scholarly journals Effectiveness of Cultured Chondrocytes in the Restoration of Bone and Cartilage Defects of the Knee Joint (Experimental Study)

2021 ◽  
pp. 13-22
Author(s):  
D.O. Zubov ◽  
Yu.V. Poliachenko ◽  
O.O. Kostrub ◽  
V.V. Kotiuk ◽  
R.I. Blonskyi ◽  
...  
Keyword(s):  
Hind Limb ◽  
Articular Chondrocytes ◽  
Critical Size ◽  
Cartilage Defects ◽  
Intercondylar Notch ◽  
Articular Surfaces ◽  
Agarose Hydrogel ◽  
Large Animals ◽  
And Cartilage

Summary. The aim of our study was to determine the effectiveness of cultured articular chondrocytes in agarose hydrogel (early follow-up, 3 months) in the restoration of simulated cartilaginous defects of the knee of critical size in large animals. Materials and Methods. The experimental series consisted of 4 dogs (right hind limb) with created defects of articular cartilage deeper than the subchondral bone in the area of the intercondylar notch of the femur with a diameter of 3 mm and 5 mm deep. At the second stage of the experiment, agarose hydrogel with cultured allogeneic chondrocytes was implanted (sealed) into the injured joint intraarticularly. The control series consisted of 4 animals (left hind limb) without agarose hydrogel with cultured allogeneic chondrocytes implantation to the intercondylar notch of the femur. Agarose hydrogel with cultured allogeneic chondrocytes was implanted by application into the defects of the articular surfaces after curettage of the bottom and walls of bone and cartilage defects of the articular surfaces. Cell preparations and cultures were microscopically magnified at 40, 100, 200, and 320 times. Histological sections 10-15 μm thick, made using a cryotome, were stained with hematoxylin-eosin and hematoxylin-picrofuxin according to van Gizon. Results. The technique of enzymatic isolation of chondrocytes articular cartilage of a dog was optimized. The satisfactory efficacy of cultured allogeneic articular chondrocytes in agarose hydrogel (early observation) in the treatment of simulated bone and cartilage defects of critical size in large animals within the planned observation period is shown. Conclusions. The experimental study explored the effectiveness of the use of cultured allogenic articular chondrocytes embedded in agarose hydrogel (early follow-up period) in the restoration of modeled knee cartilage defects of critical size in dogs within the planned follow-up period. For the selected follow-up period (3 months), the signs of regenerate formation, which was characterized by its immaturity and the presence of a mixture of fibrous connective tissue and fibrous cartilage with the chondroid structure inclusions, were revealed in experimental group.

scholarly journals Extracellular Vesicles and Their Potential Significance in the Pathogenesis and Treatment of Osteoarthritis

2021 ◽  
Vol 14 (4) ◽  
pp. 315
Author(s):  
Anne-Mari Mustonen ◽  
Petteri Nieminen
Keyword(s):  
Articular Cartilage ◽  
Extracellular Vesicles ◽  
Articular Chondrocytes ◽  
Functional Limitations ◽  
Expression Patterns ◽  
Biologically Active ◽  
Joint Disease ◽  
Cartilage Defects ◽  
Matrix Deposition ◽  
And Cartilage

Osteoarthritis (OA) is a chronic joint disease characterized by inflammation, gradual destruction of articular cartilage, joint pain, and functional limitations that eventually lead to disability. Join tissues, including synovium and articular cartilage, release extracellular vesicles (EVs) that have been proposed to sustain joint homeostasis as well as to contribute to OA pathogenesis. EVs transport biologically active molecules, and OA can be characterized by altered EV counts and composition in synovial fluid. Of EV cargo, specific non-coding RNAs could have future potential as diagnostic biomarkers for early OA. EVs may contribute to the propagation of inflammation and cartilage destruction by transporting and enhancing the production of inflammatory mediators and cartilage-degrading proteinases. In addition to inducing OA-related gene expression patterns in synoviocytes and articular chondrocytes, EVs can induce anti-OA effects, including increased extracellular matrix deposition and cartilage protection. Especially mesenchymal stem cell-derived EVs can alleviate intra-articular inflammation and relieve OA pain. In addition, surgically- or chemically-induced cartilage defects have been repaired with EV therapies in animal models. While human clinical trials are still in the future, the potential of actual cures to OA by EV products is very promising.

