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Journal ArticleDOI

Matrix-Induced Autologous Chondrocyte Implantation versus Multipotent Stem Cells for the Treatment of Large Patellofemoral Chondral Lesions: A Nonrandomized Prospective Trial.

01 Apr 2015-Cartilage (SAGE Publications)-Vol. 6, Iss: 2, pp 82-97
TL;DR: Both techniques are viable and effective for large patellofemoral chondral lesions at minimum 3-year follow-up and there was no significant difference in improvement between the 2 groups, except for the IKDC subjective score, which favored the BMAC group.
Abstract: ObjectiveTo compare the outcome of matrix-induced autologous chondrocyte implantation (MACI) and bone marrow aspirate concentrate (BMAC)–derived multipotent stem cells (MSCs) implantation in patell...

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Journal ArticleDOI
TL;DR: A systematic review of the literature on the outcomes of bone marrow aspirate concentrate for the treatment of chondral defects and osteoarthritis of the knee found varying degrees of beneficial results with the use of BMAC with and without an additional procedure.
Abstract: Background:Bone marrow aspirate concentrate (BMAC) has emerged as a novel treatment for pathology of the knee. Despite containing a limited number of stem cells, BMAC serves as a source of growth factors that are thought to play an important role as a result of their anabolic and anti-inflammatory effects. To our knowledge, there is no systematic review regarding the outcomes of bone marrow aspirate concentrate used for the treatment of chondral defects and osteoarthritis of the knee.Purpose:To perform a systematic review on the outcomes of bone marrow aspirate concentrate for the treatment of chondral defects and osteoarthritis of the knee.Study Design:Systematic review; Level of evidence, 4.Methods:A systematic review of the literature was performed using the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, PubMed, and MEDLINE from 1980 to present. Inclusion criteria were as follows: use of BMAC for treatment of chondral defects and osteoarthritis of the knee,...

178 citations


Cites background from "Matrix-Induced Autologous Chondrocy..."

  • ...7 (6-9) Knee OA BMAC injection Arthroscopic debridement in 8%, microfracture in 6....

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Journal ArticleDOI
TL;DR: This review offers a comprehensive assessment of the evidence behind the translation of basic science to the clinical practice of cartilage repair and reveals a lack of connectivity between the in vitro, pre-clinical and human data and a patchwork quilt of synergistic evidence.
Abstract: The management of articular cartilage defects presents many clinical challenges due to its avascular, aneural and alymphatic nature. Bone marrow stimulation techniques, such as microfracture, are the most frequently used method in clinical practice however the resulting mixed fibrocartilage tissue which is inferior to native hyaline cartilage. Other methods have shown promise but are far from perfect. There is an unmet need and growing interest in regenerative medicine and tissue engineering to improve the outcome for patients requiring cartilage repair. Many published reviews on cartilage repair only list human clinical trials, underestimating the wealth of basic sciences and animal studies that are precursors to future research. We therefore set out to perform a systematic review of the literature to assess the translation of stem cell therapy to explore what research had been carried out at each of the stages of translation from bench-top (in vitro), animal (pre-clinical) and human studies (clinical) and assemble an evidence-based cascade for the responsible introduction of stem cell therapy for cartilage defects. This review was conducted in accordance to PRISMA guidelines using CINHAL, MEDLINE, EMBASE, Scopus and Web of Knowledge databases from 1st January 1900 to 30th June 2015. In total, there were 2880 studies identified of which 252 studies were included for analysis (100 articles for in vitro studies, 111 studies for animal studies; and 31 studies for human studies). There was a huge variance in cell source in pre-clinical studies both of terms of animal used, location of harvest (fat, marrow, blood or synovium) and allogeneicity. The use of scaffolds, growth factors, number of cell passages and number of cells used was hugely heterogeneous. This review offers a comprehensive assessment of the evidence behind the translation of basic science to the clinical practice of cartilage repair. It has revealed a lack of connectivity between the in vitro, pre-clinical and human data and a patchwork quilt of synergistic evidence. Drivers for progress in this space are largely driven by patient demand, surgeon inquisition and a regulatory framework that is learning at the same pace as new developments take place.

176 citations


Cites background from "Matrix-Induced Autologous Chondrocy..."

