Meniscectomy alters the dynamic deformational behavior and ...

Osteoarthritis and Cartilage (2008) 16, 1545e1554 ª 2008 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.joca.2008.04.011

International Cartilage Repair Society

Meniscectomy alters the dynamic deformational behavior and cumulative strain of tibial articular cartilage in knee joints subjected to cyclic loads Y. Song M.S.yz*, J. M. Greve Ph.D.x, D. R. Carter Ph.D.yz and N. J. Giori M.D., Ph.D.yk y Bone and Joint Center, VA Palo Alto Healthcare System, Palo Alto, CA, United States z Biomechanical Engineering, Department of Mechanical Engineering, Stanford University, Stanford, CA, United States x Biomedical Imaging Lab, Genentech Inc., South San Francisco, CA, United States k Department of Orthopedic Surgery, Stanford University, Stanford, CA, United States Summary Objective: Meniscectomy-induced osteoarthritis may be mechanically based. We asked how meniscectomy alters time-dependent deformation of physiologically loaded articular cartilage. We hypothesized that meniscectomy alters nominal strain in tibial articular cartilage, and that meniscectomy affects cartilage thickness recovery following cessation of loading. Methods: A cyclic load simulating normal gait was applied to four sheep knees. A custom device was used to obtain MR images of cartilage at 4.7 T during cyclic loading. Articular cartilage thickness and nominal strain were measured every 2.5 min during 1 h of cyclic loading, and during 2.5 h after cessation of loading. Results: Following meniscectomy the loaded joints rapidly developed high strain centrally and minimal strain peripherally. Maximum nominal strains after 1 h of loading were about 55% in the intact knees and 72% in the meniscectomized knees. Nominal strains in the peripheral tibial cartilage were significantly reduced in the meniscectomized knees. Strain recovery was markedly prolonged in the meniscectomized knees. Conclusions: With meniscectomy, tibial articular cartilage in the central load bearing region remains chronically deformed and dehydrated, even after cessation of loading. Post-meniscectomy osteoarthritis may be initiated in this region by direct damage to the cartilage matrix, or by altering the hydration of the tissue. In peripheral regions, reduced loading and strain may facilitate subchondral vascular invasion, and endochondral ossification. This is consistent with the central fibrillation and peripheral osteophyte formation seen in post-meniscectomy osteoarthritis. ª 2008 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. Key words: Articular cartilage, Time-dependent deformation, Dynamic MR imaging, Cyclic loading, Meniscectomy, Osteoarthritis.

loading on articular cartilage may directly cause fibrillation of cartilage by increasing friction and structural damage18,19, while abnormally low loading may allow the advance of endochondral ossification resulting in articular cartilage thinning and peripheral osteophyte formation20,21. Fibrillation, thinning of articular cartilage, and osteophyte formation are observed on the tibial plateau of a knee following meniscectomy in humans and animals, including sheep16,17,22. Articular cartilage exhibits highly complex timedependent material behavior and non-linear deformation over time23e26. Articular cartilage material has solid and fluid phases and exhibits strain dependent permeability, where the flow of fluid through the cartilage tissue depends not only on the material of the solid phase, but on the strain state of the solid phase25,27. Studies have tested timedependent behavior of articular cartilage in tissue plugs24, and multiphasic material models of articular cartilage have been described23,25. To this point, however, our understanding of the dynamic behavior of articular cartilage in a whole joint is minimal. There have been a number of studies that have evaluated articular cartilage deformation at a single time point1,28,29, and one study has used MRI to evaluate the timedependent cartilage deformation in a human patellafemoral

Introduction Meniscectomy is a common and effective treatment for unstable meniscal tears, reducing knee pain and improving function. Meniscectomy, however, is known to change the mechanical loading of articular cartilage by concentrating high load on a markedly reduced contact area1e6. Meniscectomy has been shown in humans to be associated with increased risk of osteoarthritis many years after the procedure7e10. Alteration of the mechanical environment in the joint following meniscectomy is believed to play an important role in the development of post-meniscectomy osteoarthritis. Meniscectomy results in knee osteoarthritis in humans and in various animal models7e17. The relationship between altered mechanical loading and cartilage degeneration after meniscectomy remains poorly understood. Abnormally high *Address correspondence and reprint requests to: Dr Yongnam Song, Biomechanical Engineering, Department of Mechanical Engineering, Stanford University, 496 Lomita Mall, Durand Building, Room 226, Stanford, CA 94305-4038, United States. Tel: 1-650-736-0806; Fax: 1-650-725-1587; E-mail: kurtbain@ stanford.edu Received 31 July 2007; revision accepted 19 April 2008.