scholarly journals AB0039 AGRIN REPAIRS BONE AND CARTILAGE IN VIVO

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1052.1-1052
Author(s):  
S. Eldridge ◽  
A. Barawi ◽  
H. Wang ◽  
A. Roelofs ◽  
M. Kaneva ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Cartilage Repair ◽  
Joint Replacement ◽  
Critical Size ◽  
Joint Surface ◽  
Cartilage Defects ◽  
Osteochondral Defects ◽  
Cartilage Formation ◽  
And Cartilage

Background:Cartilage defects in the joints are reported in 61% of all arthroscopies1&2. The size of the cartilage repair market is estimated to be $2.195 million by 20253. Cartilage defects can evolve into osteoarthritis, in which abnormal load results in cartilage breakdown, joint pain and reduced mobility. Osteoarthritis is the leading cause of permanent disability and absenteeism and affects up to 1/3 of the people over 60yrs. In western countries osteoarthritis costs 1.5-2% of the GDP4. Joint replacement with a prosthesis restores some degree of independence but in up to 20% of patients it does not meet expectations 5 and has a limited life span. There is no pharmacological intervention that arrests or reverts the course of osteoarthritis, despite the desperate need.We previously published that agrin plays an important role in cartilage homeostasis6. The addition of agrin to chondrocytes in vivo resulted in enhanced cartilage formation, suggesting a potential role for agrin in cartilage repair.Objectives:Investigate the potential of agrin for use in cartilage repair.Methods:Critical size osteochondral defects were generated in mice and sheep and injected intraarticularly with type I collagen gel containing agrin or vehicle. Animals were monitored for 8 weeks or 6 months respectively. MicroCT, histological analysis, qPCR, linage tracking, reporter assays, chondrogenesis assay, immunohistochemistry were performed.Results:A single intraarticular administration of agrin induced regeneration of critical-size osteochondral defects in mice, restoring the tissue architecture and bone-cartilage interface. Agrin stem cells to the site of injury and, through simultaneous activation of CREB and suppression of canonical WNT signalling, induced GDF5 expression and differentiation into stable articular chondrocytes, forming stable articular cartilage. In sheep, agrin treatment resulted in regeneration of bone and cartilage, which promoted increased ambulatory activity.Conclusion:Agrin orchestrates repair morphogenesis at the joint surface by modulating multiple signalling pathways, supporting the therapeutic use of agrin for joint surface regeneration.References:[1]Curl, W. W. et al. Cartilage injuries: a review of 31,516 knee arthroscopies. Arthrosc. J. Arthrosc. Relat. Surg. Off. Publ. Arthrosc. Assoc. N. Am. Int. Arthrosc. Assoc. 13, 456–460 (1997).[2]Hjelle, K., Solheim, E., Strand, T., Muri, R. & Brittberg, M. Articular cartilage defects in 1,000 knee arthroscopies. Arthrosc. J. Arthrosc. Relat. Surg. Off. Publ. Arthrosc. Assoc. N. Am. Int. Arthrosc. Assoc. 18, 730–734 (2002).[3]Cartilage Repair Market Size, Share, Industry Analysis 2018-2025 | AMR. Allied Market Research https://www.alliedmarketresearch.com/cartilage-repair-market.[4]Hiligsmann, M. et al. Health economics in the field of osteoarthritis: an expert’s consensus paper from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO). Semin. Arthritis Rheum. 43, 303–313 (2013).[5]Dieppe, P., Lim, K. & Lohmander, S. Who should have knee joint replacement surgery for osteoarthritis? Int. J. Rheum. Dis. 14, 175–180 (2011).[6]Eldridge, S., et al. Agrin mediates chondrocyte homeostasis and requires both LRP4 and α-dystroglycan to enhance cartilage formation in vitro and in vivo. Annals of the rheumatic diseases 75 (6), 1228-1235 (2016).Acknowledgements:We thank the technical staff in the ARM Lab and Staff at the University of Aberdeen’s Animal Facility and Microscopy and Histology Facility for support. Funding: We gratefully acknowledge funding support of this work by the MRC (MR/L022893/1, MR/N010973/1,and MR/P026362/1), Versus Arthritis (19667, 21515, 20886, and 21621), Rosetrees Trust (A1205), the Medical College of St Bartholomew’s Hospital Trust, and the William Harvey Research Foundation.Disclosure of Interests:Suzanne Eldridge: None declared, Aida Barawi: None declared, Hui Wang: None declared, Anke Roelofs: None declared, Magdalena Kaneva: None declared, Zeyu Guan: None declared, Helen Lydon: None declared, Bethan Thomas: None declared, Anne-Sophie Thorup: None declared, Beatriz F Fernandez: None declared, Sara Caxaria: None declared, Danielle Strachan: None declared, Ahmed Ali: None declared, Kanatheepan Shanmuganathan: None declared, Costantino Pitzalis: None declared, James Whiteford: None declared, Fran Henson: None declared, Andrew McCaskie: None declared, Cosimo De Bari: None declared, Francesco Dell’Accio Consultant of: F.D. has received consultancy fees from Samumed and UCB.

