref | PubMed | Scopus (77) | Google ScholarSee all References. However, despite this theoretical advantage of directly implanting cultured MSCs to a lesion site, practical heterogeneity in the harvesting, preparation, and cultivation of MSCs may be contributory factors as to why the potential benefit of using MSCs is not realized as compared to cBMA-augmented ACs for the filling and repair of cartilage defects.
The postoperative safety profile of acellular scaffolds with or without cBMA augmentation has been well established, with up to a decade of postoperative follow-up data displaying that cartilage regeneration with ACs is safe overall45x45Kaiser, N, Jakob, R.P., Pagenstert, G., Tannast, M., and Petek, D. Stable clinical long term results after AMIC in the aligned knee. Arch Orthop Trauma Surg. 2020;
13: 13 Google ScholarSee all References. However, as the advent of MSCs in cartilage regeneration is comparatively newer, the evidence supporting the safety profile is not as well established. Primary surrogates for safety of cartilage repair procedures are the avoidance of adverse events in the postoperative period such as arthrofibrosis and revision surgeries. In our systematic review of the studies reporting such events, we observed that for the short postoperative term of up to three years, rates of revision surgery and postoperative arthrofibrosis are comparable between patients receiving either ACs or MSCs. Whilst more studies with long-term evidence are required to make a complete assessment of the safety profile of MSCs in relation to ACs, preliminary results are supportive of comparative safety profiles.
IMPLICATIONS OF KEY FINDINGS
Whilst both ACs and MSCs are effective for the treatment of critical size cartilage defects of the knee, ACs with cBMA augmentation potentially yields marginally better short-term outcomes when compared to MSCs implanted on scaffolds. This suggest that despite the increasing availability of MSCs as a treatment modality for cartilage lesions of the knee, ACs with cBMA augmentation remains a competitive and cost-effective option for cartilage repair in the present day. Ultimately, more long-term evidence on the use of MSCs is required to fully evaluate the comparability of ACs and MSCs in terms of both patient outcomes and the cost-effectiveness of both interventions. (Table 3Table 3)
Table 3Summary of Postoperative Functional Score Improvements
cBMA, concentrated bone marrow aspirate; IKDC, International Knee Documentation Committee; ACs, Acellular Scaffolds; MSC, Mesenchymal Stem Cell; VAS, visual analog scale; WMD, weighted mean difference.
This manuscript received no research funding, however, the following authors declare the following unrelated financial interests
Level of Evidence
III–Meta-Analysis of Level I-III Studies
Declaration of Competing Interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dean Wang: Hospitality payments from Arthrex, DePuy Synthes Sales, Stryker Corporation, Linvatec Corporation Consulting fees from Ipsen Biosciences Education payments from Arthrex, Smith & Nephew; Keng Lin Wong: Paid Honorarium for Lectures: 3M-KCI, Urgo Medical, Molnlycke, CellResearch Corp
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Article Info
) of binary outcome (e.g incomplete filling, reoperation rates, progression to knee arthroplasty) occurrence were respectively calculated as the ratio of the pooled proportions 
of event occurrence rates
) and upper (
) bounds for the 95% confidence intervals were estimated using the Katz-logarithmic method, wherein n1 and n2 represent the respective number of patients in each of the treatment arms being evaluated. Additionally, the p value was calculated after a natural log transformation of the relative risk z-score
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