1545

1546 joint under static loading30. However, no study has evaluated the time-dependent material behavior of articular cartilage in a joint under realistic dynamic loading and unloading. Osteoarthritis development may be related to the magnitude and duration of articular cartilage strain during dynamic physiologic loading, but no study has previously calculated and compared the magnitude and duration of articular cartilage strain in intact and meniscectomized knees subjected to cyclic loads. In order to truly understand how altered joint mechanics lead to osteoarthritis, a more sophisticated understanding of articular cartilage deformation and strain in a whole joint subjected to realistic dynamic loading is needed. The objective of this study was to measure the deformation and nominal strains of articular cartilage over time in a whole knee joint under realistic dynamic loading conditions. To develop greater understanding of meniscectomy induced osteoarthritis, the time-dependent articular cartilage nominal strain at the tibial plateau was measured and its cumulative values throughout the entire loading and relaxation cycle were calculated before and after medial meniscectomy. We hypothesized that meniscectomy leads to an alteration of nominal strain in articular cartilage during cyclic loading, and that meniscectomy affects the recovery of articular cartilage thickness following cessation of loading. Methods SAMPLE PREPARATION In this study, the sheep knee model was used as its pattern of osteoarthritis is similar to humans following meniscectomy16. Two right and two left hind limbs from four different sheep were tested. The sheep were 2 years old and weighed approximately 50 kg. Fresh sheep hind limbs were frozen after positioning at a flexion angle of 45 , which is the normal standing flexion angle for a sheep31. Twenty-four hours prior to imaging, the entire knee joint was cored with a 4.45 cm hole-saw in the medial to lateral direction while maintaining the leg in a frozen state. This core was large enough in diameter to maintain the entire tibiofemoral articulation and its supporting structures in an intact state, with no disruption to the collateral ligaments, cruciate ligaments, menisci, and meniscal attachments. The patellafemoral joint was not included in the core, and the proximal joint capsule near the patellafemoral joint was cut at the edge of the core. The joint specimen was then completely thawed in a saline solution of gadolinium and proteinase inhibitors32 in a refrigerator at 5 C for 10 h prior to MR scanning.

LOADING DEVICE A custom loading device used in a previous static study1 was modified to apply cyclic compressive loading to a knee specimen inside the MRI scanner and allow scanning of the specimen during cyclic loading (Fig. 1). The joint specimen was placed between the two half-cylinders and aligned such that the loading axis was oriented perpendicular to the articular surface at the center of the joint. Periodic axial compression of the tibio-femoral joint was accomplished by pressurized air flowing into an air bladder with a preprogrammed frequency, pressing the upper half-cylinder toward the lower half-cylinder. The magnitude of applied load was calibrated before testing. The apparatus constrained anterioreposterior translation and internaleexternal rotation, but allowed medialelateral translation and varusevalgus rotation. The loading apparatus could be sealed to contain fluid after the installation of a specimen.

CYCLIC LOADING AND MR GATE SIGNAL A custom electro-pneumatic device was designed and fabricated to control the timing and the pressure of the compressed air. The profile of ground reaction force from a force plate study of sheep gait (Dr Richard Appleyard, personal communication) was used to determine the frequency and waveform of the applied loading. The peak magnitude of cyclic loading was chosen as two times of body weight (980 N), which is the peak joint reaction force at the knee (rather than ground reaction force) during normal sheep gait33. The frequency of loading was approximately 1 Hz [Fig. 2(a)].

Y. Song et al.: Time-dependent cartilage deformation The custom electro-pneumatic device generated a gate signal synchronized with the loaded phase of the loading cycle. The gate signal was sent to the MR scanner only during the plateau region of the cyclic loading phase [Fig. 2(b)]. MR data acquisition was paused during the unloaded phase of the load cycle, resumed during next compression cycle, and so on [Fig. 2(b)].