  • ...Menisectomy 6 (19%) [103, 111, 124, 129, 131, 133] ACL reconstruction 4 (13%) [103, 111, 131, 133] Multiple (microfracture, debridement) 1 (3%) [119] ACI 2 (6%) [116, 117] None 6 (19%) [106–108, 110, 114, 118] Not specified 9 (29%) [105, 109, 112, 115, 120, 121, 126, 128, 132] PBS phosphate-buffered saline, HA hyaluronic acid, PRP plate-rich-plasma, RCT randomised controlled study, KOOS Knee and Osteoarthritis Outcome Score, IKDC score International Knee Documentation Committee Score, WOMAC the Western Ontario and McMaster Universities Arthritis Index, AOFAS the American Orthopaedic Foot & Ankle Society Goldberg et al....

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  • ...Polyglycolic acid/hyaluronan 2 (6%) [127, 131] Collagen with platelet gel 1 (3%) [116] Fibrin glue 1 (3%) [108] HYAFF 11 scaffold 1 (3%) [132] Acetate Ringer solution 1 (3%) [133] Unspecified 1 (3%) [107] Intra-articular injection PBS only 2 (6%) [104, 110] PBS with HA 2 (6%) [119, 121] Autologous serum 2 (6%) [115, 123] Ringer lactate solution 3 (10%) [103, 111, 112] PBS with serum albumin 1 (3%) [105] HA and PRP 1 (3%) [106] PRP 1 (3%) [114] Commercial serum 1 (3%) [109] Transplantation by open surgery Collagen 6 (21%) [103, 113, 118, 122, 124, 126, 129] Ascorbic acid-mediated sheet 2 (7%) [120, 123] Fibrin glue 1 (4%) [125] Cell dose Less than 10 million 8 (26%) [105, 107, 108, 114, 120, 122, 124, 129] 10–20 million 5 (16%) [113, 118, 119, 123, 125] Over 20 million 7 (23%) [103, 104, 109–112, 133] Unspecified 11 (35%) [106, 115–117, 121, 126–128, 130–132] Follow-up Up to 6 months 4 (13%) [104–106, 110] Up to 12 months 6 (19%) [103, 109, 111, 124, 125, 127] Up to 2 years 11 (35%) [107, 113–116, 120, 121, 128–131] Up to 3 years 7 (23%) [108, 112, 117, 119, 122, 126, 132] Over 3 years 2 (6%) [118, 133] Table 14 Summary of the published clinical studies (Continued) Assessments Radiology (MRI, X-ray) 24 (77%) [103–106, 109–112, 115–117, 119, 121–125, 127–133] Arthroscopic assessment incl....

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Journal ArticleDOI
TL;DR: Repairs of chondral injury using a hyaluronic acid–based scaffold with activated bone marrow aspirate concentrate provides better clinical outcomes and more durable cartilage repair at medium-term follow-up compared with microfracture.
Abstract: Background:Articular cartilage injury is frequently encountered, yet treatment options capable of providing durable cartilage repair are limited.Purpose:To investigate the medium-term clinical outcomes of cartilage repair using a 1-stage technique of a hyaluronic acid–based scaffold with activated bone marrow aspirate concentrate (HA-BMAC) and compare results with those of microfracture. A secondary aim of this study was to identify specific patient demographic factors and cartilage lesion characteristics that are associated with superior outcomes.Study Design:Cohort study; Level of evidence, 2.Methods:Fifty physically active patients (mean age, 45 years) with grade IV cartilage injury of the knee (lesion size, 1.5-24 cm2) were treated with HA-BMAC or microfracture and were observed prospectively for 5 years. Patients were placed into the HA-BMAC group if the health insurance policy of the treating institution supported this option; otherwise, they were placed into the microfracture group. Objective and s...

157 citations


Cites methods from "Matrix-Induced Autologous Chondrocy..."

  • ...In 2014, Gobbi et al15 evaluated the outcomes of a 1-stage BMAC procedure using a type I/III collagen scaffold to treat large chondral defects....

