Clinical Biomechanics 21 (2006) 9991012 www.elsevier.

com/locate/clinbiomech

Review

A review on the mechanical quality of articular cartilage Implications for the diagnosis of osteoarthritis
Sven Knecht
a

a,*

, Benedicte Vanwanseele b, Edgar Stu ssi

Institute for Biomechanics, Swiss Federal Institute of Technology Zurich, CH-8093 Zurich, Switzerland b School of Exercise and Sport Science, University of Sydney, Australia Received 3 October 2005; accepted 5 July 2006

Abstract The functional behaviour of articular cartilage in diarthrodial joints is determined by its morphological and biomechanical properties. Whereas morphological changes are mainly detectable in the progressed stages of osteoarthritis, biomechanical properties seem to be more sensitive to early degenerative variations since they are determined by the biochemical composition and structural arrangement of the extracellular matrix. The objective of this paper is to review studies focussing on variations in the mechanical compressive properties during the early pre-osteoarthritic stage. The aim is to quantify the requirements to detect the early cartilage degeneration in pre-osteoarthritis based on the mechanical parameters and to create an updated basis for a better understanding of inherent relationships between characteristic parameters in articular cartilage. Correlations between mechanical and biochemical parameters as well as magnetic resonance, ultrasonic, histological and structural parameters were observed. In early osteoarthritis, static moduli decrease below 80% of healthy controls and dynamic moduli below 30% of controls. To identify osteoarthritic changes of articular cartilage based on static or dynamic mechanical parameters in an early stage of the disease progression the accuracy of a mechanical testing method has to be adequate to detect changes of 10% in cartilage stiness. 2006 Elsevier Ltd. All rights reserved.
Keywords: Articular cartilage; Assessment; Biomechanical; Osteoarthritis

1. Introduction Osteoarthritis (OA) is a disease with many complex etiologies, aecting all adjacent tissues in diarthrodial joints. Morphological, biochemical, structural, and biomechanical changes of the extracellular matrix (ECM) and the cells are manifested in OA which leads to the degeneration of the articular cartilage (AC) with softening, brillation, ulceration, and nally to cartilage loss (Keuttner and Goldberg, 1995). As the functionality of diarthrodial joints cannot be sustained without articular cartilage, the precise and early diagnosis of the disease is fundamental to prevent

Corresponding author. E-mail address: sknecht@ethz.ch (S. Knecht).

or reduce long-term disability (Bjorklund, 1998). Morphological and biomechanical properties are very useful parameters to assess cartilage tissue as they determine the functional behaviour of AC. Magnetic Resonance Imaging (MRI) combined with state-of-the-art post-processing methods enables to obtain accurate and highly reproducible quantitative data of the morphology in healthy (Eckstein et al., 1996) and progressed osteoarthritic cartilage (Burgkart et al., 2001) even from restricted areas of interest (Vanwanseele et al., 2003). However, OA does not result inevitably in detectable morphological changes in an early stage of its progression. It is generally accepted that the biomechanical properties of articular cartilage depend on the biochemical composition, the ultrastructural organisation, and the interaction of the matrix molecules. Thus, biomechanical

0268-0033/$ - see front matter 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.clinbiomech.2006.07.001

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Nomenclature E Edyn E2s G jG*j Geq Gu Youngs modulus dynamic Youngs modulus two-second creep modulus shear modulus complex shear modulus equilibrium shear modulus unrelaxed shear modulus GR HA J(t) L(s) m j relaxed shear modulus aggregate modulus shear compliance retardation-time spectrum Poissons ratio permeability

properties seem to be more sensitive to pathological changes of the tissue since alterations of the structural and biochemical properties are one of the rst events in articular cartilage degeneration (Buckwalter and Mankin, 1998). For this paper, we have reviewed the past publications in regard to changes of mechanical properties with the progression of osteoarthritis. We summarise changes in mechanical compressive properties and review signicant relationships between mechanical and physical, morphological, histological and biochemical parameters during the early stages in OA-like cartilage. The aim is to investigate the potential of the biomechanical compressive parameters for the sensitive assessment of articular cartilage and to deduce specications for novel diagnostic tools based on mechanical parameters to detect pre-osteoarthritic cartilage degenerations. In the rst part of this review, we give a rough abstract of the commonly used biomechanical methods to assess articular cartilage. In the main section, publications mainly focussing on degenerative variations of the cartilage compressive behaviour are summarised and studies showing correlations between the dierent parameters are extracted. According to the origin of the sample, this part is structured into groups of OA-like cartilage from specic in vitro degeneration and from in vivo animal models, and of osteoarthritic cartilage from spontaneously occurring OA in vivo. Studies with correlations between the assessed parameters were summarised in tables. 2. Biomechanical assessment of articular cartilage Dependent on the problem to be addressed, well-established mechanical testing methods such as shear, tension and compression tests or cartilage specic osmotic loading method can be performed to characterise articular cartilage biomechanically. Whereas tension and compression tests only allow investigating the equilibrium properties of the solid matrix, shear tests under innitesimal strain enable to acquire the intrinsic viscoelastic, ow-independent properties of the collagen-proteoglycan solid matrix. Therewith, the magnitude of the complex shear modulus jG*j as intrinsic stiness at a specic frequency and the phase angle d as ratio of viscous to elastic eects can be determined from dynamic shear experiments (Setton et al., 1995), whereas

