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• W1981342213 abstract "Articular cartilage defects are common after joint injuries. When left untreated, the biomechanical protective function of cartilage is gradually lost, making the joint more susceptible to further damage, causing progressive loss of joint function1Buckwalter J.A. Mankin H.J. Articular cartilage: degeneration and osteoarthritis, repair, regeneration, and transplantation.Instr Course Lect. 1998; 47: 487-504PubMed Google Scholar and eventually osteoarthritis (OA). In the process of translating promising tissue-engineering cartilage repair approaches from bench to bedside, pre-clinical animal models including mice, rabbits, goats, and horses, are widely used2Chu C.R. Szczodry M. Bruno S. Animal models for cartilage regeneration and repair.Tissue Eng Part B Rev. 2010; 16: 105-115Crossref PubMed Scopus (373) Google Scholar. The equine species is becoming an increasingly popular model for the in vivo evaluation of regenerative orthopaedic approaches3McIlwraith C.W. Fortier L.A. Frisbie D.D. Nixon A.J. Equine models of articular cartilage repair.Cartilage. 2011; 2: 317-326Crossref PubMed Scopus (81) Google Scholar. As there is also an increasing body of evidence suggesting that successful lasting tissue reconstruction requires an implant that mimics natural tissue organization, it is imperative that depth-dependent characteristics of equine osteochondral tissue are known, to assess to what extent they resemble those in humans. Therefore, osteochondral cores (4–8 mm) were obtained from the medial and lateral femoral condyles of equine and human donors. Cores were processed for histology and for biochemical quantification of DNA, glycosaminoglycan (GAG) and collagen content. Equine and human osteochondral tissues possess similar geometrical (thickness) and organizational (GAG, collagen and DNA distribution with depth) features. These comparable trends further underscore the validity of the equine model for the evaluation of regenerative approaches for articular cartilage. Osteochondral cores (4–8 mm) were taken from the central sites of both medial and lateral femoral condyles of cadaveric horses (n = 15 for cartilage thickness, n = 14 for biochemical analysis, mean age: 10.5 years) and humans (n = 7 for biochemical analysis, n = 23 for cartilage thickness, mean age: 74.4 years). Donor horses had been euthanized for reasons unrelated to their femorotibial joints. Human material was obtained from human cadavers. After harvest, osteochondral cores were either fixed in 10% formalin (for histology) or frozen at −20°C for biochemical analyses. Osteochondral samples for histology were decalcified using Luthra solution (3.2% 11 M HCl, 10% formic acid in distilled water). After decalcification, samples were dehydrated, cleared in xylene and embedded in paraffin. Subsequently, the samples were sectioned (5 μm) and stained with haematoxylin and eosin for cells or with haematoxylin, fast green and safranin-O for proteoglycan distribution. The sections were examined using a light microscope (Olympus, BX51, USA) and scored according to the histological and histochemical grading system (HHGS) as described by Mankin et al.4Mankin H.J. Dorfman H. Lippiello L. Zarins A. Biochemical and metabolic abnormalities in articular cartilage from osteo-arthritic human hips. II. Correlation of morphology with biochemical and metabolic data.J Bone Joint Surg Am. 1971; 53: 523-537Crossref PubMed Scopus (1934) Google Scholar The cartilage of the frozen osteochondral plugs was sectioned in the tangential plane, i.e. parallel to the joint surface, to yield 50 μm slices using a cryotome (Cryocut 1800, Leica, Germany). Four consecutive sections were stored together as 200 μm aliquots (approximately 15 mg tissue) at −20°C until further use. After thawing, samples were digested overnight in 20 ml papain solution (0.01 M cysteine, 250 mg/ml papain, 0.2 M NaH2PO4 and 0.01 M EDTA) per mg cartilage tissue at 60°C. The cartilage digests were used for GAG, DNA and collagen analysis. GAG content was determined spectrophotometrically after reaction with dimethylmethylene blue (DMMB, Sigma–Aldrich, USA) as previously described5Farndale R.W. Buttle D.J. Barrett A.J. Improved quantitation and discrimination of sulphated glycosaminoglycans by use of dimethylmethylene blue.Biochim Biophys Acta. 1986; 883: 173-177Crossref PubMed Scopus (2897) Google Scholar. DNA content was determined using the Picogreen DNA assay (Invitrogen, P7589) in accordance with the manufacturer's instructions. Collagen content and cross-links were analysed by HPLC-MS/MS using multiple reaction monitoring (MRM). Cartilage samples were hydrolysed (110°C, 18–20 h) in 6 M HCl. Homo-arginine was added to the hydrolysed samples as an internal standard, after which they were vacuum-dried and dissolved in 30% methanol containing 0.2% Heptafluorobutyric acid (HFBA). The supernatants were subjected to HPLC-MS/MS analysis, using an API3000 mass-spectrometer (Applied Biosystems/MDS Sciex, Foster City, CA) at a source temperature of 300°C and a spray voltage of 4.5 kV. Amino acids were separated on a Synergi MAX-RP 80A (250 × 3 mm, 4 μm) column (Phenomenex Inc., Torrance, CA) at a flow rate of 400 μl/min, using a gradient from MilliQwater (Millipore, Billerica, MA) containing 0.2% HFBA to methanol. Amino acids and collagen were analysed in MRM mode using the mass transitions 189.2/143.7 for homo-arginine, 131.8/67.8 for hydroxyproline (Hyp). Data were analysed by reference to the corresponding calibration curves and corrected for the recovery of internal standard. Collagen content was calculated as follows: μg collagen (pmol Hyp/300) × 0.3 (300 is the number of Hyp residues in one collagen triple helix, 0.3 is the molecular weight of collagen, 300,000 Da). To measure cartilage thickness, digital images of haematoxylin and eosin-stained sections were analysed using cellˆF software (Olympus, USA). Average thickness of the articular cartilage of each sample was determined by averaging four measurements per image at different locations. Statistical comparisons of Mankin scores and cartilage thickness were conducted using a paired two-tailed Student's t test. For comparison of the GAG, DNA, and, collagen content at each of the different depths a repeated measurement analysis (one-way ANOVA) was performed, followed by a Bonferroni post-hoc test. Significance level was set at a P-value smaller than 0.05. All data are represented as mean ± standard deviation. Cartilage from both the lateral and medial femoral equine condyles was macroscopically healthy, as confirmed by relatively low average Mankin scores [0.9 ± 0.9, Fig. 1(A) ]. Mankin scores for human osteochondral tissues were higher [3.7 ± 1.8, Fig. 1(B)], illustrated by early signs of OA with increasing age in these samples, such as decreased staining for proteoglycans [Fig. 1(A and B)] and hypercellularity. Equine cartilage thickness ranged from 0.96 to 3.13 mm, closely resembling cartilage thickness observed in the human samples (0.65–3.52 mm). The equine cartilage at the centre of the medial femoral condyle was significantly thicker than on the lateral side (2.19 ± 0.80 mm vs 1.35 ± 0.31 mm, P = 0.003) [Fig. 1(C)]. Cartilage thickness on the human femoral condyles did not show a statistically significant difference between the medial and the lateral side (2.01 ± 0.75 mm vs 1.96 ± 0.45 mm, P = 0.95). The GAG content significantly increased over the first 600 μm from the surface in both the lateral and medial equine samples [lateral P = 0.001 and medial P = 0.0002, Fig. 2(A) ], beyond this depth, GAG levels stayed constant until the bone–cartilage interface. The same trend was observed for human cartilage tissue from both the lateral and medial condyles with only a significant difference between 400 μm and 600 μm on the lateral condyle (P = 0.041) [Fig. 2(B)]. DNA content in samples derived from both the medial and the lateral equine femoral condyles decreased with depth up to approximately 1000 μm, whereafter a relatively constant level was reached [Fig. 2(C)]. Both lateral and medial equine condyles showed significant differences between subsequent 200 μm sections (lateral respectively, P = 0.002, P = 0.0004, P < 0.0001, P < 0.0001 and medial respectively, P = 0.002, P < 0.0001, P < 0.0001, P < 0.0001). When comparing the lateral and medial equine condyles, no significant differences in DNA content were observed in the first 200 μm sections. However, the deeper layers had a significantly lower DNA content in the medial equine condyle (P = 0.002). A similar decreasing trend in DNA content was observed in human cartilage, although no significant differences were found between the subsequent 200 μm sections [Fig. 2(D)]. No significant differences in hydroxyproline, as a measure of collagen content, were observed with depth or location (lateral and medial) in equine and human articular cartilage [Fig. 2(E and F)]. The in vivo evaluation of cartilage tissue engineering applications is inevitable when aiming at the implementation of new regenerative techniques. Over the past few years, the equine model has gained popularity for this purpose2Chu C.R. Szczodry M. Bruno S. Animal models for cartilage regeneration and repair.Tissue Eng Part B Rev. 2010; 16: 105-115Crossref PubMed Scopus (373) Google Scholar, 3McIlwraith C.W. Fortier L.A. Frisbie D.D. Nixon A.J. Equine models of articular cartilage repair.Cartilage. 