Artrosis y Roemodelacion

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Review

A review on the mechanical quality of articular cartilage Implicationsfor the diagnosis of osteoarthritis

Sven Knecht a,*, Benedicte Vanwanseele b, Edgar Stussi a

a Institute for Biomechanics, Swiss Federal Institute of Technology Zurich, CH-8093 Zurich, Switzerlandb 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 bemore sensitive to early degenerative variations since they are determined by the biochemical composition and structural arrangementof the extracellular matrix. The objective of this paper is to review studies focussing on variations in the mechanical compressive prop-erties during the early pre-osteoarthritic stage. The aim is to quantify the requirements to detect the early cartilage degeneration inpre-osteoarthritis based on the mechanical parameters and to create an updated basis for a better understanding of inherent relationshipsbetween characteristic parameters in articular cartilage.

Correlations between mechanical and biochemical parameters as well as magnetic resonance, ultrasonic, histological and structuralparameters were observed. In early osteoarthritis, static moduli decrease below 80% of healthy controls and dynamic moduli below30% of controls. To identify osteoarthritic changes of articular cartilage based on static or dynamic mechanical parameters in an earlystage of the disease progression the accuracy of a mechanical testing method has to be adequate to detect changes of 10% in cartilagestiffness. 2006 Elsevier Ltd. All rights reserved.

Keywords: Articular cartilage; Assessment; Biomechanical; Osteoarthritis

1. Introduction

Osteoarthritis (OA) is a disease with many complex eti-ologies, affecting all adjacent tissues in diarthrodial joints.Morphological, biochemical, structural, and biomechanical

changes of the extracellular matrix (ECM) and the cells aremanifested in OA which leads to the degeneration of thearticular cartilage (AC) with softening, fibrillation, ulcera-tion, and finally to cartilage loss (Keuttner and Goldberg,1995). As the functionality of diarthrodial joints cannotbe sustained without articular cartilage, the precise andearly diagnosis of the disease is fundamental to prevent

or reduce long-term disability (Bjorklund, 1998). Morpho-logical and biomechanical properties are very usefulparameters to assess cartilage tissue as they determine thefunctional behaviour of AC. Magnetic Resonance Imaging(MRI) combined with state-of-the-art post-processing

methods enables to obtain accurate and highly reproduc-ible 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 resultinevitably in detectable morphological changes in an earlystage of its progression.

It is generally accepted that the biomechanical proper-ties of articular cartilage depend on the biochemical com-position, the ultrastructural organisation, and theinteraction 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

* Corresponding author.E-mail address:[email protected](S. Knecht).

www.elsevier.com/locate/clinbiomech

Clinical Biomechanics 21 (2006) 9991012
mailto:[email protected]:[email protected]


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properties seem to be more sensitive to pathologicalchanges of the tissue since alterations of the structuraland biochemical properties are one of the first events inarticular cartilage degeneration (Buckwalter and Mankin,1998).

For this paper, we have reviewed the past publicationsin regard to changes of mechanical properties with the pro-

gression of osteoarthritis. We summarise changes inmechanical compressive properties and review significantrelationships between mechanical and physical, morpho-logical, histological and biochemical parameters duringthe early stages in OA-like cartilage. The aim is to investi-gate the potential of the biomechanical compressiveparameters for the sensitive assessment of articular carti-lage and to deduce specifications for novel diagnostic toolsbased on mechanical parameters to detect pre-osteoar-thritic cartilage degenerations.

In the first part of this review, we give a rough abstractof the commonly used biomechanical methods to assess

articular cartilage. In the main section, publications mainlyfocussing on degenerative variations of the cartilage com-pressive behaviour are summarised and studies showingcorrelations between the different parameters are extracted.According to the origin of the sample, this part is struc-tured into groups of OA-like cartilage from specificin vitro degeneration and from in vivo animal models, andof osteoarthritic cartilage from spontaneously occurringOA in vivo. Studies with correlations between the assessedparameters were summarised in tables.

2. Biomechanical assessment of articular cartilage

Dependent on the problem to be addressed, well-estab-lished mechanical testing methods such as shear, tensionand compression tests or cartilage specific osmotic loadingmethod can be performed to characterise articular cartilagebiomechanically. Whereas tension and compression testsonly allow investigating the equilibrium properties of thesolid matrix, shear tests under infinitesimal strain enableto acquire the intrinsic viscoelastic, flow-independent prop-erties of the collagen-proteoglycan solid matrix. Therewith,the magnitude of the complex shear modulus jG*jas intrin-sic stiffness at a specific frequency and the phase angle d asratio of viscous to elastic effects can be determined from

dynamic shear experiments (Setton et al., 1995), whereas

the equilibrium shear modulus Geq can be calculated fromstress-relaxation experiments. The most frequently usedmethods for mechanical characterisation of articular carti-lage are unconfined, confined compression and indentation(Fig. 1).