the equilibrium shear modulus Geq can be calculated from stress-relaxation experiments. The most frequently used methods for mechanical characterisation of articular cartilage are unconned, conned compression and indentation (Fig. 1). In unconned compression, static Youngs modulus E and Poissons ratio m are calculated directly from the stress-strain ratio at equilibrium if lateral displacement is measured. A dynamic modulus Edyn is calculated as the ratio of stress and strain amplitudes from the last cycle of a sinusoidal loading (Toyras et al., 2003) or from stressstrain data obtained instantaneously after the application of a strain step (Saarakkala et al., 2003). From conned compression tests, the aggregate modulus HA is calculated from the slope of the best linear t of the equilibrium stress plotted against the applied strain. The permeability j can be estimated afterwards by means of a best-t regression of the theoretical surface displacement and the experimental data (Soltz and Ateshian, 1998). Indentation measurements, in combination with singlephase linear elastic models, yield the shear modulus G and the Youngs modulus E (Hayes et al., 1972). Kempson et al. Kempson et al. (1971) and Roberts et al. (1986) calculated the instantaneous two-second creep modulus E2s from indentation tests at 2 s after load application. To account for the time-dependent viscous behaviour of AC, the viscoelastic spring-dashpot model is used (Parsons and Black, 1977). The creep response was analysed to yield the shear compliance J(t), which is the inverse of the apparent modulus. Thus, the unrelaxed shear modulus Gu, the relaxed shear modulus GR, and the retardation-time spectrum L(s) can be calculated. Basically, L(s) is a measure of the rate and duration of the creep process, Gu the apparent modulus of the sample in response to rapid loading and GR reects the extent of the creep process. Using the biphasic theory (Mow et al., 1980), the compressive modulus E, the hydraulic permeability j, and the Poissons ratio m can be calculated. The osmotic loading method is an alternative to compressive and tensile testing especially in small animals where the preparation of the sample is more demanding (Flahi et al., 2004). The calculated uniaxial modulus reects the balance between interstitial swelling pressure and mechanical stiness of the cartilage matrix and relates well to the moduli obtained from uniaxial tensile tests

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1001

Load

Load

Load

Permeable piston Cartilage sample

Indenter Cartilage

Impermeable plate

Confining chamber

Subchondral bone

Fig. 1. Commonly used mechanical testing congurations: unconned compression (a), conned compression (b), and indentation (c).

(Narmoneva et al., 2001). Collagen network stiness can also be determined by instantaneous deformation (ID) measurements (Bank et al., 2000). ID is expressed as percentage of supercial diameter change of the sample in unconned compression tests parallel and perpendicular to the collagen bre orientation. As the percentage of instantaneous deformation (% ID) is mainly determined by the collagen bre network (Mizrahi et al., 1986), the measure can be related to the tensile and shear properties of the collagen network. Non-destructive in vivo measurements of cartilage material properties were done by using handheld arthroscopic indentation devices to measure the resisting force to an applied deformation on the cartilage surface (Niederauer et al., 2004). For more information on the experimental testing conguration and data analysis, readers are referred to a comprehensive review by Hasler et al. (1999). 3. Properties of osteoarthritic and OA-like cartilage Kempson et al. (1970) were the rst to systematically quantify the correlation between mechanical parameters and biochemical composition of healthy human femoral head cartilage. They showed that the two-second creep modulus E2s strongly correlates with the total glycosaminoglycan (GAG) (r = 0.854), Chondroitin (r = 0.810), and Keratansulphate content per dry weight (r = 0.800), but weakly with collagen content. They concluded that both GAGs determine compressive stiness of healthy human articular cartilage whereas collagen contributes only little to this property. In the following years, various other groups also investigated healthy articular cartilage for relations between mechanical and other physical, biochemical or histological properties (Froimson et al., 1997; Jurvelin et al., 1988; Treppo et al., 2000; Williamson et al., 2001). They conrmed the positive correlation between sulphated glycosaminoglycan (sGAG) and the equilibrium shear (Jurvelin et al., 1988) and equilibrium aggregate modulus (Treppo et al., 2000; Williamson et al., 2001) at least in specic regions (Froimson et al., 1997). Some of them demonstrated an inverse correlation between HA and water content (Froimson et al., 1997; Treppo et al., 2000) and a weak correlation between permeability and biochemical properties (Treppo et al., 2000; Williamson et al., 2001).

In contrast to healthy cartilage, quantitative measures of osteoarthritic cartilage are rare, as they are much more complicated to obtain. Indeed, articular cartilage from progressed and nal stage of OA can be obtained quite easily post-mortem or from living subjects during joint replacement surgeries. However, it is obviously very dicult to obtain human joint tissue from well-dened early stages of the degenerative process, before overall cartilage loss occurs. Thus, only few details of the biomechanical parameters of early progression of OA in human articular cartilage are available from the literature. Since the OA is a clinically dened disease, osteoarthritic cartilage has to be from a patient who was clinically diagnosed with OA. However, macroscopically degenerated and histologically dened pre-osteoarthritic cartilage without a clinical history of OA shows all changes observed in OA cartilage (van Valburg et al., 1997). Thus, spontaneously degenerated cartilage in vivo represents a pre-clinical form of OA, which is useful to study the process of degeneration in OA. Another approach is to degeneration articular cartilage synthetically, either in vitro or in vivo, to obtain OA-like cartilage in an early stage of the disease. This paper reviews all relevant studies, in which biomechanical analysis of osteoarthritic or OA-like articular cartilage were performed. 3.1. OA-like changes in degenerated cartilage in vitro The extracellular matrix in healthy articular cartilage is subjected to a dynamic remodelling, in which degradative and synthetic processes are balanced. This dynamic equilibrium is disturbed in the early stage of osteoarthritic cartilage degeneration. An increased synthesis of some matrix components can be observed to compensate for an increased degradation. The shift of the equilibrium in OA cartilage is determined roughly by a complex combination of an increased degradation and a decreased synthesis of the matrix components. The catabolic degradative process in OA cartilage is catalysed in vivo by proteolytic enzymes from chondrocytes and synovial cells, which have the capacity to degrade, disorganise, and release fragments of the macromolecular components of the cartilage matrix. These proteinases are grouped into matrix metallo-proteinases, the a disintegrin and metallo-proteinase with