2011; 2: 317-326Crossref PubMed Scopus (81) Google Scholar, but more insight is required in the histological and biochemical characteristics of equine cartilage and how these relate to the human situation to better appreciate the value of this model. Cartilage thickness allows for the accommodation of the stresses and strains that are exerted on the cartilage matrix6Simon W.H. Scale effects in animal joints. I. Articular cartilage thickness and compressive stress.Arthritis Rheum. 1970; 13: 244-256Crossref PubMed Scopus (131) Google Scholar during daily movement and is thus an important factor when choosing a suitable animal model. Cartilage thickness of the equine and human knee joints was found to be within the same range and in line with earlier reports7Frisbie D.D. Cross M.W. McIlwraith C.W. A comparative study of articular cartilage thickness in the stifle of animal species used in human pre-clinical studies compared to articular cartilage thickness in the human knee.Vet Comp Orthop Traumatol. 2006; 19: 142-146PubMed Google Scholar, 8Shepherd D.E. Seedhom B.B. Thickness of human articular cartilage in joints of the lower limb.Ann Rheum Dis. 1999; 58: 27-34Crossref PubMed Scopus (393) Google Scholar. This is of relevance when studying the healing capacity of the tissue after creating a full-thickness critical size defect. It is known that in smaller animal species, such as rabbits, average osteochondral defects are smaller due to the thinner cartilage in these animals7Frisbie D.D. Cross M.W. McIlwraith C.W. A comparative study of articular cartilage thickness in the stifle of animal species used in human pre-clinical studies compared to articular cartilage thickness in the human knee.Vet Comp Orthop Traumatol. 2006; 19: 142-146PubMed Google Scholar. Thinner cartilage often leads to cartilage defects that protrude into the subchondral bone or growth plate, thereby stimulating spontaneous repair. Results obtained from small animal studies are therefore more difficult to extrapolate to the human situation. The significant difference in cartilage thickness between the lateral and medial condyle in equine tissue might be attributed to the larger loading that the medial condyle experiences. Indeed, it has been suggested that cartilage thickness is area-specific and proportional to local loading7Frisbie D.D. Cross M.W. McIlwraith C.W. A comparative study of articular cartilage thickness in the stifle of animal species used in human pre-clinical studies compared to articular cartilage thickness in the human knee.Vet Comp Orthop Traumatol. 2006; 19: 142-146PubMed Google Scholar. Joint congruency plays a role too with thinner cartilage in a more congruent joint, as the stresses can more easily be distributed over a larger surface area8Shepherd D.E. Seedhom B.B. Thickness of human articular cartilage in joints of the lower limb.Ann Rheum Dis. 1999; 58: 27-34Crossref PubMed Scopus (393) Google Scholar. A higher degree of congruence of the lateral equine condyle may explain the difference with the human knee joints, where we did not observe a significant difference in cartilage thickness between the lateral and medial condyle (n = 23), which is in line with earlier reports8Shepherd D.E. Seedhom B.B. Thickness of human articular cartilage in joints of the lower limb.Ann Rheum Dis. 1999; 58: 27-34Crossref PubMed Scopus (393) Google Scholar. This may be a gradual difference, however, as Hall and Wyshak9Hall F.M. Wyshak G. Thickness of articular cartilage in the normal knee.J Bone Joint Surg Am. 1980; 62: 408-413PubMed Google Scholar investigated cartilage thickness on arthrograms (n = 370) of young (average age 34.7 years) patients and found a small but significant difference, suggesting that differences in thickness between the medial and lateral femoral condyle are not non-existent in humans, but less evident than in horses. GAGs are important extracellular matrix components in articular cartilage; they attract water molecules and thereby aid in shock absorbance10Martel-Pelletier J. Boileau C. Pelletier J.P. Roughley P.J. Cartilage in normal and osteoarthritis conditions.Best Pract Res Clin Rheumatol. 