MR IMAGING OF CYCLICALLY LOADED JOINT SAMPLE Imaging was performed on a 4.7-T MRI scanner (Varian Inc., Palo Alto, CA)1. A fast low resolution full 3D MR scan of the intact knee was obtained using a gradient echo sequence prior to loading. This was used as a scout to identify the location of the central load bearing region of the medial compartment. One sagittal slice passing through this region of medial compartment was selected from this 3D scan. The selected slice was identified by its position from the medial end of the sample and by the detailed local shape of the physis. The previously selected sagittal slice through the center of the medial condyle was imaged repeatedly during the experiment. A segmented gradient echo sequence in which multiple phase encoding steps are acquired per gating event provided 58 mm2 in-plane resolution (TR/TE: 22/6 ms, matrix: 5122, zero-filled to 10242, FOV: 6 cm2, slice thickness: 1 mm, NEX: 8, 32 lines of phase encode acquired per gate). Implementation of this sequence was analogous to segmented k-space approaches commonly used in cardiovascular imaging34. With the current cyclic loading paradigm, the scanner collected a fraction of data only during the loading phase of each cycle. After 128 cycles, approximately 2.5 min later, data acquisition for a single image was completed. The image obtained reflected the deformation at peak loading averaged over each 2.5-min period. For each sample, the entire experiment took 2 days. On day 1, an initial 3D MR data set was acquired, a single slice from this data set was selected, the knee specimen was cyclically loaded in the MRI scanner for 1 h, and 24 images of the selected slice spaced at 2.5-min intervals were taken. Cyclic loading of the knee was then stopped, and the unloaded knee was imaged again at 2.5-min intervals for 2.5 h. The joint sample was then removed from the loading device and stored in a load-free condition immersed in a saline solution of proteinase inhibitors and gadolinium for 24 h to allow articular cartilage thickness recovery. On day 2, the medial meniscus was carefully removed. Another full 3D scan of the medially meniscectomized sample was acquired, and using information on position of the slice and the shape of the physis, the same sagittal slice through the center of the load bearing region of the medial compartment of the knee was selected. The medially meniscectomized knee was then imaged during cyclic loading and after loading, as had been done on the first day.

IMAGE PROCESSING AND THICKNESS MEASUREMENT In each of the 170 images from each specimen (one unloaded, 24 cyclically loaded and 60 relaxation images for the intact and the meniscectomy cases) the tibial cartilage surface and the subchondral bone boundary were manually segmented using a custom program. The images were registered by aligning the subchondral bone surface in each image, as this surface did not exhibit detectable deformation. Cartilage thickness was defined as the perpendicular distance from a selected point on the subchondral bone surface to the articular cartilage boundary1. The nominal strain was defined as the change in articular cartilage thickness between the unloaded state and the loaded state, divided by the original unloaded cartilage thickness. The accuracy and precision of this articular cartilage thickness measurement technique has been previously reported1. Coefficients of variation (CV) of mean and maximum thickness measurements for repeated scanning of the same specimen and for repeated segmentation of the same scan were all less than 2%. The root mean square errors of MRI thickness measurements when compared to micro-CT measurements were less than 100 mm.

Results ARTICULAR CARTILAGE THICKNESS CHANGES IN INTACT OR MENISCECTOMIZED KNEES

Movies of evolving articular cartilage surfaces of one of the four knees during 1-h cyclic compression and 2.5-h relaxation for both the intact (Movie 1) and meniscectomized cases (Movie 2) are available as supplementary data. A graphical representation of this cartilage deformation for one of the samples is shown in Fig. 3. Only the central 70% of the thickness data (from points P1 to P2 in Fig. 3) were evaluated because the cartilage deformation outside of this region was minimal. Following meniscectomy, there

1547

Osteoarthritis and Cartilage Vol. 16, No. 12

Fig. 1. A schematic diagram of the loading device is shown. The sample position and loading axis inside the loading device are displayed.

was a greater and more rapid reduction of cartilage thickness on the central contact area. The articular cartilage thickness just outside of the contact area was slightly increased in the meniscectomized joint. The averaged mean and maximum articular cartilage nominal strains of the four tested knee samples were plotted as a function of time in intact and meniscectomized cases (Fig. 4). The maximum cartilage nominal strains in meniscectomized cases were significantly greater (P < 0.05, Student’s t test) than in intact cases during both compression and relaxation periods although no significant differences in mean nominal strains were observed (P > 0.05). TIME TO STEADY-STATE (SS) DEFORMATION