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thrombospondin-like motifs, and all other proteinases (Sandy, 2003). By using these proteinases or by activating the proteolytic cascade using organo-mercurial compounds (Bonassar et al., 1996) or proinammatory cytokines (Martel-Pelletier, 2004), specic modication of the cartilage structure and composition on excised cartilage samples can be performed. The aim of these approaches is, to study systematically the degradative eects of these substances on the cartilage matrix and the structurefunction relationship of the components in articular cartilage in vitro. This information is inevitable for the understanding of the initiation and progression of OA. However, selectively removing one component of the matrix is impossible without inuencing another component due to the complex interplay in the matrix. Interleukin-1a reduced the GAG content by 75% after 11 days of culture and increased denatured and cleaved type II collagen content by 2.5 and 5.5 times compared with control samples, respectively (Legare et al., 2002). Static Youngs modulus E decreased by 80% and dynamic stiness Edyn by 70% compared to control. These results are consistent with the ndings of Bonassar et al. (1997). They found that treatment with recombinant human Interleukin-1b and all-trans retinoic acid both caused GAG loss of more than 90% and a decrease in equilibrium modulus E by more than 80%. Furthermore, the electrokinetic coupling coecient ke was signicantly lower whereas the hydraulic permeability j was about 15 times higher than the control group. Activation of the matrix metalloproteinases with 4-aminophenylmercuric acetate also resulted in a loss in tissue GAG content of 80% and a more than threefold increase in denatured type II collagen after 3 days (Bonassar et al., 1996). Dynamic stiness Edyn, aggregate modulus HA and streaming potential V decreased by more than 80% and electrokinetic coupling coecient ke by more than 50%. Stromelysin 1 degradation resulted in a signicant loss of GAG content (90%) after 3 days (Bonassar et al., 1995). Moreover, matrix collagen type IX and II were degraded, which led to an increased tissue swelling of 25%. This proteolytic matrix degradation involved a 90% decrease of both aggregate modulus HA and dynamic stiness Edyn, and a 15 times higher hydraulic permeability j. During the incubation of adult human cartilage with lysosomal proteinases cathepsin D and B1 for 100 h a large proportion of the total proteoglycan was released from the tissue (Kempson et al., 1976). This resulted in a considerable increase of initial elastic compressive strain and creep compressive strain after 1 and 2 min of uniaxial compression of the cartilage plugs. Chondroitinase and collagenase treatment of cartilage samples decreased collagen content, proteoglycan (PG) content and water content (Wayne et al., 2003). However, chondroitinase treatment resulted in greater reduction of PG content (>61%) compared to collagenase (35%), whereas collagenase treatment resulted in greater collagen content reduction (>57%) compared to chondroitinase

(21%). Collagenase and chondroitinase ABC digestion decreased the Youngs modulus by approximately 40% and 60%, respectively (Nieminen et al., 2000; Toyras et al., 1999) and the aggregate modulus by 30% and 70%, respectively (Wayne et al., 2003). However, chondroitinase ABC treatment (and thus PG digestion) has a stronger eect on the equilibrium than on the dynamic Youngs modulus (57% and 24%, respectively) (Laasanen et al., 2003). Selective type II collagen degradation by collagenase type VII decreased equilibrium and dynamic modulus by 67% and 45%, respectively. They concluded that collagens are mainly responsible for dynamic instantaneous properties, whereas PGs aect more the static equilibrium properties (Laasanen et al., 2003). Furthermore, quantitative MR microscopy revealed an increase in the supercial cartilage T2 time in samples treated with collagenase, which was considered as a sensitive parameter for the integrity of the collagen structure in the extracellular matrix (Nieminen et al., 2000). In another study both MR imaging parameters T1 and T2 from the gadolinium-enhanced MR-Imaging method showed changes caused by matrix depletion whereas the increase in T2 could also be used to distinguish between collagen and PG loss (Wayne et al., 2003). They showed a positive linear correlation of the aggregate modulus HA with PG content per wet weight (r2 = 0.89), a weak negative correlation of permeability j with PG content (r2 = 0.32), a negative correlation of aggregate modulus HA with T2 (r2 = 0.51), and a negative correlation of PG content with T2 (r2 = 0.44) could be observed (Table 1). Ultrasound indentation measurements revealed a decrease in the dynamic modulus Edyn of 30% and 23% by trypsin and collagenase type VII, respectively, whereas chondroitinase ABC treatment resulted in no detectable changes (Laasanen et al., 2002). Rieppo et al. (2003) presented that the Youngs modulus could be correlated with thickness of the supercial zone for controls and degraded specimens (r = 0.408). Strong correlations between the area integrated optical density as spatial information on the PG concentration obtained by Digital Densitometry (Panula et al., 1998) and the Youngs modulus were detected for the supercial zone and the full sample thickness of controls and all pooled samples (Table 1). In this study the only sensitive biochemical parameter for the Youngs modulus was the uronic acid content in the incubation medium (r = 0.673). All other biochemical and microscopical parameters appeared to be poor estimates for tissue equilibrium stiness. Trypsin digestion resulted in an decreased in GAG content of 65% mainly in the outer areas of the plug (DiSilvestro and Suh, 2002). Similar to the other studies Youngs modulus showed a reduction by 80% and a more than 6-fold increase in permeability. Whereas all of the above-mentioned groups degraded articular cartilage plugs after dissection from the joint, Niederauer et al. (2004) degenerated an entire femoral condyle from goats in a trypsin solution. The aggregate modulus showed a strong positive correlation with PG content (R2 = 0.77). Parsons and Black (1987) incubated entire

S. Knecht et al. / Clinical Biomechanics 21 (2006) 9991012 Table 1 Properties of in vitro degenerated articular cartilage Author Parsons and Black (1987) Sample Rabbit Control HYA Parameters GR 1.08 (0.16) 0.57 (0.13)** L(s) 11.5 (2.8) 28.9 (6.3)** HEX 40.6 (4.9) 15.7 (9.1)** Water 75.0 (2.9) 70.3 (5.2) Correlations

1003

GRHEX (normal) r = 0.73** GRHEX (HYA) r = 0.76** L(s)HEX (normal) r = 0.72** L(s)HEX (HYA) r = 0.79** Eh (sup) r = 0.408*** EOD (sup) r = 0.873*** EOD (full) r = 0.741*** HAPG R2 = 0.89*** jPG: R2 = 0.32** HAj R2 = 0.3* HA T2 R2 = 0.51***

Rieppo et al. (2003)

Bovine Control COLL ChABC ELAST

E 1.1 0.6 0.3 0.7 HA #30%*** #70%*** (0.2) (0.3)*** (0.17)*** (0.36)***

h (sup) 257 181 261 221 j "21% "91%* (53) (38)** (54) (40)

OD (sup) 0.93 0.63 0.33 0.63 (0.26) (0.14)*** (0.15)*** (0.14)***

OD (full) 1.67 1.60 1.35 1.56 PG #21%*** #61%*** (0.27) (0.19) (0.17)** (0.169)

Wayne et al. (2003)

Porc COLL ChABC

Collagen #57%*** #35%***

Mean (SD), *P < 0.05, **P < 0.01, ***P < 0.001. ChABC = chondroitinase ABC; COLL = collagenase; ELAST = elastase; full = full thickness; HYA = hyaluronidase, sup = supercial zone; E = Youngs modulus [MPa]; GR = relaxed shear modulus [105 N/m2]; h = thickness [lm]; HA = Aggregate modulus [MPa]; HEX = Hexosamine content [lg/mg per dry tissue]; j = hydraulic permeability 1015 m4/N s]; L(s) = Retardation time spectra [mm2/N-In t], OD = optical density [absorbance units]; PG = proteoglycan content per wet weight []; Water = water content [%].