2008; 22: 351-384Abstract Full Text Full Text PDF PubMed Scopus (371) Google Scholar. This is the first time that depth-dependent GAG concentrations were biochemically quantified in the equine femorotibial joint. Previous research has only focused on the metacarpophalangeal joint and showed depth-dependent distributions, similar to our findings11Brama P.A. Holopainen J. van Weeren P.R. Firth E.C. Helminen H.J. Hyttinen M.M. Influence of exercise and joint topography on depth-related spatial distribution of proteoglycan and collagen content in immature equine articular cartilage.Equine Vet J. 2009; 41: 557-563Crossref PubMed Scopus (25) Google Scholar. Collagen is another key building block of articular cartilage, providing structural integrity and tensile strength10Martel-Pelletier J. Boileau C. Pelletier J.P. Roughley P.J. Cartilage in normal and osteoarthritis conditions.Best Pract Res Clin Rheumatol. 2008; 22: 351-384Abstract Full Text Full Text PDF PubMed Scopus (371) Google Scholar. Throughout the different layers of articular cartilage, the orientation of the collagen fibrils changes, from parallel in the superficial zone to perpendicular in the deep zone12Herzog W. Federico S. Considerations on joint and articular cartilage mechanics.Biomech Model Mechanobiol. 2006; 5: 64-81Crossref PubMed Scopus (35) Google Scholar. This contributes to the different mechanical properties of each of the three zones. In the present study, no distinct significant differences were found in collagen content throughout the different cartilage layers in either equine or human samples. This suggests that although the alignment of the fibres changes throughout the tissue, the collagen content remains stable. DNA content showed a clear depth-dependent distribution in both equine and human tissue with declining cell numbers with increasing distance to the surface, in line with previous reports13Klein T.J. Malda J. Sah R.L. Hutmacher D.W. Tissue engineering of articular cartilage with biomimetic zones.Tissue Eng Part B Rev. 2009; 15: 143-157Crossref PubMed Scopus (253) Google Scholar. No substantial differences were observed in DNA content between equine and human tissue, which is noteworthy, as cellularity of the cartilage tissue is known to be higher in smaller animals14Stockwell R.A. The interrelationship of cell density and cartilage thickness in mammalian articular cartilage.J Anat. 1971; 109: 411-421PubMed Google Scholar. The increased cell number may relate to the more naturally occurring spontaneous cartilage repair in smaller animals, which again brings about extrapolation issues towards the human situation. The comparable trends in GAG, collagen and DNA distributions throughout the different layers in both human and equine articular cartilage underscore the translational value of the equine model. However, there are additional advantages to using this model. First, naturally occurring cartilage defects due to osteochondrosis or trauma are not uncommon in equine veterinary medicine. Hence, performing pre-clinical testing of regenerative cartilage repair applications in the horse may be of direct clinical benefit to the species itself. Furthermore, the size of the equine femorotibial joint allows for second-look arthroscopies to evaluate the ongoing repair process in vivo and allows for monitoring by means of biomarker analysis of serially sampled synovial fluid15De Grauw J.C. van de Lest C.H.A. van Weeren P.R. Inflammatory mediators and cartilage biomarkers in synovial fluid after a single inflammatory insult: a longitudinal experimental study.Arthritis Res Ther. 2009; 11: R35Crossref PubMed Scopus (91) Google Scholar. Moreover, long-term follow-up studies are impossible in small rodents, but pivotal in evaluating functional performance of cartilage regenerative techniques. Lastly, the high degree of mechanical loading in the equine knee joint is advantageous for pre-clinical evaluation of new therapies, as novel cartilage regenerative applications that are successful in horses are much more likely to survive the less biomechanically challenging environment of the human knee joint. In conclusion, these findings add to the knowledge base on comparative equine and human osteochondral biology and may provide valuable information for researchers who consider using the equine model for pre-clinical animal testing of new cartilage tissue engineering applications. Conception and design of the study: Malda, Klein, de Grauw, Hutmacher, Saris, van Weeren, Dhert. Acquisition of data: Malda, Benders, de Grauw, Kik. Analysis and interpretation of data: Malda, Benders, de Grauw. Drafting of article or revising it critically for intellectual content: Malda, Benders, Klein, de Grauw, Kik, Hutmacher, Saris, van Weeren, Dhert." @default.
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• W1981342213 title "Comparative study of depth-dependent characteristics of equine and human osteochondral tissue from the medial and lateral femoral condyles" @default.
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