In unconfined compression, static Youngs modulus Eand Poissons ratio m are calculated directly from the

stress-strain ratio at equilibrium if lateral displacement ismeasured. A dynamic modulus Edyn is calculated as theratio of stress and strain amplitudes from the last cycle ofa sinusoidal loading (Toyras et al., 2003) or from stress-strain data obtained instantaneously after the applicationof a strain step (Saarakkala et al., 2003).

From confined compression tests, the aggregate modu-lus HA is calculated from the slope of the best linear fitof the equilibrium stress plotted against the applied strain.The permeabilityj can be estimated afterwards by meansof a best-fit regression of the theoretical surface displace-ment and the experimental data (Soltz and Ateshian, 1998).

Indentation measurements, in combination with single-phase linear elastic models, yield the shear modulus Gand the Youngs modulus E(Hayes et al., 1972). Kempsonet al.Kempson et al. (1971)and Roberts et al. (1986)cal-culated the instantaneous two-second creep modulusE2s from indentation tests at 2 s after load application.To account for the time-dependent viscous behaviour ofAC, the viscoelastic spring-dashpot model is used (Parsonsand Black, 1977). The creep response was analysed to yieldthe shear complianceJ(t), which is the inverse of the appar-ent modulus. Thus, the unrelaxed shear modulus Gu, therelaxed shear modulus GR, and the retardation-time spec-trum L(s) can be calculated. Basically, L(s) is a measureof the rate and duration of the creep process, Guthe appar-ent modulus of the sample in response to rapid loading andGRreflects the extent of the creep process. Using the bipha-sic theory (Mow et al., 1980), the compressive modulus E,the hydraulic permeability j, and the Poissons ratio m canbe calculated.

The osmotic loading method is an alternative to com-pressive and tensile testing especially in small animalswhere the preparation of the sample is more demanding(Flahiff et al., 2004). The calculated uniaxial modulusreflects the balance between interstitial swelling pressureand mechanical stiffness of the cartilage matrix and relates

well to the moduli obtained from uniaxial tensile tests

Nomenclature

E Youngs modulusEdyn dynamic Youngs modulusE2s two-second creep modulus

G shear modulusjG*j complex shear modulusGeq equilibrium shear modulusGu unrelaxed shear modulus

GR relaxed shear modulusHA aggregate modulusJ(t) shear compliance

L(s

) retardation-time spectrumm Poissons ratioj permeability

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(Narmoneva et al., 2001). Collagen network stiffness canalso be determined by instantaneous deformation (ID)measurements (Bank et al., 2000). ID is expressed as per-centage of superficial diameter change of the sample inunconfined compression tests parallel and perpendicularto the collagen fibre orientation. As the percentage ofinstantaneous deformation (% ID) is mainly determinedby the collagen fibre network (Mizrahi et al., 1986), themeasure can be related to the tensile and shear propertiesof the collagen network. Non-destructive in vivo measure-ments of cartilage material properties were done by usinghandheld arthroscopic indentation devices to measure theresisting force to an applied deformation on the cartilagesurface (Niederauer et al., 2004). For more informationon the experimental testing configuration and data analy-sis, readers are referred to a comprehensive review byHasler et al. (1999).

3. Properties of osteoarthritic and OA-like cartilage

Kempson et al. (1970) were the first to systematicallyquantify the correlation between mechanical parametersand biochemical composition of healthy human femoralhead cartilage. They showed that the two-second creepmodulusE2sstrongly correlates with the total glycosamino-glycan (GAG) (r= 0.854), Chondroitin (r= 0.810), andKeratansulphate content per dry weight (r= 0.800), butweakly with collagen content. They concluded that bothGAGs determine compressive stiffness of healthy humanarticular cartilage whereas collagen contributes only littleto this property. In the following years, various othergroups also investigated healthy articular cartilage for rela-tions between mechanical and other physical, biochemicalor histological properties (Froimson et al., 1997; Jurvelinet al., 1988; Treppo et al., 2000; Williamson et al., 2001 ).They confirmed the positive correlation between sulphatedglycosaminoglycan (sGAG) and the equilibrium shear(Jurvelin et al., 1988) and equilibrium aggregate modulus(Treppo et al., 2000; Williamson et al., 2001) at least in spe-cific regions (Froimson et al., 1997). Some of them demon-strated an inverse correlation between HA and watercontent (Froimson et al., 1997; Treppo et al., 2000) and aweak correlation between permeability and biochemical

properties (Treppo et al., 2000; Williamson et al., 2001).