femoral condyles of rabbits in testicular hyaluronidase. Biochemical analysis revealed a decrease in GAG content of 60%, whereas water and hydroxyproline contents were not dierent from control. The mean unrelaxed shear modulus Gu was elevated, but only signicantly dierent in moderately concentrated hyaluronidase solution (+63%) compared to normal. However, relaxed shear modulus GR was notably decreased by 1850%, depending on the solution concentration. A linear correlation between relaxed shear modulus and hexosamine content for normal (r = 0.73) and degraded cartilage (r = 0.76) was observed (Table 1). The retardation-time spectrum L(s) increased monotonically with increasing matrix digestion and is strongly related to hexosamine content for normal (r = 0.72) and degraded tissue (r = 0.79). In summary, the proteolytic breakdown of cartilage extracellular matrix reproduced by synthetic degradation of cartilage explants in vitro showed noticeable biochemical and minor structural changes, which resulted in decreased values of the mechanical parameters. Overall glycosaminoglycan content was reduced between 60% (Wayne et al., 2003) and 90% (Bonassar et al., 1995, 1997), whereas the reduction occurred mainly on supercial cartilage zone (Rieppo et al., 2003) and in the outer areas of the plugs. Denatured and cleaved type II collagen content was more than doubled, but also dependent on the used degradative medium. Structural collagen changes could be observed on the supercial zone after specic collagen degradation

(Nieminen et al., 2000). The selective collagen degradation resulted in greater reduction of dynamic modulus Edyn and selective proteoglycan degradation in greater reduction of static modulus. Correlation between biomechanical and biochemical parameters, as well as magnetic resonance parameters (Nieminen et al., 2004b; Wayne et al., 2003) and cartilage thickness (Rieppo et al., 2003) could be observed. 3.2. OA-like changes in animal models in vivo Animal models are widespread in orthopaedic research to investigate eects of traumatic injuries on articular cartilage in vivo, to study the pathological variation in disease progression or to evaluate the potential of disease-modifying drugs. The main advantage of animal models is, besides the well-dened time course, the easier access to the joint and its tissues, which enables the quantication of the disease progression with a variety of methods. Limitations are ethical issues, high costs, slow time course with large animals (Grith and Schrier, 2003) and the physiological and anatomical dierences between animals and humans (Athanasiou et al., 1995). As a consequence, the transfer of the gained information from animal models to human disease is limited (Bendele et al., 1999). Spontaneous OA animal models occur quite sporadically in knee joints of various strains of mice, in bovine, and more predictably in guinea pigs. Despite the slow progression

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and the unknown cause of onset, these are promising models to study OA pathogenesis due to their similarity to human disease progression. Transgenetic and knockout mice are more reliable and facilitate studying the role of specic mediators in the pathogenesis of OA and mimicking dierent stages and forms of osteoarthritic changes in articular cartilage (Hyttinen et al., 2001). Experimentally induced OA models are divided into a chemical and physical type (Brandt, 2002). Injection of chemical reagents and biological mediators into the joint of commonly small animals leads rapidly to macroscopic or histopathologic lesion similar to OA. Physically induced OA models often have rapid and more severe cartilage degeneration than spontaneous models. Similar to chemical induction, they show a very consistent onset but a slower progression. This surgical induction is mainly performed in larger animals such as dogs, cats and rabbits. Common methods are meniscectomy and transection of the anterior cruciate ligament (ACLT), which both result in a true instability of the joint and mimic naturally occurring OA progression in humans after traumatic injury (Roos et al., 1995). Alteration of the joint load by tibial osteotomy (Panula et al., 1997), by immobilisation (Leroux et al., 2001) or by replacement of the femoral trochlea with a hemiarthroplasty implant (LaBerge et al., 1993) are other used physical knee OA models. Hip animal models are rare and performed by chemical induction, for instance by injection of papain (Bentley, 1971; Scheck and Sakovich, 1972) or by pelvic osteotomy (Heinegard, 1987). As the analysis is mainly restricted to biochemical or histological characterisation of the tissue, only knee joint animal models are included in this review. Knockout mice of the inactivated type II procollagen gene showed no spontaneous OA dierences in cartilage thickness and PG distribution compared to control group (Hyttinen et al., 2001). However, a signicant increased OA occurrence from 21% in the control group to 73% in the knockout mice was detected by the presence of supercial brillation. Indentation stiness revealed a cartilage softening by 45%. Histological evaluation after transection of the anterior cruciate ligament in dogs revealed mild alterations, including chondrocyte proliferation, mild surface disruption, chondrolysis and focal reduction of safranin-O staining (Altman et al., 1984). The total PG content showed only little change, whereas PG aggregates were reduced in size. Biomechanical analysis revealed a small increase in unrelaxed Gu and relaxed shear modulus Gr of 37% and 22%, respectively, in the early group and an increase of nearly 50% of Gu in the late group (1016 weeks after transection). Another study showed similar histological alterations at numerous sides on the surface of tibial cartilage but no change in cartilage thickness compared to control (Setton et al., 1994). But aggregate and shear modulus both were lowered by 44% and 25% after 6 and 12 weeks, respectively in zones covered by the meniscus whereas they were lowered by 30% and 26%, respectively after 6 weeks and by