The time to SS deformation of articular cartilage was defined as the time at which the maximum nominal strain

reached 95% of the greatest maximum nominal strain during the entire 1-h compression. The meniscectomized joints reached the SS deformation in almost half the time of the intact joints (P ¼ 0.005; Fig. 4). ARTICULAR CARTILAGE THICKNESS RECOVERY AFTER 24 h OF RELAXATION

To evaluate whether full articular cartilage thickness recovery had occurred following 24 h of relaxation time after the intact loading experiment (day 1), the mean cartilage thickness of the unloaded scans for intact (day 1) and meniscectomized joints (day 2) were compared in each sample. The samples recovered 92.0 8.9% of their original thickness on average after 24 h of recovery time. Thus, after 24 h of relaxation time, the cartilage was deformed less than what is observed after the initial 2.5 min of cyclic loading, our smallest time step.

Fig. 2. (a) Applied cyclic loading (blue) was calibrated to match real sheep gait data (red; Appleyard RC, personal communication) in both magnitude and frequency. (b) The gate signal to the MR scanner was synchronized with the loading cycle to allow scanning only during the compression phase of loading.

1548

Y. Song et al.: Time-dependent cartilage deformation

Fig. 3. Articular cartilage deformation and thickness changes at various time points in one of the (a) intact and (b) meniscectomized knees during cyclic compression and relaxation are displayed. Thickness values were calculated for central 70% of contact area in tibial articular cartilage with either meniscus and femoral articular cartilage.

EVOLUTION OF ARTICULAR CARTILAGE NOMINAL STRAIN PATTERNS

The nominal strain measurements after 60 min of cyclic loading were used as a reference. Three strain ranges (high, moderate, low) were defined from the distribution of articular cartilage nominal strain at this reference state. High strain was defined as the highest 10% of strains, and low strain was defined as the lowest 10% of strains from the measurements at the 60-min time point. The central 80% of this strain range was defined as moderate

strain. The distribution of articular cartilage nominal strain over the selected slice after 60 min of cyclic loading in one of the intact and meniscectomized samples is displayed in Fig. 5. The three strain ranges for all four samples are displayed in Fig. 6. An analysis of the percentage of cartilage surface experiencing high, moderate, and low strain as defined above was done to demonstrate the evolution of strain distribution over time for all intact and meniscectomized knees during (Fig. 7) and after cyclic loading (Fig. 8).


1549

Fig. 4. Averaged mean and maximum strain are plotted in intact and meniscectomized knees. SS deformation times are indicated. Error bars indicate 1 standard deviation. CUMULATIVE NOMINAL STRAIN

The strain observed in this study during cyclic compression and relaxation was further evaluated by applying the concepts of cumulative stress and strain that have been previously described to influence skeletal tissue differentiation and remodeling21,35e37. We calculated the cumulative

nominal strains within the central 70% of the load bearing area of tibial articular cartilage in intact and meniscectomized knees (Fig. 9). Calculations at the very periphery of the articular cartilage surface (outside of the central 70%) were not done due to the thin articular cartilage surface. Due to the variability of the size between specimens, the

Fig. 5. One example of the strain determination; (a) three strain ranges (high, moderate, low) were derived from the articular cartilage deformation in an intact joint after 60 min of cyclic loading. (b) The same ranges defined in intact case were applied to the corresponding meniscectomized case.

1550


Fig. 6. The range of high, moderate and low strain for each sample was displayed.

distances of data collection points were normalized by the entire length of load bearing region from anterior (0%) to posterior (100%). In order to combine information on the magnitude and duration of strain that we obtained in this study, we calculated cumulative nominal strain at each location of the tibial articular cartilage surface. Cumulative nominal strain (xc) for 1 h of cyclic loading and 2.5-h relaxation was expressed by the time integral of the nominal

strains during the compression phase (3c) and during the relaxation phase (3r). Z 60 min Z 210 min xc ¼ 3c dt þ 3r dt 0 min

60 min

The cumulative nominal strain value reflects the nominal strains experienced by the articular cartilage during entire

Fig. 7. The distributions of low, moderate, and high strains are displayed as a function of time in (a) intact and (b) meniscectomized joints during cyclic compressive loading. SS strain distributions are also indicated.


