Piramal HealthCare Canada

Laval, Canada

Piramal HealthCare Canada

Laval, Canada

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Chen H.,Ecole Polytechnique de Montréal | Chevrier A.,Ecole Polytechnique de Montréal | Hoemann C.D.,Ecole Polytechnique de Montréal | Sun J.,Piramal HealthCare Canada | And 2 more authors.
Osteoarthritis and Cartilage | Year: 2013

Objective: The aim of this study was to compare the early repair response of cartilage defects in trochlea (TR) and medial femoral condyle (MFC) at 2-3 weeks after bone marrow stimulation. Design: Bilateral full-thickness cartilage defects were generated in central trochlear groove and MFC of skeletally mature rabbits. Four subchondral perforations were made on each defect, either by microfracture to 2mm deep, or by drilling to 2mm or 6mm deep. Rabbits were sacrificed either on Day 14 post-operatively or on Day 21. Defects were analyzed by histology, stereology, histomorphometry and micro-computed tomography (CT). Intact femurs (N=4) served as controls. Results: Stromal cell density recruitment was similar in all defects, irrespective of defect location and surgical techniques used. There was a robust appearance of chondrocytes at Day 21 in TR defects with significantly higher volume fraction of chondrocytes in TR compared to MFC (P=0.013). Chondrogenic foci were observed in marrow penetrating holes, with a significantly higher frequency and larger foci in TR vs MFC defects at Day 21 (P=0.043 and P=0.0014, respectively). Micro-CT analysis showed that deep drilling elicited significantly more mineralized bone fill compared to shallower perforations at 2 and 3 weeks repair (all at P≤0.0008). Conclusions: Bone marrow stimulation induced greater chondrogenesis in TR vs MFC defects in adult rabbits, with more chondrocytes and larger chondrogenic foci appearing in TR vs MFC on Day 21 post-operation. © 2013 Osteoarthritis Research Society International.


Chevrier A.,Ecole Polytechnique de Montréal | Hoemann C.D.,Ecole Polytechnique de Montréal | Sun J.,Piramal Healthcare Canada | Buschmann M.D.,Ecole Polytechnique de Montréal
Osteoarthritis and Cartilage | Year: 2011

Objective: Subchondral drilling initiates a cartilage repair response involving formation of chondrogenic foci in the subchondral compartment. The purpose of this study was to structurally characterize these sites of chondrogenesis and to investigate the effects of chitosan-glycerol phosphate (GP)/blood implants on their formation. Method: Thirty-two New Zealand White rabbits received bilateral cartilage defects bearing four subchondral drill holes. One knee per rabbit was treated by solidifying a chitosan-GP/blood implant over the defect. After 1-56 days of repair, chondrogenic foci were characterized by histostaining and immunostaining. Collagen fiber orientation was characterized by polarized light microscopy. Results: Glycosaminoglycan and collagen type II were present throughout the foci while the upper zone expressed collagen type I and the lower zone collagen type X. Large chondrogenic foci had a stratified structure with flatter cells closer to the articular surface, and round or hypertrophic chondrocytes deeper in the drill holes that showed signs of calcification after 3 weeks of repair in control defects. Markers for pre-hypertrophic chondrocytes (Patched) and for proliferation (Ki-67) were detected within foci. Some cells displayed a columnar arrangement where collagen was vertically oriented. For treated defects, chondrogenic foci appeared 1-3 weeks later, foci were nascent and mature rather than resorbing, and foci developed closer to the articular surface. Conclusions: Chondrogenic foci bear some similarities to growth cartilage and can give rise to a repair tissue that has similar zonal stratification as articular cartilage. The temporal and spatial formation of chondrogenic foci can be modulated by cartilage repair therapies. © 2010 Osteoarthritis Research Society International.