27% and 22%, respectively compared to control in uncovered regions. Hydraulic permeability increased only after 12 weeks by 70% and 26% in covered and uncovered regions, respectively. Water content increased from 74.2% to 83.4% 12 weeks after transection of the ACLT in covered and from 84.1% to 89.0% in uncovered regions (Table 2). An increase in water content was also observed on posterior and distal sides of the medial femoral condyle in a subsequent study (Setton et al., 1995). Equilibrium compressive stiness Es and equilibrium shear modulus Geq decreased 6 weeks after transection of the ligament but did not dier between 6 and 12 weeks. On posterior sides, shear and compressive stiness decreased by more than 80 and 72%, respectively, whereas distal sides showed a reduction of 53% and 70%, respectively. The magnitude of the complex shear modulus G* from dynamic shear tests also decreased after 6 weeks by an average value of 56% combined for both sides, whereas thickness did not change signicantly. Statistical analysis revealed a weak correlation of the complex shear modulus with water content (r = 0.55) and a strong correlation between the equilibrium shear and compressive properties (r = 0.75) (Table 2). Transection of the ACLT in cats increased the mean thickness of femoral and patellar cartilage between 48% and 102%, whereas tibial cartilage showed no signicant changes (Herzog et al., 1998). In contrast to other published data, dierences neither in the Youngs modulus nor in the permeability could be observed between experimental and contralateral sites. Only the total contact area of the patellofemoral joint increased due to the increased cartilage thickness. Cartilage of medial femoral condyles from ACLT transected rabbit knees showed an increased water content of approximately 775% after 9 weeks (Sah et al., 1997). A trend towards a decrease in GAG content per wet weight of the sample was observed. All femoral condyles displayed gross morphological changes from brillation to erosion of the surface, but no thickness changes could be detected. The aggregate modulus was reduced by 18% and showed a positive correlation with tissue GAG content of control (r = 0.66) and OA-like samples (r = 0.62) (Table 2). Pooling of the osteoarthritic and the healthy group revealed a negative relationship between aggregate modulus and water content of tissue (r = 0.38). Analysis of the distinct groups revealed a weak correlation among normal specimens but none in OA samples. Bilateral (on both knee joints) lateral meniscectomy initiates experimental osteoarthritis in the ovine femoro-tibial joint (Appleyard et al., 2003) as well as in the patellar cartilage (Appleyard et al., 1999). Histological signs of OA changes were mainly detected in central and lateral regions of the patellar cartilage surface whereas the thickness was not changed. An average decrease of initial Gi, relaxed Gr, and unloaded shear modulus Gu of 34, 32, and 22%, respectively, was shown, while permeability was increased by 72%. Proteoglycan content was increased (+52%) in the outer regions of the meniscectomized lateral compart-

S. Knecht et al. / Clinical Biomechanics 21 (2006) 9991012 Table 2 Properties of articular cartilage in animal models of osteoarthritis Author Appleyard et al. (2003) Sample Sheep NOC Parameters G* 2.67 (1.92) to 0.19 (0.12) #4570% h 0.30 (0.18) to 1.23 (0.29) "26135% GAGdry Water

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Correlations G*GAGdry neg (lat NOC) G*HYPRO pos (all) G*Water neg (MEN) G* h neg (all) EAIOD r = 0.870* GeqAIR r = 0.626** Birefring. #1530% all regions G*birefring. q = 0.44 G* h q = 0.47 G*Total TB q = 0.42 HAGAG r = 0.66*** (healthy) r = 0.62** (OA) HAWater r = 0.35* (healthy + OA) jWater r = 0.75*** (healthy + OA) HAWater r = 0.25* (healthy + OA)

Lateral MEN

#27%

"5%

LeRoux et al. (2000)

Canine Medial MEN 12 wk

E #50% Medial G* #50% TM #30% TL #46% P HA 0.75 (0.28) 0.61 (0.21)

Geq #50% Medial h "3040%

AIOD # 20%

Oakley et al. (2004)

Sheep Medial MEN 16 wk

Total TB #4050% MFC, LFC

Sah et al. (1997)

Rabbit NOC ACLT

j 0.631 (0.28) 0.644 (0.35)

GAGwet 27.6 (9.8) 24.6 (8.9)

Water 70.3 (4.1) 75.2 (4.0)

Setton et al. (1994)

Canine NOC Cov. Unc. ACLT 6 wk Cov. Unc. 12 wk Cov. Unc.

HA

Water

0.56 (0.19) 0.49 (0.19) 0.31 (0.10) 0.34 (0.09) 0.42 (0.10) 0.36 (0.07) E

2.4 (1.3) 5.0 (1.7) 2.6 (0.4) 5.8 (0.4) 4.1 (1.0) 6.3 (1.0) Geq

0.85 (0.17) 1.7 8 (0.4) 0.85 (0.11) 1.5 (0.2) 0.94 (0.24) 1.4 (0.3) jG*j

74.2 (4.8) 84.1 (2.0) 79.5 (2.3) 89.5 (1.6) 83.4 (3.3) 89.0 (1.1) Water

Setton et al. (1995)

Canine NOC Post. Dist. ACLT 6 wk Post. Dist. 12 wk Post. Dist.

WaterjG*j: r = 0.55** (healthy/OA)

0.29 (0.10) 0.14 (0.03)

0.22 (0.04) 0.13 (0.09)

0.79 (0.25) 0.44 (0.22)

78.0 (1.5) 73.8 (4.8)

0.04 (0.02) 0.04 (0.01) 0.05 (0.03) 0.05 (0.03)

0.07 (0.02) 0.06 (0.03) 0.06 (0.01) 0.06 (0.04)

0.26 (0.07) 0.25 (0.08) 0.24 (0.11) 0.31 (0.19)

79.9 (1.3) 79.7 (0.9) 81.1 (0.9) 80.3 (1.4)

Mean (SD), *P < 0.05, **P < 0.01, ***P < 0.001. ACLT = anterior cruciate ligament transection, birefring. = supercial collagen birefringence, Cov = meniscus covered area, Dist. = distal; MEN = meniscectomy, neg = negative, NOC = non-operated controls, pos = positive, Post. = posterior; TB = toluedine blue staining intensity, Unc. = meniscus uncovered area, wk = weeks; AIOD = area integrated optical density [lm2]; AIR = area-adjusted integrated retardation [nm/lm2]; E = Youngs modulus [MPa]; jG*j = shear modulus [MPa]; GAG = glycosaminoglycan content [mg/g]; Geq = equilibrium shear modulus [MPa]; h = thickness [mm], HA = aggregate modulus [MPa]; j = hydraulic permeability [1015 m4/N s]; Water = water content [%].

ment and decreased in the lateral middle and inner regions by 2132% (Appleyard et al., 2003). The middle and outer

regions of the meniscus-protected medial compartments even showed a slight increase in PG content of 1419%.