Overlapping Allografts Provide Superior and More Reliable Surface Topography Matching Than Oblong Allografts: A Computer-Simulated Model Study

2021 ◽  
pp. 036354652110030
Author(s):  
Hailey P. Huddleston ◽  
Atsushi Urita ◽  
William M. Cregar ◽  
Theodore M. Wolfson ◽  
Brian J. Cole ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Surface Topography ◽  
Osteochondral Allograft ◽  
Cartilage Defects ◽  
Radius Of Curvature ◽  
Cartilage Surface ◽  
3 Dimensional ◽  
Cloud Models ◽  
And Cartilage ◽  
Osteochondral Allografts

Background: Osteochondral allograft transplantation is 1 treatment option for focal articular cartilage defects of the knee. Large irregular defects, which can be treated using an oblong allograft or multiple overlapping allografts, increase the procedure’s technical complexity and may provide suboptimal cartilage and subchondral surface matching between donor grafts and recipient sites. Purpose: To quantify and compare cartilage and subchondral surface topography mismatch and cartilage step-off for oblong and overlapping allografts using a 3-dimensional simulation model. Study Design: Controlled laboratory study. Methods: Human cadaveric medial femoral hemicondyles (n = 12) underwent computed tomography and were segmented into cartilage and bone components using 3-dimensional reconstruction and modeling software. Segments were then exported into point-cloud models. Modeled defect sizes of 17 × 30 mm were created on each recipient hemicondyle. There were 2 types of donor allografts from each condyle utilized: overlapping and oblong. Grafts were virtually harvested and implanted to optimally align with the defect to provide minimal cartilage surface topography mismatch. Least mean squares distances were used to measure cartilage and subchondral surface topography mismatch and cartilage step-off. Results: Cartilage and subchondral topography mismatch for the overlapping allograft group was 0.27 ± 0.02 mm and 0.80 ± 0.19 mm, respectively. In comparison, the oblong allograft group had significantly increased cartilage (0.62 ± 0.43 mm; P < .001) and subchondral (1.49 ± 1.10 mm; P < .001) mismatch. Cartilage step-off was also found to be significantly increased in the oblong group compared with the overlapping group ( P < .001). In addition, overlapping allografts more reliably provided a significantly higher percentage of clinically acceptable (0.5- and 1-mm thresholds) cartilage surface topography matching (overlapping: 100% for both 0.5 and 1 mm; oblong: 90% for 1 mm and 56% for 0.5 mm; P < .001) and cartilage step-off (overlapping: 100% for both 0.5 and 1 mm; oblong: 86% for 1 mm and 12% for 0.5 mm; P < .001). Conclusion: This computer simulation study demonstrated improved topography matching and decreased cartilage step-off with overlapping osteochondral allografts compared with oblong osteochondral allografts when using grafts from donors that were not matched to the recipient condyle by size or radius of curvature. These findings suggest that overlapping allografts may be superior in treating large, irregular osteochondral defects involving the femoral condyles with regard to technique. Clinical Relevance: This study suggests that overlapping allografts may provide superior articular cartilage surface topography matching compared with oblong allografts and do so in a more reliable fashion. Surgeons may consider overlapping allografts over oblong allografts because of the increased ease of topography matching during placement.