Changoor A.,Ecole Polytechnique de Montréal | Tran-Khanh N.,Ecole Polytechnique de Montréal | Methot S.,Piramal Healthcare Canada | Garon M.,Biomomentum Inc. | And 3 more authors.
Osteoarthritis and Cartilage | Year: 2011

Objectives: Collagen organization, a feature that is critical for cartilage load bearing and durability, is not adequately assessed in cartilage repair tissue by present histological scoring systems. Our objectives were to develop a new polarized light microscopy (PLM) score for collagen organization and to test its reliability. Design: This PLM score uses an ordinal scale of 0-5 to rate the extent that collagen network organization resembles that of young adult hyaline articular cartilage (score of 5) vs a totally disorganized tissue (score of 0). Inter-reader reliability was assessed using Intraclass Correlation Coefficients (ICC) for Agreement, calculated from scores of three trained readers who independently evaluated blinded sections obtained from normal (n= 4), degraded (n= 2) and repair (n= 22) human cartilage biopsies. Results: The PLM score succeeded in distinguishing normal, degraded and repair cartilages, where the latter displayed greater complexity in collagen structure. Excellent inter-reader reproducibility was found with ICCs for Agreement of 0.90 [ICC(2,1)] (lower boundary of the 95% confidence interval is 0.83) and 0.96 [ICC(2,3)] (lower boundary of the 95% confidence interval is 0.94), indicating the reliability of a single reader's scores and the mean of all three readers' scores, respectively. Conclusion: This PLM method offers a novel means for systematically evaluating collagen organization in repair cartilage. We propose that it be used to supplement current gold standard histological scoring systems for a more complete assessment of repair tissue quality. © 2010 Osteoarthritis Research Society International.


Changoor A.,Ecole Polytechnique de Montréal | Nelea M.,Ecole Polytechnique de Montréal | Methot S.,Piramal Healthcare Canada | Tran-Khanh N.,Ecole Polytechnique de Montréal | And 5 more authors.
Osteoarthritis and Cartilage | Year: 2011

Objective: This study characterizes collagen organization (CO) in human normal (n = 6), degraded (n = 6) and repair (n = 22) cartilages, using polarized light (PLM) and scanning electron (SEM) microscopies. Design: CO was assessed using a recently developed PLM-CO score (Changoor et al. Osteoarthritis Cartilage 2011;19:126-35), and zonal proportions measured. SEM images were captured from locations matched to PLM. Fibre orientations were assessed in SEM and compared to those observed in PLM. CO was also assessed in individual SEM images and combined to generate a SEM-CO score for overall CO analogous to PLM-CO. Fibre diameters were measured in SEM. Results: PLM-CO and SEM-CO scores were correlated, r = 0.786 (P < 0.00001, n = 32), after excluding two outliers. Orientation observed in PLM was validated by SEM since PLM/SEM correspondence occurred in 91.6% of samples. Proportions of the deep (DZ), transitional (TZ) and superficial (SZ) zones averaged 74.0 ± 9.1%, 18.6 ± 7.0%, and 7.3 ± 1.2% in normal, and 45.6 ± 10.7%, 47.2 ± 10.1% and 9.5 ± 3.4% in degraded cartilage, respectively. Fibre diameters in normal cartilage increased with depth from the articular surface [55.8 ± 9.4 nm (SZ), 87.5 ± 1.8 nm (TZ) and 108.2 ± 1.8 nm (DZ)]. Fibre diameters were smaller in repair biopsies [60.4 ± 0.7 nm (SZ), 63.2 ± 0.6 nm (TZ) and 67.2 ± 0.8 nm (DZ)]. Degraded cartilage had wider fibre diameter ranges and bimodal distributions, possibly reflecting new collagen synthesis and remodelling or collagen fibre unravelling. Repair tissues revealed the potential of microfracture-based repair procedures to produce zonal CO resembling native articular cartilage structure. Values are reported as mean ± 95% confidence interval. Conclusion: This detailed assessment of collagen architecture could benefit the development of cartilage repair strategies intended to recreate functional collagen architecture. © 2011 Osteoarthritis Research Society International.