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Total collagen content was not dierent from control group, but a gradual decrease was evident from outer to inner regions in lateral and medial compartments. Cartilage thickness increased between 26% and 135% in the lateral and between 19% and 30% in the medial compartment, whereas the water content was only increased in lateral middle and inner regions. The dynamic shear modulus G* decreased by 4570% in the lateral tibial compartment, whereas it remained unaected in the medial compartment. A strong negative correlation between the sGAG content and the dynamic eective shear modulus G* of the entire and the lateral plateau solely in non-operated control group was shown (Table 2). In contrast, the water content and shear modulus showed only a strong negative correlation in meniscectomized knees. All samples showed a strong negative correlation between shear modulus G* and thickness and between shear modulus and collagen content. In dogs no change in total thickness was shown 12 weeks after total medial meniscectomy (LeRoux et al., 2000). However, thickness of the cartilage supercial zone at medial points decreased (59%) but not at intermediate and lateral points of the central tibial plateau. Loss in GAG content was detected only in medial intermediate region. Close to these positions, equilibrium compressive Es and equilibrium shear modulus Geq decreased signicantly by approximately 50% of control values but not in lateral tibial plateau. A strong correlation (r = 0.857) between the GAG content and the compressive modulus was shown for the meniscectomized but not for control samples (Table 2). As soon as 2 weeks after the medial meniscectomy the uronic acid content decreased on the tibial plateau cartilage by more than 25% in rabbit knee, whereas only a small decrease of 8% was detectable on the lateral tibial plateau (Hoch et al., 1983). Surprisingly after 6 months, both regions regained their initial uronic acid content. This recovery trend was also apparent for the Youngs modulus calculated from indentation tests. Youngs modulus of medial tibial cartilage decreased by 72% after 2 weeks and increased to near normal after 6 months. This observation was conrmed by the strong correlation between Youngs modulus and uronic acid content. Four months after medial meniscectomy in sheep large histological damage was observed on the medial surfaces, followed by patello-femoral and lateral surfaces (Oakley et al., 2004). The intensity of supercial collagen birefringence decreased for all surfaces by 1530%. Changes in PG, measured by toluedine-blue staining, were most severe in the medial compartment with a reduction of 4050% compared to control. Cartilage thickness, however, increased uniformly by 1520% after 4 weeks and by the same magnitude between 4 and 16 weeks in all regions of the joint. Biomechanical assessment revealed a 46% reduction in dynamic shear modulus G* of patellar cartilage and a 50% reduction in medial tibial cartilage. Furthermore a reduction by 30% of G* in the contralateral (lateral) part of the tibial articular cartilage was detected which was not found in previous studies. Strong correlations between

G* and collagen birefringence, toluedine-blue staining, and thickness were observed (Table 2). A multivariate analysis revealed that collagen organisation contributed twice as much to dynamic shear modulus as the PG content. Oakley et al. proposed that for the maintenance of cartilage stiness, collagen integrity was more important than PG content. A specic OA animal model is the joint immobilisation of canine knees (Leroux et al., 2001). Cast immobilisation for 4 weeks resulted in a 75% lower equilibrium shear modulus Geq compared to control group and in a 53% dierence compared to the contralateral leg. Dierences of the equilibrium modulus Es were not signicant. In addition, no dierences in biochemical properties were found. However, it was concluded that these ndings are consistent with a mild form of cartilage degeneration. Further information about the eect of immobilisation on the mechanical, biochemical and morphological properties of articular cartilage can be found in Vanwanseele et al. (2002). In conclusion cartilage from OA animal models showed an increase in water content of up to 20% (Setton et al., 1994) and a spatial decrease in PG content of up to 50% (Oakley et al., 2004). No signicant changes of collagen content were reported, but a variation in collagen birefringence was shown in one publication (Oakley et al., 2004). Few studies reported an increased cartilage thickness (Appleyard et al., 2003; Herzog et al., 1998; Oakley et al., 2004), but also a loss of cartilage supercial zone in some regions was observed (LeRoux et al., 2000). Except one group (Herzog et al., 1998), all of the recent publications of OA-like animal models reported at least in temporarily decreased mechanical properties (Hoch et al., 1983). Furthermore, correlations between mechanical parameters and biochemical parameters, as well as structural parameters (LeRoux et al., 2000; Oakley et al., 2004) and cartilage thickness (Appleyard et al., 2003; Oakley et al., 2004) were shown. 3.3. Spontaneous occurring OA-like changes in vivo For spontaneously occurring OA-like cartilage it is common practice to examine the surface visually for classication of the sample as neither the stimulus nor the duration of degeneration, nor the degenerative environment are known. A few groups (Brocklehurst et al., 1984; van Valburg et al., 1997) found a good correlation between the ndings from histology and visual appearance in autopsy specimens. However, several other authors showed that visual surface properties are not reliable to distinguish between healthy and degraded tissue (LaBerge et al., 1993; Orford et al., 1983; Panula et al., 1997; Stockwell et al., 1983; Vignon and Arlot, 1981). India ink staining of the articular surface in vitro could indeed improve the expressiveness, since the ink particles are entrapped in surface irregularities and adhere to brillated cartilage (Collins and McElligott, 1960). But an intact non-stained cartilage surface can cover heavily ssure lamellae, whereas

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the surface of structural healthy cartilage can show a slightly rough surface (Clark and Simonian, 1997). Neither the absence of visual surface disruption nor the on bone cartilage compliance or thickness measurements necessarily constitute sensitive indicators of the biomechanical health of cartilage (Broom and Flachsmann, 2003). However, due to the lack of more suitable and more reliable methods the (arthroscopic) cartilage classication in vivo and the pre-classication in the following in vitro sections of OA-like cartilage are commonly performed visually. Armstrong and Mow (1982) were the rst ones who extensively investigated the spontaneous variations of the mechanical properties with age and OA of human autopsy

patellae. Histologicalhistochemical grading according to Mankin et al. (1971) revealed a broad variance of this score between 1 and 12 (Table 3). The thickness of 103 samples in the age between 16 and 85 years was diversied between 1.69 and 5.17 mm, whereas water content varied from 72.8% to 88.4%. Biomechanical analysis displayed a mean aggregate modulus of 0.79 MPa and a mean permeability of 4.7 1015 m4/(N s). A linear relationship between the inverse of permeability, the so-called frictional drag, and the water content was shown (r = 0.50) (Table 3). The strongest correlation was the linear decrease of aggregate modulus with increasing water content (r = 0.73). Since no correlation between biomechanical parameters and the