scholarly journals Allogeneic Umbilical Cord Blood–Derived Mesenchymal Stem Cell Implantation Versus Microfracture for Large, Full-Thickness Cartilage Defects in Older Patients: A Multicenter Randomized Clinical Trial and Extended 5-Year Clinical Follow-up

2021 ◽  
Vol 9 (1) ◽  
pp. 232596712097305
Author(s):  
Hong-Chul Lim ◽  
Yong-Beom Park ◽  
Chul-Won Ha ◽  
Brian J. Cole ◽  
Beom-Koo Lee ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Adverse Events ◽  
Cartilage Repair ◽  
Older Patients ◽  
Cartilage Defects ◽  
Full Thickness ◽  
Phase 3 ◽  
Randomized Controlled ◽  
Cartilage Restoration

Background: There is currently no optimal method for cartilage restoration in large, full-thickness cartilage defects in older patients. Purpose: To determine whether implantation of a composite of allogeneic umbilical cord blood–derived mesenchymal stem cells and 4% hyaluronate (UCB-MSC-HA) will result in reliable cartilage restoration in patients with large, full-thickness cartilage defects and whether any clinical improvements can be maintained up to 5 years postoperatively. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: A randomized controlled phase 3 clinical trial was conducted for 48 weeks, and the participants then underwent extended 5-year observational follow-up. Enrolled were patients with large, full-thickness cartilage defects (International Cartilage Repair Society [ICRS] grade 4) in a single compartment of the knee joint, as confirmed by arthroscopy. The defect was treated either with UCB-MSC-HA implantation through mini-arthrotomy or with microfracture. The primary outcome was proportion of participants who improved by ≥1 grade on the ICRS Macroscopic Cartilage Repair Assessment (blinded evaluation) at 48-week arthroscopy. Secondary outcomes included histologic assessment; changes in pain visual analog scale (VAS) score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and International Knee Documentation Committee (IKDC) score from baseline; and adverse events. Results: Among 114 randomized participants (mean age, 55.9 years; 67% female; body mass index, 26.2 kg/m2), 89 completed the phase 3 clinical trial and 73 were enrolled in the 5-year follow-up study. The mean defect size was 4.9 cm2 in the UCB-MSC-HA group and 4.0 cm2 in the microfracture group ( P = .051). At 48 weeks, improvement by ≥1 ICRS grade was seen in 97.7% of the UCB-MSC-HA group versus 71.7% of the microfracture group ( P = .001); the overall histologic assessment score was also superior in the UCB-MSC-HA group ( P = .036). Improvement in VAS pain, WOMAC, and IKDC scores were not significantly different between the groups at 48 weeks, however the clinical results were significantly better in the UCB-MSC-HA group at 3- to 5-year follow-up ( P < .05). There were no differences between the groups in adverse events. Conclusion: In older patients with symptomatic, large, full-thickness cartilage defects with or without osteoarthritis, UCB-MSC-HA implantation resulted in improved cartilage grade at second-look arthroscopy and provided more improvement in pain and function up to 5 years compared with microfracture. Registration: NCT01041001, NCT01626677 (ClinicalTrials.gov identifier).

scholarly journals Autologous Matrix-Induced Chondrogenesis for Treatment of Focal Cartilage Defects in the Knee: A Follow-up Study

2021 ◽  
Vol 9 (2) ◽  
pp. 232596712098187
Author(s):  
Justus Gille ◽  
Ellen Reiss ◽  
Moritz Freitag ◽  
Jan Schagemann ◽  
Matthias Steinwachs ◽  
...  
Keyword(s):  
Repeated Measures ◽  
Demographic Data ◽  
Case Series ◽  
Defect Size ◽  
Lysholm Score ◽  
Outcome Analysis ◽  
Cartilage Defects ◽  
Chondral Defects ◽  
The Mean