1551

Fig. 8. The distributions of low, moderate, and high strains are displayed as a function of time in (a) intact and (b) meniscectomized joints after unloading.

loading and relaxation period. The cumulative nominal strain values for four specimens were then averaged and the differences in intact and meniscectomized knees were displayed in Fig. 9(b). The corresponding positions on an actual MR image are indicated in Fig. 9(a). A significant increase in the cumulative nominal strain was observed in the central portion of the tibial articular cartilage [Fig. 9(b)]. This region corresponded roughly to the region that is in direct contact with the opposing femoral condyle. Significant decreases in the cumulative nominal strain were observed in peripheral articular cartilage [Fig. 9(b)].

Discussion In this study, we obtained sagittal MR images of whole knee joints loaded at a physiologic magnitude and frequency. We found that, centrally, meniscectomy accelerates articular cartilage deformation during loading, and results in slowed recovery of cartilage thickness after unloading. Peripheral areas experience reduced deformation after meniscectomy. Real loads in a knee involve rolling and sliding, which were not duplicated here. Furthermore, the patellafemoral joint was not included, and it was necessary to violate the joint capsule and lose the native synovial fluid in order to prepare the specimen. Though these differences from the natural condition of the joint would affect our quantitative results, the loading, condition of the capsule, and fluid bathing the joint were consistent between the intact and meniscectomized knee tests.

In addition, the intact and meniscectomy conditions could not be tested in a randomized order, but we felt that 24 h was an adequate amount of time between tests as residual cartilage deformation before the meniscectomized testing was less than what was observed after the initial 2.5 min of cyclic loading, our smallest time step. Further evaluation of the mechanical integrity of the cartilage, other than by gross inspection, was not performed, but testing was done at load magnitudes that were physiologic, and should have been below the threshold of causing significant damage to the tissue. The time to SS deformation in this study is similar to the time found in a static study on the patellafemoral joint30. The mean strain value of 30% for an intact knee at SS computed in this study is for a two-dimensional slice of the knee through the medial center of contact, and overestimates the mean strain of the entire surface. From one of our ongoing studies, a mean strain of 30% in such a two-dimensional slice corresponds to a mean strain of about 17% over the entire three-dimensional surface. This is comparable to the 14% mean strain reported in human knee cartilage after 20 min of running38. Because 70% of the wet weight of articular cartilage is water, and water is nearly incompressible, water flow through and out of the tissue must play an important role in determining its response to loading. A healthy meniscus has lower permeability than articular cartilage39e41. It may be that the meniscus acts to seal the articular cartilage surface that is not in direct contact with the opposing articular cartilage surface. Meniscectomy may thus make it easier for water to escape the mechanically loaded articular cartilage. Fluid flow was not measured in this study, however, and further

1552


Fig. 9. Averaged changes in cumulative nominal strain for four samples following meniscectomy within tibial load bearing region during cyclic compressive load and relaxation. Distances of data collection points were normalized by the entire length of load bearing region from anterior (0%) to posterior (100%). Central 70% of data were displayed.

studies are needed to determine whether the meniscus alters patterns of fluid flow before and after meniscectomy. Once water is squeezed out of the tissue and the solid matrix consolidates, the permeability of the tissue to fluid flow reduces, making it difficult for the water to flow back into the tissue once the tissue is unloaded. Following meniscectomy, the central load bearing region of the articular cartilage deforms more and stays relatively deformed and dehydrated for a long period of time compared to the intact knee following loading. Our research suggests that with intermittent activity, the articular cartilage in the central load bearing region of the meniscectomized knee may never fully recover its original thickness, staying in a deformed and dehydrated state. This could have profound effects on chondrocyte metabolic processes that likely require proper balance of charge, soluble ions, pH, etc. to proceed properly. Such a dramatic change in the articular cartilage biochemical environment could be another mechanism to alter chondrocyte gene expression toward a degenerative pathway, and should be the subject of further investigation. Integrating the localized articular cartilage nominal strain over the time combines two important elements of the tissue