Table 3 Properties of articular cartilage during spontaneous occurring osteoarthritis Author Armstrong and Mow (1982) Sample Human autopsy Parameters HA 0.131.91 Lateral facet of patella Mean 0.79 (0.36) Nieminen et al. (2004a) Bovine patellar Intact Moderate Advanced Nissi et al. (2004) Bovine patellar Es 0.32 (0.15) 0.26 (0.13) 0.08 (0.08) Es Mean 4.7 (3.6) Edyn 7.06 (4.83) 2.12 (1.58) 0.54 (0.36) Edyn Mean 78.63 (3.86) Uronic 10.2 (3.5) 6.7 (1.5) 4.1 (1.2) Uronic Mean 6.33 (2.58) Water 79.9 (2.4) 81.6 (1.2) 84.1 (2.6) T1,Gd j 0.519.5 Water 72.888.4 Mankin 112 Correlations HAWater r = 0.73*** 1/jWater r = 0.50*** HA*Mankin r = 0.25* EeqUS speed rs = 0.790** EdynUS speed rs = 0.898** Eeq T1,Gd r = 0.625* T1,GdUronic r = 0.624* EeqBulk[Gd] r = 0.609* OA: HAsGAG r = 0.803* HAWater r = 0.426* jsGAG r = 0.360* Non-OA: jWater r = 0.315* EdynMankin r = 0.777* EdynWater r = 0.686* EdynUronic r = 0.876* EMankin r = 0.674* EWater r = 0.586* EUronic r = 0.717*

Intact Moderate Advanced Rivers et al. (2000) Human CMC Non-OA (OA)

0.40 (0.11) 0.24 (0.12) 0.06 (0.03) HA

9.74 (2.83) 1.63 (0.48) 0.44 (0.20) j

12.17 (2.01) 6.24 (0.79) 3.95 (1.19) sGAGwet

405 (47) 376 (25) 316 (64) Water

0.82 (0.20) 0.52 (0.22)

4.04 (2.91) 2.92 (1.00)

21.5 (4.4) 16.4 (6.5)

72.5 (3.7) 74.8 (3.8)

Saarakkala et al. (2003)

Bovine patellar

Edyn

Edyn_ultra

Water

Intact Discolor. Superc. Deep Defects

0.28 0.23 0.27 0.06

(0.12) (0.11) (0.12) (0.04)

7.5 1.5 1.2 0.5

(5.6) (0.6) (0.6) (0.3)

9.2 2.4 2.1 1.5

(5.8) (0.3) (1.0) (0.3)

80.3 82.0 83.6 83.5

(2.0) (1.3) (3.0) (2.0)

Mean (SD), *P < 0.05, **P < 0.01, ***P < 0.001. CMC = carpometacarpal, Discolor. = slightly discoloured surface; Mankin = Mankin score, Superc. = supercial defects; Bulk [Gd] = GD-DTPA content; Edyn = dynamic Youngs modulus [MPa]; Edyn_ultra = equilibrium Youngs modulus form ultrasound indentation device [MPa]; E = equilibrium Youngs modulus [MPa]; HA = aggregate modulus [MPa]; j = hydraulic permeability [1015 m4/N s]; sGAG = sulphated glycosaminoglycan content [mg/g]; T1,Gd = T1 relaxation in presence of Gd-DTPA, Uronic = uronic acid content [lg/ml].

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visual or any of the histological appearances could be detected, Mankin et al. (1971) concluded that these properties might be a poor indication for the functional characterisation of the material in the intact joint. Cartilage samples from osteoarthritic human thumb carpometacarpal joints revealed signicant dierences in water content, sGAG content, aggregate modulus, and permeability compared to healthy samples (Rivers et al., 2000). Whereas collagen content stayed constant, the proteoglycan content decreased by 24%, and the water content increased by 2.3% in OA samples. Biomechanical analysis demonstrated reduction of the aggregate modulus in OA cartilage by 36%. In contrast to other studies, an increased permeability of 28% was observed. The competing eect of the increase of j with extracellular matrix loss and the decrease of matrix compaction during indentation may explain these ndings. Correlation between aggregate modulus HA and the biochemical parameters water, and sGAG content were observed for OA joints but not for non-OA joints (Table 3). All correlations between the biochemical composition and the biomechanical parameters were found to be stronger in OA than in healthy joints. Bae et al. (2003) measured the functional indentation stiness on anterior regions of cadaveric human lateral and medial femoral condyles by means of a handheld indentation device. This stiness parameter varied markedly between the normal group without OA-typical macroscopic surface appearance and the degenerated sample groups. India ink staining and histopathology scoring displayed identical results. Only little variations between the normal samples from dierent age groups were observed. Averaged cartilage thickness did reveal only negligible eects between normal aging and degeneration. Correlation between indentation stiness and reectance score from India ink stained surfaces (R2 = 0.35), histopathology overall score (q2 = 0.44), and histopathology surface irregularity score (q2 = 0.34) were observed. Human autopsy samples of OA femoral cartilage displayed a lower thickness compared to normal (Roberts et al., 1986). Furthermore, the PG content, the mechanical compressive and tensile properties were lower in the OA samples. However, no correlation between the mechanical property and the PG content was found. Bank et al. performed instantaneous deformation (ID) tests on samples from femoral heads and condyles of OA patients of total joint replacement surgery and from normal cadaveric joints (Bank et al., 2000). The percentage of instantaneous deformation (% ID), parallel and perpendicular, showed a linear positive correlation with the percentage of degraded collagen (r = 0.81 and r = 0.87, respectively) but not with xed charge density. They conrmed that the decreased ID stiness is strongly related to the amount of degraded collagen network. Ding et al. (1998) classied the early-stage OA samples as macroscopically degenerated and brillated cartilage and conrmed this histologically. Medial proximal tibial cartilage showed a mean Mankin score of 4.9 (37) and was denoted as osteoarthritic. They found a distinct