Background: Autologous matrix-induced chondrogenesis (AMIC) is a well-established treatment for full-thickness cartilage defects. Purpose: To evaluate the long-term clinical outcomes of AMIC for the treatment of chondral lesions of the knee. Study Design: Case series; Level of evidence, 4. Methods: A multisite prospective registry recorded demographic data and outcomes for patients who underwent repair of chondral defects. In total, 131 patients were included in the study. Lysholm, Knee injury and Osteoarthritis Outcome Score (KOOS), and visual analog scale (VAS) score for pain were used for outcome analysis. Across all patients, the mean ± SD age of patients was 36.6 ± 11.7 years. The mean body weight was 80.0 ± 16.8 kg, mean height was 176.3 ± 7.9 cm, and mean defect size was 3.3 ± 1.8 cm2. Defects were classified as Outerbridge grade III or IV. A repeated-measures analysis of variance was used to compare outcomes across all time points. Results: The median follow-up time for the patients in this cohort was 4.56 ± 2.92 years. Significant improvement ( P < .001) in all scores was observed at 1 to 2 years after AMIC, and improved values were noted up to 7 years postoperatively. Among all patients, the mean preoperative Lysholm score was 46.9 ± 19.6. At the 1-year follow-up, a significantly higher mean Lysholm score was noted, with maintenance of the favorable outcomes at 7-year follow-up. The KOOS also showed a significant improvement of postoperative values compared with preoperative data. The mean VAS had significantly decreased during the 7-year follow-up. Age, sex, and defect size did not have a significant effect on the outcomes. Conclusion: AMIC is an effective method of treating chondral defects of the knee and leads to reliably favorable results up to 7 years postoperatively.

scholarly journals Potential predictive value of axial T2 mapping at 3 Tesla MRI in patients with untreated patellar cartilage defects over a mean follow-up of four years

2020 ◽  
Vol 28 (2) ◽  
pp. 215-222 ◽  
Author(s):  
S.R. Apprich ◽  
M.M. Schreiner ◽  
P. Szomolanyi ◽  
G.H. Welsch ◽  
U.K. Koller ◽  
...  
Keyword(s):  
Predictive Value ◽  
T2 Mapping ◽  
3 Tesla ◽  
Cartilage Defects ◽  
Patellar Cartilage ◽  
3 Tesla Mri

scholarly journals Metabolic Syndrome Predisposes to Osteoarthritis: Lessons from Model System

Cartilage ◽  
2020 ◽  
pp. 194760352098016
Author(s):  
Sampath Samuel Joshua Pragasam ◽  
Vijayalakshmi Venkatesan
Keyword(s):  
Subchondral Bone ◽  
Fat Mass ◽  
Articular Chondrocytes ◽  
Bone Cyst ◽  
Primary Cultures ◽  
Abdominal Circumference ◽  
Enzyme Linked Immunosorbent Assay ◽  
Micro Ct ◽  
Tnf Α ◽  
And Cartilage

Objective The present study aims to assess for temporal changes in tibial subchondral bone and cartilage in WNIN/Gr-Ob rats (portraying obesity, insulin resistance, dyslipidemia, impaired glucose tolerance, hypertension) in comparison with Wistar controls (WNIN) using anthropometry, micro-computed tomography (micro-CT), scanning electron microscopy (SEM), histopathology, enzyme-linked immunosorbent assay (ELISA), and immunofluorescence. Design Body weight, abdominal circumference, body mass index (BMI), lean/fat mass, serum tumor necrosis factor (TNF)-α levels were measured (ELISA), followed by ultrastructural analysis of tibial subchondral bone (micro-CT) and cartilage architecture (histopathology and SEM) in WNIN/Gr-Ob and WNIN rats with age (3, 6 and 9 months). Additionally, primary cultures of articular chondrocytes isolated from 6-month-old WNIN/Gr-Ob and WNIN rats were assessed for matrix metalloproteinase (MMP)-13 and Collagen type II (COL2A1) by immunofluorescence. Results WNIN/Gr-Ob rats exhibited frank obesity with increased BMI, lean and fat mass vis-à-vis significantly higher levels of serum TNF-α (6>9>3 months) as compared with the controls. With an increase in BMI, WNIN/Gr-Ob rats presented with tibial cartilage fibrillation, erosion, osteophyte formation (6 months) and subchondral bone cyst (9 months) confirmed by histology and SEM. An increase in subchondral trabecular bone volume (sclerosis with decreased plate porosity) was observed in all ages in WNIN/Gr-Ob rats compared to their Control. Gaining insights, primary cultures of articular chondrocytes complemented with altered cellular expressions of COL2A1 and MMP-13 from WNIN/Gr-Ob rats, indicating osteoarthritis (OA) progression. Conclusion Multiple metabolic perturbations featured in WNIN/Gr-Ob rats were effective to induce spontaneous OA-like degenerative changes affecting knee joints akin to human OA.