mechanical state during the experiment, the duration and the magnitude of deformation experienced by the tissue. Calculated high or low cumulative nominal strain areas in meniscectomized joints were consistent with the areas of central cartilage fibrillation and of peripheral osteophyte formation that have been observed in in vivo postmeniscectomy osteoarthritis studies16,17. In conclusion, we successfully developed a MR imaging technique and device to measure the evolution of articular cartilage deformation over time in whole knee joints during cyclic loading of physiologic magnitude and frequency. On the periphery of the tibial condyle, meniscectomy results in prolonged reduction of strain and low cumulative strain. In vivo following meniscectomy, the peripheral region of articular cartilage is the typical region of endochondral ossification and osteophyte formation16,17,20,21,42e44. In the central load bearing region of the tibial condyle, meniscectomy results in rapid development of high strains which are sustained even after a prolonged period of unloading. In in vivo models of meniscectomy, this area of high cumulative strain develops fibrillation. The dramatically slowed strain recovery seen in the central region of the tibial

Osteoarthritis and Cartilage Vol. 16, No. 12 condyle is likely due to the strain dependent permeability of articular cartilage. Because articular cartilage thickness recovery in the central load bearing region of the meniscectomized tibial condyle is so prolonged, the cartilage may never reach original thickness and may remain in a chronically deformed and dehydrated state during normal intermittent activity. Fibrillation that is seen centrally may thus be started either by direct strain-induced damage to the articular cartilage matrix, or by chronically changing the hydration of the tissue and altering the local biochemical environment of the chondrocyte. Cumulative strain captures the duration and magnitude of strain in the tissue and can be useful in describing the dynamic behavior of articular cartilage subjected to physiologic loads.

Conflict of interest None of the authors have any financial and personal relationships with other people or organizations that could inappropriately influence or bias this study.

Acknowledgments We thank Dr Richard Appleyard for providing sheep gait data, and thank JJ&F market for providing the tissue specimens used in this study. This work was supported by a Whitaker Foundation Research Grant. This material is the result of work supported in part with resources and the use of facilities at the office of Research and Development (Rehabilitation R&D Service), Department of Veterans Affairs.

Supplementary data Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.joca.2008. 04.011.

References 1. Song Y, Greve JM, Carter DR, Koo S, Giori NJ. Articular cartilage MR imaging and thickness mapping of a loaded knee joint before and after meniscectomy. Osteoarthritis Cartilage 2006 Aug;14(8):728e37 (Epub 2006 Mar 13). 2. Lee SJ, Aadalen KJ, Malaviya P, Lorenz EP, Hayden JK, Farr J, et al. Tibiofemoral contact mechanics after serial medial meniscectomies in the human cadaveric knee. Am J Sports Med 2006 Aug;34(8): 1334e44 (Epub 2006 Apr 24). 3. Haemer JM, Wang MJ, Carter DR, Giori NJ. Benefit of single-leaf resection for horizontal meniscus tear. Clin Orthop Relat Res 2006 Dec 14 (Epub ahead of print). 4. von Lewinski G, Stukenborg-Colsman C, Ostermeier S, Hurschler C. Experimental measurement of tibiofemoral contact area in a meniscectomized ovine model using a resistive pressure measuring sensor. Ann Biomed Eng 2006 Oct;34(10):1607e14 (Epub 2006 Sep 30). 5. McKinley TO, English DK, Bay BK. Trabecular bone strain changes resulting from partial and complete meniscectomy. Clin Orthop Relat Res 2003 Feb;(407):259e67. 6. Wilson W, van Rietbergen B, van Donkelaar CC, Huiskes R. Pathways of load-induced cartilage damage causing cartilage degeneration in the knee after meniscectomy. J Biomech 2003 Jun;36(6):845e51. 7. Englund M. Meniscal tear e a feature of osteoarthritis. Acta Orthop Scand Suppl 2004 Apr;75(312):1e45 (Backcover). 8. Chatain F, Adeleine P, Chambat P, Neyret P, Societe Francaise d’Arthroscopie. A comparative study of medial versus lateral arthroscopic partial meniscectomy on stable knees: 10-year minimum follow-up. Arthroscopy 2003 Oct;19(8):842e9 (Review).