In contrast to healthy cartilage, quantitative measures ofosteoarthritic cartilage are rare, as they are much morecomplicated to obtain. Indeed, articular cartilage from pro-gressed and final stage of OA can be obtained quite easilypost-mortem or from living subjects during joint replace-ment surgeries. However, it is obviously very difficult toobtain human joint tissue from well-defined early stagesof the degenerative process, before overall cartilage lossoccurs. Thus, only few details of the biomechanical param-eters of early progression of OA in human articular carti-lage are available from the literature.

Since the OA is a clinically defined disease, osteoar-thritic cartilage has to be from a patient who was clinicallydiagnosed with OA. However, macroscopically degener-ated and histologically defined pre-osteoarthritic cartilagewithout a clinical history of OA shows all changes observedin OA cartilage (van Valburg et al., 1997). Thus, spontane-ously degenerated cartilagein vivo represents a pre-clinicalform of OA, which is useful to study the process of degen-

eration in OA. Another approach is to degeneration artic-ular cartilage synthetically, either in vitro or in vivo, toobtain OA-like cartilage in an early stage of the disease.This paper reviews all relevant studies, in which biome-chanical analysis of osteoarthritic or OA-like articular car-tilage were performed.

3.1. OA-like changes in degenerated cartilage in vitro

The extracellular matrix in healthy articular cartilage issubjected to a dynamic remodelling, in which degradativeand synthetic processes are balanced. This dynamic equilib-rium is disturbed in the early stage of osteoarthritic carti-lage degeneration. An increased synthesis of some matrixcomponents can be observed to compensate for anincreased degradation. The shift of the equilibrium in OAcartilage is determined roughly by a complex combinationof an increased degradation and a decreased synthesis ofthe matrix components. The catabolic degradative processin OA cartilage is catalysed in vivoby proteolytic enzymesfrom chondrocytes and synovial cells, which have thecapacity to degrade, disorganise, and release fragments ofthe macromolecular components of the cartilage matrix.These proteinases are grouped into matrix metallo-pro-

teinases, the a disintegrin and metallo-proteinase with

Load

Impermeable

plate

Cartilage

sample

Permeable

piston

Confining

chamber

Load

Subchondral

bone

Cartilage

Indenter

Load

Fig. 1. Commonly used mechanical testing configurations: unconfined compression (a), confined compression (b), and indentation (c).

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thrombospondin-like motifs, and all other proteinases(Sandy, 2003). By using these proteinases or by activatingthe proteolytic cascade using organo-mercurial compounds(Bonassar et al., 1996) or proinflammatory cytokines(Martel-Pelletier, 2004), specific modification of the cartilagestructure and composition on excised cartilage samples can

be performed. The aim of these approaches is, to study sys-tematically the degradative effects of these substances onthe cartilage matrix and the structurefunction relationshipof the components in articular cartilage in vitro. This infor-mation is inevitable for the understanding of the initiationand progression of OA. However, selectively removing onecomponent of the matrix is impossible without influencinganother component due to the complex interplay in thematrix.

Interleukin-1a reduced the GAG content by 75% after11 days of culture and increased denatured and cleavedtype II collagen content by 2.5 and 5.5 times comparedwith control samples, respectively (Legare et al., 2002).

Static Youngs modulus Edecreased by 80% and dynamicstiffness Edyn by 70% compared to control. These resultsare consistent with the findings of Bonassar et al. (1997).They found that treatment with recombinant human Inter-leukin-1band all-transretinoic acid both caused GAG lossof more than 90% and a decrease in equilibrium modulusEby more than 80%. Furthermore, the electrokinetic cou-pling coefficient ke was significantly lower whereas thehydraulic permeability j was about 15 times higher thanthe control group. Activation of the matrix metallo-proteinases with 4-aminophenylmercuric acetate alsoresulted in a loss in tissue GAG content of 80% and a more

than threefold increase in denatured type II collagen after 3days (Bonassar et al., 1996). Dynamic stiffnessEdyn, aggre-gate modulus HA and streaming potential V decreased bymore than 80% and electrokinetic coupling coefficient keby more than 50%.