Canal wall cholesteatoma following canalplasty

2009 ◽  
Vol 123 (10) ◽  
pp. 1174-1176 ◽  
Author(s):  
M Martinez Del Pero ◽  
N Donnelly ◽  
N Antoun ◽  
P Axon
Keyword(s):  
Late Complication ◽  
Canal Wall ◽  
Ear Canal ◽  
Early Complications ◽  
Cartilage Reconstruction ◽  
Air Cells ◽  
And Cartilage ◽  
Mastoid Air Cells

AbstractIntroduction:Bony canalplasty is a common otological procedure performed to widen a narrow ear canal. The aim of this report is to describe two unusual patients who presented with a canal wall cholesteatoma many years after bony canalplasty.Cases:Two patients, aged 28 and 52 years, are presented. Both underwent canalplasty, 14 and 17 years before re-presenting with cholesteatoma evident through posterior canal wall defects. Both patients underwent exploration of the mastoid cavities and cartilage reconstruction of the canal walls. There was no recurrence at 24 and three month follow-up examinations (variously), hearing was preserved in both cases, and the patients suffered no early complications.Conclusions:The most frequent long-term complication of canalplasty is re-stenosis of the external auditory canal. The importance of sealing any inadvertently opened mastoid air cells, in order to avoid the late complication reported, is emphasised.

scholarly journals Combined Autologous Chondrocyte and Bone Marrow Mesenchymal Stromal Cell Implantation in the Knee: An 8-year Follow Up of Two First-In-Man Cases

2019 ◽  
Vol 28 (7) ◽  
pp. 924-931
Author(s):  
Jingsong Wang ◽  
Karina T. Wright ◽  
Jade Perry ◽  
Bernhard Tins ◽  
Timothy Hopkins ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mesenchymal Stromal Cell ◽  
Stromal Cell ◽  
Knee Function ◽  
Cartilage Defects ◽  
Repair Site ◽  
Cell Implantation ◽  
Autologous Chondrocyte

Autologous chondrocyte implantation (ACI) has been used to treat cartilage defects for >20 years, with promising clinical outcomes. Here, we report two first-in-man cases (patient A and B) treated with combined autologous chondrocyte and bone marrow mesenchymal stromal cell implantation (CACAMI), with 8-year follow up. Two patients with International Cartilage Repair Society (ICRS) grade III–IV cartilage lesions underwent a co-implantation of autologous chondrocytes and bone marrow-derived mesenchymal stromal cells (BM-MSCs) between February 2008 and October 2009. In brief, chondrocytes and BM-MSCs were separately isolated and culture-expanded in a good manufacturing practice laboratory for a period of 2–4 weeks. Cells were then implanted in combination into cartilage defects and patients were clinically evaluated preoperatively and postoperatively, using the self-reported Lysholm knee score and magnetic resonance imaging (MRI). Postoperative Lysholm scores were compared with the Oswestry risk of knee arthroplasty (ORKA) scores. Patient A also had a second-look arthroscopy, at which time a biopsy of the repair site was taken. Both patients demonstrated a significant long-term improvement in knee function, with postoperative Lysholm scores being consistently higher than ORKA predictions. The most recent Lysholm scores, 8 years after surgery were 100/100 (Patient A) and 88/100 (Patient B), where 100 represents a fully functioning knee joint. Bone marrow lesion (BML) volume was shown to decrease on postoperative MRIs in both patients. Cartilage defect area increased in patient A, but declined initially for patient B, slightly increasing again 2 years after treatment. The repair site biopsy taken from patient A at 14 months postoperatively, demonstrated a thin layer of fibrocartilage covering the treated defect site. The use of a combination of cultured autologous chondrocytes and BM-MSCs appears to confer long-term benefit in this two-patient case study. Improvements in knee function perhaps relate to the observed reduction in the size of the BML.

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