Hoemann C.,Ecole Polytechnique de Montréal | Kandel R.,University of Toronto | Roberts S.,Keele University | Saris D.B.F.,University Utrecht | And 5 more authors.
Cartilage | Year: 2011

Cartilage repair strategies aim to resurface a lesion with osteochondral tissue resembling native cartilage, but a variety of repair tissues are usually observed. Histology is an important structural outcome that could serve as an interim measure of efficacy in randomized controlled clinical studies. The purpose of this article is to propose guidelines for standardized histoprocessing and unbiased evaluation of animal tissues and human biopsies. Methods were compiled from a literature review, and illustrative data were added. In animal models, treatments are usually administered to acute defects created in healthy tissues, and the entire joint can be analyzed at multiple postoperative time points. In human clinical therapy, treatments are applied to developed lesions, and biopsies are obtained, usually from a subset of patients, at a specific time point. In striving to standardize evaluation of structural endpoints in cartilage repair studies, 5 variables should be controlled: 1) location of biopsy/sample section, 2) timing of biopsy/sample recovery, 3) histoprocessing, 4) staining, and 5) blinded evaluation with a proper control group. Histological scores, quantitative histomorphometry of repair tissue thickness, percentage of tissue staining for collagens and glycosaminoglycan, polarized light microscopy for collagen fibril organization, and subchondral bone integration/structure are all relevant outcome measures that can be collected and used to assess the efficacy of novel therapeutics. Standardized histology methods could improve statistical analyses, help interpret and validate noninvasive imaging outcomes, and permit cross-comparison between studies. Currently, there are no suitable substitutes for histology in evaluating repair tissue quality and cartilaginous character. © The Author(s) 2011.


Chen H.,Ecole Polytechnique de Montréal | Chevrier A.,Ecole Polytechnique de Montréal | Hoemann C.D.,Ecole Polytechnique de Montréal | Sun J.,Piramal Healthcare Canada | And 2 more authors.
American Journal of Sports Medicine | Year: 2011

Background: Microfracture and drilling are bone marrow-stimulation techniques that initiate cartilage repair by providing access to cell populations in subchondral bone marrow. This study examined the effect of hole depth and of microfracture versus drilling on subchondral bone repair and cartilage repair in full-thickness chondral defects. Hypotheses: Repaired subchondral bone does not reconstitute its native structure and exhibits atypical morphologic features. Drilling deeper induces greater bone remodeling and is related to improved cartilage repair. Study Design: Controlled laboratory study. Methods: Trochlear cartilage defects debrided of the calcified layer were prepared bilaterally in 16 skeletally mature rabbits. Drill holes were made to a depth of 2 mm or 6 mm and microfracture holes to 2 mm. Animals were sacrificed 3 months postoperatively, and joints were scanned by micro-computed tomography before histoprocessing. Bone repair was assessed with a novel scoring system and by 3-dimentional micro-computed tomography and compared with intact controls. Correlation of subchondral bone features to cartilage repair outcome was performed. Results: Although surgical holes were partly repaired with mineralized tissue, atypical features such as residual holes, cysts, and bony overgrowth were frequently observed. For all treatment groups, repair led to an average bone volume density similar to that of the controls but the repair bone was more porous and branched as shown by significantly higher bone surface area density and connectivity density. Deeper versus shallower drilling induced a larger region of repairing and remodeling subchondral bone that positively correlated with improved cartilage repair. Conclusion: Incomplete reconstitution of normal bone structure and continued remodeling occurred in chondral defects 3 months after bone marrow stimulation. Deep drilling induced a larger volume of repairing and remodeling bone, which appeared beneficial for chondral repair. Clinical Relevance: Bone marrow stimulation does not reconstitute normal bone structure. Strategies that increase subchondral bone involvement in marrow stimulation could further benefit cartilage repair. © 2011 The Author(s).


Chen H.,Ecole Polytechnique de Montréal | Hoemann C.D.,Ecole Polytechnique de Montréal | Sun J.,Piramal Healthcare Canada | Chevrier A.,Ecole Polytechnique de Montréal | And 4 more authors.
Journal of Orthopaedic Research | Year: 2011

Subchondral drilling and microfracture are bone marrow stimulation techniques commonly used for the treatment of cartilage defects. Few studies to date have examined the technical variants which may influence the success of the cartilage repair procedures. This study compared the effect of hole depth (6 mm vs. 2 mm) and hole type (drill vs. microfracture) on chondral defect repair using a mature rabbit model. Results from quantitative histomorphometry and histological scoring showed that deeper versus shallower drilling elicited a greater fill of the cartilage defect with a more hyaline character in the repair matrix indicated by significant improvement (p = 0.021) in the aggregate measure of increased cartilage defect fill, increased glycosaminoglycan and type II collagen content and reduced type I collagen content of total soft repair tissue. Compared to microfracture at the same 2 mm depth, drilling to 2 mm produced a similar quantity and quality of cartilage repair (p = 0.120) according to the aggregate indicator described above. We conclude that the depth of bone marrow stimulation can exert important influences on cartilage repair outcomes. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc.