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Journal ArticleDOI
TL;DR: Young age, lower BMI, smaller lesion size for focal lesions and earlier stages of OA joints, have been shown to correlate with better outcomes, even though the available data strength doesn’t allow to define clear cutoff values.
Abstract: Mesenchymal stem cells (MSCs) have emerged as a promising option to treat articular defects and early osteoarthritis (OA) stages. However, both their potential and limitations for a clinical use remain controversial. Thus, the aim of this systematic review was to examine MSCs treatment strategies in clinical settings, in order to summarize the current evidence of their efficacy for the treatment of cartilage lesions and OA.Among the 60 selected studies, 7 were randomized, 13 comparative, 31 case series, and 9 case reports; 26 studies reported the results after injective administration, whereas 33 used surgical implantation. One study compared the two different modalities. With regard to the cell source, 20 studies concerned BMSCs, 17 ADSCs, 16 BMC, 5 PBSCs, 1 SDSCs, and 1 compared BMC versus PBSCs. Overall, despite the increasing literature on this topic, the evidence is still limited, in particular for high-level studies. On the other hand, the available studies allow to draw some indications. First, no major adverse events related to the treatment or to the cell harvest have been reported. Second, a clinical benefit of using MSCs therapies has been reported in most of the studies, regardless of cell source, indication, or administration method. This effectiveness has been reflected by clinical improvements and also positive MRI and macroscopic findings, whereas histologic features gave more controversial results among different studies. Third, young age, lower BMI, smaller lesion size for focal lesions, and earlier stages of OA joints have been shown to correlate with better outcomes, even though the available data strength does not allow to define clear cutoff values. Finally, definite trends can be observed with regard to the delivery method: currently cultured cells are mostly being administered by i.a. injection, while one-step surgical implantation is preferred for cell concentrates. In conclusion, while promising results have been shown, the potential of these treatments should be confirmed by reliable clinical data through double-blind, controlled, prospective and multicenter studies with longer follow-up, and specific studies should be designed to identify the best cell sources, manipulation, and delivery techniques, as well as pathology and disease phase indications.

115 citations


Cites background or result from "Matrix-Induced Autologous Chondrocy..."

  • ...BM Concentrate Gobbi [47] 2015 Cartilage Comparative Surgical delivery MAST HA matrix Knee cartilage defects patellofemoral 19 MACT 18 BMC 3 years Significant scores improvement in both groups....

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  • ...The good results obtained with scaffolds implanted with BMC have been compared with chondrocyte-based surgical techniques, showing similar outcomes, but with the advantage of the one-step approach [42, 43, 47]....

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  • ...Fibrocartilaginous tissue at histology Adachi [27] 2005 J Rheumatol Case report Surgical delivery MAST Hydroxyapatite ceramic Knee osteochondral defect 1 Cartilage-like and bone tissue regeneration at 2nd look arthroscopy Wakitani [32] 2004 Cell Transplant Case report Surgical delivery BMSCs + collagen gel + periosteum Knee cartilage defect Patella 2 5 years Short-term clinical improvement, then stable at 24 months fibrocartilage defect filling Wakitani [33] 2002 Osteoarthritis & Cartilage Comparative Surgical delivery Collagen gel sheet + periosteum Knee OA 12 BMSCs + HTO 12 cell-free control + HTO 16 months Comparable clinical outcomes, but better arthroscopic and histological score in celltransplanted group BM Concentrate Gobbi [47] 2015 Cartilage Comparative Surgical delivery MAST HA matrix Knee cartilage defects patellofemoral 19 MACT 18 BMC 3 years Significant scores improvement in both groups....

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  • ...[47], who observed superior outcomes using BMC instead of chondrocytes for the treatment of large patellofemoral defects....

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Journal ArticleDOI
TL;DR: The studies of intra-articular cellular therapy injections for osteoarthritis and focal cartilage defects in the human knee suggested positive results with respect to clinical improvement and safety, however, the improvement was modest and a placebo effect cannot be disregarded.
Abstract: Background: Intra-articular cellular therapy injections constitute an appealing strategy that may modify the intra-articular milieu or regenerate cartilage in the settings of osteoarthritis and focal cartilage defects. However, little consensus exists regarding the indications for cellular therapies, optimal cell sources, methods of preparation and delivery, or means by which outcomes should be reported. Methods: We present a systematic review of the current literature regarding the safety and efficacy of cellular therapy delivered by intra-articular injection in the knee that provided a Level of Evidence of III or higher. A total of 420 papers were screened. Methodological quality was assessed using a modified Coleman methodology score. Results: Only 6 studies (4 Level II and 2 Level III) met the criteria to be included in this review; 3 studies were on treatment of osteoarthritis and 3 were on treatment of focal cartilage defects. These included 4 randomized controlled studies without blinding, 1 prospective cohort study, and 1 retrospective therapeutic case-control study. The studies varied widely with respect to cell sources, cell characterization, adjuvant therapies, and assessment of outcomes. Outcome was reported in a total of 300 knees (124 in the osteoarthritis studies and 176 in the cartilage defect studies). Mean follow-up was 21.0 months (range, 12 to 36 months). All studies reported improved outcomes with intra-articular cellular therapy and no major adverse events. The mean modified Coleman methodology score was 59.1 ± 16 (range, 32 to 82). Conclusions: The studies of intra-articular cellular therapy injections for osteoarthritis and focal cartilage defects in the human knee suggested positive results with respect to clinical improvement and safety. However, the improvement was modest and a placebo effect cannot be disregarded. The overall quality of the literature was poor, and the methodological quality was fair, even among Level-II and III studies. Effective clinical assessment and optimization of injection therapies will demand greater attention to study methodology, including blinding; standardized quantitative methods for cell harvesting, processing, characterization, and delivery; and standardized reporting of clinical and structural outcomes. Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