dierence in the stiness of the cartilage and of the subchondral bone of OA compared to healthy samples. Cartilage with slight ssures on its supercial zone showed a reduced stiness by 29% compared to age-matched samples. Mean thickness of OA cartilage was 2.3 mm, which was thinner than lateral comparison and age-matched samples. The stiness of osteoarthritic cartilage did correlate neither with bone the stiness or cartilage mean thickness. However, a correlation between cartilage and bone was shown in the normal age matched and lateral comparison groups. Apparently healthy tibial cartilage from patients with diagnosed unicompartimental OA and from cadavers was on average 22% thinner and 71% softer than control cartilage from normal knees (Obeid et al., 1994). In addition to the commonly used biochemical, biomechanical or histological methods, ultrasound and MR properties were investigated to assess articular cartilage (Nieminen et al., 2004a). They classied the cartilage samples with early OA changes according to Mankin score into three groups. Equilibrium Es and dynamic Youngs moduli Edyn was respectively 18% and 70% lower in moderate and 87.5% and 90%, respectively, in advanced degenerated cartilage compared to healthy samples. Cartilage thickness increased by approximately 20% with OA progression. A decrease of 60% in uronic acid content and of 40% in hydroxyproline content was shown, whereas the water content increased from 79.9% to 84.1% with OA progression. Linear correlation between Mankin score and ultrasound speed (rs = 0.755), ultrasound attenuation (rs = 0.567), uronic acid (rs = 0.817) and hydroxyproline content (rs = 0.644) was demonstrated (Table 3). Ultrasound speed, integrated- and amplitude attenuation was related to all biochemical and biomechanical parameters (Table 3). Saarakkala et al. (2003) assessed the cartilage quality using an ultrasound indentation instrument and unconned compression tests. Dynamic modulus Edyn of samples with supercial defects decreased by 85%, whereas static Youngs modulus remained unchanged. The mechanical properties were impaired by concurrent increase of tissue water content and decrease of uronic acid content (Table 3). Cartilage dynamic and equilibrium modulus were positively correlated with tissue uronic acid content (r = 0.876, r = 0.717) and negatively with tissue water content (r = 0.686, r = 0.586) and Mankin score (r = 0.777, r = 0.674) (Table 3). Several studies demonstrated the potential of gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) enhanced T1 and T2 imaging techniques for the assessment of biomechanical properties of healthy (Kurkijarvi et al., 2004; Nieminen et al., 2004b) and spontaneous degenerated bovine cartilage (Nissi et al., 2004). Bulk T1 relaxation time in the presence of Gd-DTPA as well as Gd-DTPA content showed a linear correlation with Youngs modulus in a high magnetic eld strength MRI machine in healthy samples (Nieminen et al., 2004b). As T2 relaxation time is highly related to the three-dimensional collagen architecture, the combination of these parameters can lead to use-

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ful information on mechanical, biochemical and structural parameters on healthy and spontaneously degenerated articular cartilage. Nissi et al. (2004) presented similar parameters on normal, early and advanced degenerated bovine patellar cartilage samples. It was assumed that the advanced degenerated group corresponded most probably to the initial stage of cartilage degeneration. Youngs modulus and dynamic modulus decreased by 85% and 95%, respectively, PG content lowered by 67% and collagen content per wet weight by 50% in advanced OA samples. This resulted in increased supercial T2 and in decreased supercial and bulk T1 parameters in the presence of Gd-DTPA with OA progression (Table 3). Samples were also slightly thicker than normal samples. The results from spontaneous osteoarthritic changes in vivo were comparable to animal models in terms of decrease in mechanical properties and GAG content, and increase in water content. However, structural and morphological dierences were reported more frequently. Particularly human cadaveric samples displayed a reduction in cartilage thickness compared to the reported increased thickness of the bovine samples. This is probably due to the more advanced OA progression of the human cadaveric samples. Furthermore, a signicant reduction in total collagen content of up to 50% (Nissi et al., 2004) and in the amount of degraded collagen was reported (Bank et al., 2000). Mechanical parameters were correlated with biochemical properties as well as with the Mankin score (Armstrong and Mow, 1982; Saarakkala et al., 2003), ultrasonic parameters (Nieminen et al., 2004a), and MR parameters (Nissi et al., 2004). 4. Summary and conclusion The progression of osteoarthritis is generally divided into three broad stages, namely the proteolytic breakdown of the cartilage matrix, the brillation and erosion of the cartilage surface, and the beginning of the synovial inammation (Martel-Pelletier, 2004). Due to the limited regenerative capability of AC, the progression of this degenerative joint disease has to be detected before irreversible morphological changes become manifested. Early diagnosis of OA will enable an early treatment, the reduction of pain and disability and thus the improvement of the quality of life of the patient. As shown in numerous studies, the values of the mechanical compressive parameters (E, HA, Edyn) of articular cartilage in the early pre-osteoarthritic stage are reduced between 20% and 80% (Fig. 2) compared to healthy tissue. These early changes (mild, moderate and advanced) might remain undetected using common clinical methods such as plain radiographs or arthroscopy due to the lack of cartilage loss and the marginal supercial changes (Nissi et al., 2004). Several studies showed that the Youngs modulus is already 20% lower in early OA samples compared to the healthy samples. Consequently, pre-osteoarthritic changes might be detected in this moder-

1 20% decrease standardized moduli 0.8 0.6 0.4 0.2 0 mild moderate advanced Es HA Edyn

Fig. 2. Mean of the static (Es, HA) and dynamic compressive moduli (Edyn) of pre-osteoarthritic cartilage samples, standardized by the mean of the healthy control and plotted against the stages of early OA (mild = slightly discoloured defects on the supercial zone or Mankin score 1; moderate = supercial ssures and/or moderate reduction in PG content or Mankin score 24; advanced = deep ssures or Mankin score > 4).

ate degenerative stage using the cartilage static moduli (HA, E). Moreover, the decrease of the dynamic Youngs modulus Edyn is even more pronounced in the early degenerative stage. Therefore, the use of this material parameter could enable the detection of mild pre-osteoarthritic cartilage changes. This review showed that measuring the cartilage static and dynamic modulus has the potential to identify early degenerative changes in articular cartilage. The accuracy (or measurement error) of a mechanical testing device has to be adequate to detect changes of 10% in stiness in order to detect reliably the degeneration of articular cartilage even in the early osteoarthritic stage. Improvement of the previously validated arthroscopic indentation devices, as recommended by Brommer et al. (2006), or the numerical analysis of MR-controlled patellofemoral compression test in vivo, as already performed in vitro by Herberhold et al. (1999), might allow for such measurements in clinical practice. Such methods might enable to classify pre-OA cartilage based on its mechanical properties and consequently on its functional quality and might enable to track early degenerative cartilage changes. Acknowledgement We would like to thank the International Society of Biomechanics ISB for nancial support and Mr. T. Fischbach for the help with the manuscript. References
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