1553 9. Roos H, Lauren M, Adalberth T, Roos EM, Jonsson K, Lohmander LS. Knee osteoarthritis after meniscectomy: prevalence of radiographic changes after twenty-one years, compared with matched controls. Arthritis Rheum 1998 Apr;41(4):687e93. 10. Jorgensen U, Sonne-Holm S, Lauridsen F, Rosenklint A. Long-term follow-up of meniscectomy in athletes. A prospective longitudinal study. J Bone Joint Surg Br 1987 Jan;69(1):80e3. 11. Fahlgren A, Messner K, Aspenberg P. Meniscectomy leads to an early increase in subchondral bone plate thickness in the rabbit knee. Acta Orthop Scand 2003 Aug;74(4):437e41. 12. Messner K, Fahlgren A, Ross I, Andersson B. Simultaneous changes in bone mineral density and articular cartilage in a rabbit meniscectomy model of knee osteoarthrosis. Osteoarthritis Cartilage 2000 May;8(3): 197e206. 13. Ghosh P, Sutherland J, Bellenger C, Read R, Darvodelsky A. The influence of weight-bearing exercise on articular cartilage of meniscectomized joints. An experimental study in sheep. Clin Orthop Relat Res 1990 Mar;(252):101e13. 14. Ghosh P, Read R, Numata Y, Smith S, Armstrong S, Wilson D. The effects of intraarticular administration of hyaluronan in a model of early osteoarthritis in sheep. II. Cartilage composition and proteoglycan metabolism. Semin Arthritis Rheum 1993 Jun;22(6 Suppl 1):31e42. 15. Armstrong S, Read R, Ghosh P. The effects of intraarticular hyaluronan on cartilage and subchondral bone changes in an ovine model of early osteoarthritis. J Rheumatol 1994 Apr;21(4):680e8. 16. Appleyard RC, Burkhardt D, Ghosh P, Read R, Cake M, Swain MV, et al. Topographical analysis of the structural, biochemical and dynamic biomechanical properties of cartilage in an ovine model of osteoarthritis. Osteoarthritis Cartilage 2003 Jan;11(1):65e77. 17. Oakley SP, Lassere MN, Portek I, Szomor Z, Ghosh P, Kirkham BW, et al. Biomechanical, histologic and macroscopic assessment of articular cartilage in a sheep model of osteoarthritis. Osteoarthritis Cartilage 2004 Aug;12(8):667e79. 18. Andriacchi TP, Briant PL, Bevill SL, Koo S. Rotational changes at the knee after ACL injury cause cartilage thinning. Clin Orthop Relat Res 2006 Jan;442:39e44. 19. Panula HE, Helminen HJ, Kiviranta I. Slowly progressive osteoarthritis after tibial valgus osteotomy in young beagle dogs. Clin Orthop Relat Res 1997 Oct;(343):192e202. 20. Carter DR, Beaupre GS, Wong M, Smith RL, Andriacchi TP, Schurman DJ. The mechanobiology of articular cartilage development and degeneration. Clin Orthop Relat Res 2004 Oct;(Suppl 427): S69e77. 21. Carter DR, Beaupre´ GS. Skeletal Function and Form: Mechanobiology of Skeletal Development, Aging, and Regeneration. 1st edn. Cambridge: Cambridge University Press; 2001. 22. Moskowitz RW, Goldberg VM. Osteophyte evolution: studies in an experimental partial meniscectomy model. J Rheumatol 1987 May; (14 Spec No):116e8. 23. Garcia JJ, Cortes DH. A nonlinear biphasic viscohyperelastic model for articular cartilage. J Biomech 2006;39(16):2991e8 (Epub 2005 Nov 28). 24. Neu CP, Hull ML. Toward an MRI-based method to measure nonuniform cartilage deformation: an MRI-cyclic loading apparatus system and steady-state cyclic displacement of articular cartilage under compressive loading. J Biomech Eng 2003 Apr;125(2):180e8. 25. Wu JZ, Herzog W. Finite element simulation of location- and timedependent mechanical behavior of chondrocytes in unconfined compression tests. Ann Biomed Eng 2000 Mar;28(3):318e30. 26. Holmes MH, Mow VC. The nonlinear characteristics of soft gels and hydrated connective tissues in ultrafiltration. J Biomech 1990;23(11): 1145e56. 27. Wong M, Carter DR. Articular cartilage functional histomorphology and mechanobiology: a research perspective. Bone 2003 Jul;33(1):1e13 (Review). 28. Kaab MJ, Ito K, Clark JM, Notzli HP. The acute structural changes of loaded articular cartilage following meniscectomy or ACL-transection. Osteoarthritis Cartilage 2000 Nov;8(6):464e73. 29. Eckstein F, Schnier M, Haubner M, Priebsch J, Glaser C, Englmeier KH, et al. Accuracy of cartilage volume and thickness measurements with magnetic resonance imaging. Clin Orthop Relat Res 1998 Jul;(352): 137e48. 30. Herberhold C, Faber S, Stammberger T, Steinlechner M, Putz R, Englmeier KH, et al. In situ measurement of articular cartilage deformation in intact femoropatellar joints under static loading. J Biomech 1999 Dec;32(12):1287e95. 31. Tapper JE, Ronsky JL, Powers MJ, Sutherland C, Majima T, Frank CB, et al. In vivo measurement of the dynamic 3-D kinematics of the ovine stifle joint. J Biomech Eng 2004 Apr;126(2):301e5. 32. Chen AC, Klisch SM, Bae WC, Temple MM, McGowan KB, Gratz KR, et al. Mechanical characterization of native and tissue-engineered cartilage. Methods Mol Med 2004;101:157e90. 33. Taylor WR, Ehrig RM, Heller MO, Schell H, Seebeck P, Duda GN. Animal models for knee injury frequently underestimate the mechanical