103 citations


Additional excerpts

  • ...Type of study (15) 0 15 15 10 15 15 11....

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References
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Journal ArticleDOI
TL;DR: Cultured autologous chondrocytes can be used to repair deep cartilage defects in the femorotibial articular surface of the knee joint.
Abstract: Background Full-thickness defects of articular cartilage in the knee have a poor capacity for repair. They may progress to osteoarthritis and require total knee replacement. We performed autologous chondrocyte transplantation in 23 people with deep cartilage defects in the knee. Methods The patients ranged in age from 14 to 48 years and had full-thickness cartilage defects that ranged in size from 1.6 to 6.5 cm2. Healthy chondrocytes obtained from an uninvolved area of the injured knee during arthroscopy were isolated and cultured in the laboratory for 14 to 21 days. The cultured chondrocytes were then injected into the area of the defect. The defect was covered with a sutured periosteal flap taken from the proximal medial tibia. Evaluation included clinical examination according to explicit criteria and arthroscopic examination with a biopsy of the transplantation site. Results Patients were followed for 16 to 66 months (mean, 39). Initially, the transplants eliminated knee locking and reduced pain and s...

5,375 citations


"Matrix-Induced Autologous Chondrocy..." refers background or methods in this paper

  • ...Over the years, autologous chondrocyte implantation (ACI) has been established as a good treatment option to deal with large full-thickness chondral lesions.(5,6) The first-generation ACI technique was complex, required periosteal tissue harvest and a meticulous sewing of the patch over the defect to ensure a “watertight” closure preventing spillage of the chondrocytes(7); furthermore, it was associated with donor site morbidity due to periosteal patch retrieval....

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  • ...The first-generation ACI technique was complex, required periosteal tissue harvest and a meticulous sewing of the patch over the defect to ensure a “watertight” closure preventing spillage of the chondrocytes(7); furthermore, it was associated with donor site morbidity due to periosteal patch retrieval.(5,7) Second-generation ACI was introduced when periosteum was exchanged with a resorbable membrane out of collagen....

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Journal ArticleDOI
TL;DR: A new activity grading scale, where work and sport activities were graded numerically, was constructed as complement to the functional score, showing that the symptom-related score gave a more differentiated picture of the disability.
Abstract: Many different methods of evaluating disability after knee ligament injury exist. Most of them differ in design. Some are based on only patients' symptoms. Other include patients' symptoms, activity grading, performance in a test, and clinical findings. The rating in these evaluating systems can be either numerical, as in a score, or binary, with yes/no answers. Comparison between a symptom-related score and a score of more complex design showed that the symptom-related score gave a more differentiated picture of the disability. It was also shown that the binary rating system gave less detailed information than a score and that differences in a binary rating can depend on at what level the symptoms are regarded as "significant." A new activity grading scale, where work and sport activities were graded numerically, was constructed as complement to the functional score. When evaluating knee ligament injuries, stability testing, functional knee score, performance test, and activity grading are all important. However, the relative importance varies during the course of treatment, and therefore they should not all be included in one and the same score.