Marchand C.,Ecole Polytechnique de Montréal | Marchand C.,Piramal Healthcare Canada | Chen G.,Ecole Polytechnique de Montréal | Tran-Khanh N.,Ecole Polytechnique de Montréal | And 5 more authors.
Tissue Engineering - Part A | Year: 2012

This study analyzed the long-term cartilage and subchondral bone repair of microdrilled defects treated with chitosan glycerol-phosphate/blood implant, using thrombin (Factor IIa) to accelerate in situ solidification. We also evaluated the cartilage repair response to six smaller microdrill holes compared with two larger holes. Bilateral knee trochlear cartilage defects were created in n=8 skeletally mature rabbits, drilled with six proximal 0.5mm and two distal 0.9mm holes, then covered with in situ-solidified IIa-implants (treated) or with IIa-alone (control). After 6.5 months of repair, cartilage repair tissues were analyzed by histological scoring and histomorphometry for hyaline matrix characteristics and osseous integration. Subchondral repair bone was analyzed by 3D microcomputed tomography and compared to acute defects (n=6) and intact trochlea (n=8). Implant-treated cartilage repair tissues had higher structural integrity through the entire defect (p=0.02), twofold higher percent staining for glycosaminoglycan (p=0.0004), and ∼24% more collagen type II staining over the smaller drill holes (p=0.008) compared with controls. Otherwise, hole diameter had no specific effect on cartilage repair. The subchondral bone plate was partially restored in treated and control defects but less dense than intact trochlea, with evidence of incomplete regeneration of the calcified cartilage layer. More residual drill holes (p=0.054) were detected in control versus treated defects, and control defects with more than 40% residual holes presented abnormally thicker trabeculae compared with treated defects. Low osteoclast numbers after 6.5 months repair suggested that bone was no longer remodeling. The subchondral bone plate surrounding the defects exhibited a significant thickening compared with age-matched intact trochlea. These data suggest that debridement and drilling can lead to long-term subchondral bone changes outside the cartilage defect. Compared with drilled controls, chitosan implants solidified with thrombin elicited a more hyaline and structurally integrated osteochondral unit, features needed for long-term durability. © 2012. Mary Ann Liebert, Inc.


PubMed | University Utrecht, Piramal Healthcare Canada, University of Bristol, Ecole Polytechnique de Montréal and 3 more.
Type: Journal Article | Journal: Cartilage | Year: 2015

Cartilage repair strategies aim to resurface a lesion with osteochondral tissue resembling native cartilage, but a variety of repair tissues are usually observed. Histology is an important structural outcome that could serve as an interim measure of efficacy in randomized controlled clinical studies. The purpose of this article is to propose guidelines for standardized histoprocessing and unbiased evaluation of animal tissues and human biopsies. Methods were compiled from a literature review, and illustrative data were added. In animal models, treatments are usually administered to acute defects created in healthy tissues, and the entire joint can be analyzed at multiple postoperative time points. In human clinical therapy, treatments are applied to developed lesions, and biopsies are obtained, usually from a subset of patients, at a specific time point. In striving to standardize evaluation of structural endpoints in cartilage repair studies, 5 variables should be controlled: 1) location of biopsy/sample section, 2) timing of biopsy/sample recovery, 3) histoprocessing, 4) staining, and 5) blinded evaluation with a proper control group. Histological scores, quantitative histomorphometry of repair tissue thickness, percentage of tissue staining for collagens and glycosaminoglycan, polarized light microscopy for collagen fibril organization, and subchondral bone integration/structure are all relevant outcome measures that can be collected and used to assess the efficacy of novel therapeutics. Standardized histology methods could improve statistical analyses, help interpret and validate noninvasive imaging outcomes, and permit cross-comparison between studies. Currently, there are no suitable substitutes for histology in evaluating repair tissue quality and cartilaginous character.

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