1554

34.

35. 36. 37. 38. 39.

conditions of the clinical situation. In: Transactions of 51st Annual Meeting of the Orthopedic Research Society 2005;51:469. Boxerman JL, Mosher TJ, McVeigh ER, Atalar E, Lima JA, Bluemke DA. Advanced MR imaging techniques for evaluation of the heart and great vessels. Radiographics 1998 MayeJun;18(3): 543e64 (Review). Carter DR, Fyhrie DP, Whalen RT. Trabecular bone density and loading history: regulation of connective tissue biology by mechanical energy. J Biomech 1987;20(8):785e94. Fyhrie DP, Carter DR. A unifying principle relating stress to trabecular bone morphology. J Orthop Res 1986;4(3):304e17. Mikic B, Carter DR. Bone strain gage data and theoretical models of functional adaptation. J Biomech 1995 Apr;28(4):465e9. Mosher TJ, Smith HE, Collins C, Liu Y, Hancy J, Dardzinski BJ, et al. Change in knee cartilage T2 at MR imaging after running: a feasibility study. Radiology 2005 Jan;234(1):245e9. LeRoux MA, Setton LA. Experimental and biphasic FEM determinations of the material properties and hydraulic permeability of the meniscus in tension. J Biomech Eng 2002 Jun;124(3):315e21.

Y. Song et al.: Time-dependent cartilage deformation 40. Joshi MD, Suh JK, Marui T, Woo SL. Interspecies variation of compressive biomechanical properties of the meniscus. J Biomed Mater Res 1995 Jul;29(7):823e8. 41. Armstrong CG, Mow VC. Variations in the intrinsic mechanical properties of human articular cartilage with age, degeneration, and water content. J Bone Joint Surg Am 1982 Jan;64(1):88e94. 42. Kijowski R, Blankenbaker DG, Stanton PT, Fine JP, De Smet AA. Radiographic findings of osteoarthritis versus arthroscopic findings of articular cartilage degeneration in the tibiofemoral joint. Radiology 2006 Jun;239(3):818e24 (Epub 2006 Apr 26). 43. Hayami T, Pickarski M, Wesolowski GA, McLane J, Bone A, Destefano J, et al. The role of subchondral bone remodeling in osteoarthritis: reduction of cartilage degeneration and prevention of osteophyte formation by alendronate in the rat anterior cruciate ligament transection model. Arthritis Rheum 2004 Apr;50(4):1193e206. 44. Sarzi-Puttini P, Cimmino MA, Scarpa R, Caporali R, Parazzini F, Zaninelli A, et al. Osteoarthritis: an overview of the disease and its treatment strategies. Semin Arthritis Rheum 2005 Aug;35(1 Suppl 1):1e10 (Review).