3,857 citations

Journal ArticleDOI
TL;DR: The KOOS proved reliable, responsive to surgery and physical therapy, and valid for patients undergoing anterior cruciate ligament reconstruction, and can be used to evaluate the course of knee injury and treatment outcome.
Abstract: There is broad consensus that good outcome measures are needed to distinguish interventions that are effective from those that are not. This task requires standardized, patient- centered measures that can be administered at a low cost. We developed a questionnaire to assess short- and long-term patient-relevant outcomes following knee injury, based on the WOMAC Osteoarthritis Index, a literature review, an expert panel, and a pilot study. The Knee Injury and Osteoarthritis Outcome Score (KOOS) is self-administered and assesses five outcomes: pain, symptoms, activities of daily living, sport and recreation function, and knee-related quality of life. In this clinical study, the KOOS proved reliable, responsive to surgery and physical therapy, and valid for patients undergoing anterior cruciate ligament reconstruction. The KOOS meets basic criteria of outcome measures and can be used to evaluate the course of knee injury and treatment outcome.

3,003 citations

Journal ArticleDOI
TL;DR: The International Knee Documentation Committee Subjective Knee Form is a reliable and valid knee-specific measure of symptoms, function, and sports activity that is appropriate for patients with a wide variety of knee problems.
Abstract: A committee of international knee experts created the International Knee Documentation Committee Subjective Knee Form, which is a knee-specific, rather than a disease-specific, measure of symptoms, function, and sports activity. The purpose of this study was to evaluate the reliability and validity of the new International Knee Documentation Committee Subjective Knee Form. To provide evidence for reliability and validity, we administered the final version of the form, along with the Short Form-36, to 533 patients with a variety of knee problems. Analyses were performed to determine reliability, validity, and differential item function related to age, sex, and diagnosis. Factor analysis revealed a single dominant component, making it reasonable to combine all questions into a single score. Internal consistency and test-retest reliability were 0.92 and 0.95, respectively. Based on test-retest reliability, the value for a true change in the score was 9.0 points. The International Knee Documentation Committee Subjective Knee Form score was related to concurrent measures of physical function (r = 0.47 to 0.66) but not to emotional function (r = 0.16 to 0.26). Analysis of differential item function indicated that the questions functioned similarly for men versus women, young versus old, and for those with different diagnoses. In conclusion, the International Knee Documentation Committee Subjective Knee Form is a reliable and valid knee-specific measure of symptoms, function, and sports activity that is appropriate for patients with a wide variety of knee problems. Use of this instrument will permit comparisons of outcome across groups with different knee problems.

1,674 citations

Journal ArticleDOI
TL;DR: There was no significant difference in macroscopic or histological results between the two treatment groups and no association between the histological findings and the clinical outcome at the two-year time-point.
Abstract: Background: New methods have been used, with promising results, to treat full-thickness cartilage defects. The objective of the present study was to compare autologous chondrocyte implantation with microfracture in a randomized trial. We are not aware of any previous randomized studies comparing these methods. Methods: Eighty patients without general osteoarthritis who had a single symptomatic cartilage defect on the femoral condyle in a stable knee were treated with autologous chondrocyte implantation or microfracture (forty in each group). We used the International Cartilage Repair Society, Lysholm, Short Form-36 (SF-36), and Tegner forms to collect data. An independent observer performed a follow-up examination at twelve and twenty-four months. Two years postoperatively, arthroscopy with biopsy for histological evaluation was carried out. The histological evaluation was done by a pathologist and a clinical scientist, both of whom were blinded to each patient's treatment. Results: In general, there were small differences between the two treatment groups. At two years, both groups had significant clinical improvement. According to the SF-36 physical component score at two years postoperatively, the improvement in the microfracture group was significantly better than that in the autologous chondrocyte implantation group (p = 0.004). Younger and more active patients did better in both groups. There were two failures in the autologous chondrocyte implantation group and one in the microfracture group. No serious complications were reported. Biopsy specimens were obtained from 84% of the patients, and histological evaluation of repair tissues showed no significant differences between the two groups. We did not find any association between the histological quality of the tissue and the clinical outcome according to the scores on the Lysholm or SF-36 form or the visual analog scale. Conclusions: Both methods had acceptable short-term clinical results. There was no significant difference in macroscopic or histological results between the two treatment groups and no association between the histological findings and the clinical outcome at the two-year time-point. Level of Evidence: Therapeutic study, Level I-1a (randomized controlled trial [significant difference]). See Instructions to Authors for a complete description of levels of evidence.

1,220 citations


"Matrix-Induced Autologous Chondrocy..." refers result in this paper

  • ...The observed level of maturity seems higher in the BMAC group than that obtained with MACI at this time point, as in previous reports.(46,54) MRI evaluation showed complete filling of the defect in both groups with no signs of hypertrophy in either group....

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