Stromelysin 1 degradation resulted in a significant lossof GAG content (90%) after 3 days (Bonassar et al.,1995). Moreover, matrix collagen type IX and II weredegraded, which led to an increased tissue swelling of25%. This proteolytic matrix degradation involved a 90%decrease of both aggregate modulus HAand dynamic stiff-ness Edyn, and a 15 times higher hydraulic permeability j.During the incubation of adult human cartilage with lyso-somal proteinases cathepsin D and B1 for 100 h a largeproportion of the total proteoglycan was released fromthe tissue (Kempson et al., 1976). This resulted in a consid-erable increase of initial elastic compressive strain andcreep compressive strain after 1 and 2 min of uniaxial com-pression of the cartilage plugs.

Chondroitinase and collagenase treatment of cartilagesamples decreased collagen content, proteoglycan (PG)content and water content (Wayne et al., 2003). However,chondroitinase treatment resulted in greater reduction ofPG content (>61%) compared to collagenase (35%),whereas collagenase treatment resulted in greater collagen

content reduction (>57%) compared to chondroitinase

(21%). Collagenase and chondroitinase ABC digestiondecreased the Youngs modulus by approximately 40%and 60%, respectively (Nieminen et al., 2000; Toyraset al., 1999) and the aggregate modulus by 30% and 70%,respectively (Wayne et al., 2003). However, chondroitinaseABC treatment (and thus PG digestion) has a stronger

effect on the equilibrium than on the dynamic Youngsmodulus (57% and 24%, respectively) (Laasanenet al., 2003). Selective type II collagen degradation bycollagenase type VII decreased equilibrium and dynamicmodulus by 67% and 45%, respectively. They concluded thatcollagens are mainly responsible for dynamic instantaneousproperties, whereas PGs affect more the static equilibriumproperties (Laasanen et al., 2003). Furthermore, quantita-tive MR microscopy revealed an increase in the superficialcartilageT2time in samples treated with collagenase, whichwas considered as a sensitive parameter for the integrity ofthe collagen structure in the extracellular matrix (Nieminenet al., 2000). In another study both MR imaging parame-

tersT1andT2from the gadolinium-enhanced MR-Imagingmethod showed changes caused by matrix depletionwhereas the increase in T2could also be used to distinguishbetween collagen and PG loss (Wayne et al., 2003). Theyshowed a positive linear correlation of the aggregate mod-ulusHAwith PG content per wet weight (r

2 = 0.89), a weaknegative correlation of permeability j with PG content(r2 = 0.32), a negative correlation of aggregate modulusHA with T2 (r

2 = 0.51), and a negative correlation of PGcontent withT2 (r

2 = 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, whereaschondroitinase ABC treatment resulted in no detectablechanges (Laasanen et al., 2002). Rieppo et al. (2003) pre-sented that the Youngs modulus could be correlated withthickness of the superficial zone for controls and degradedspecimens (r= 0.408). Strong correlations between the areaintegrated optical density as spatial information on thePG concentration obtained by Digital Densitometry (Pan-ula et al., 1998) and the Youngs modulus were detected forthe superficial zone and the full sample thickness of con-trols and all pooled samples (Table 1). In this study theonly sensitive biochemical parameter for the Youngs mod-ulus was the uronic acid content in the incubation medium(r= 0.673). All other biochemical and microscopicalparameters appeared to be poor estimates for tissue equi-librium stiffness. Trypsin digestion resulted in an decreasedin GAG content of 65% mainly in the outer areas of theplug (DiSilvestro and Suh, 2002). Similar to the other stud-ies Youngs modulus showed a reduction by 80% and amore than 6-fold increase in permeability.

Whereas all of the above-mentioned groups degradedarticular cartilage plugs after dissection from the joint,Niederauer et al. (2004)degenerated an entire femoral con-dyle from goats in a trypsin solution. The aggregate mod-ulus showed a strong positive correlation with PG content

(R2 = 0.77). Parsons and Black (1987) incubated entire



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and the unknown cause of onset, these are promisingmodels to study OA pathogenesis due to their similarityto human disease progression. Transgenetic and knockoutmice are more reliable and facilitate studying the role ofspecific mediators in the pathogenesis of OA and mimick-ing different stages and forms of osteoarthritic changes in

articular cartilage (Hyttinen et al., 2001). Experimentallyinduced OAmodels are divided into a chemical and physi-cal type (Brandt, 2002). Injection of chemical reagents andbiological mediators into the joint of commonly small ani-mals leads rapidly to macroscopic or histopathologic lesionsimilar to OA. Physically induced OA models often haverapid and more severe cartilage degeneration than sponta-neous models. Similar to chemical induction, they show avery consistent onset but a slower progression. This surgi-cal induction is mainly performed in larger animals such asdogs, cats and rabbits. Common methods are meniscec-tomy 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 humansafter traumatic injury (Roos et al., 1995). Alteration of thejoint load by tibial osteotomy (Panula et al., 1997), byimmobilisation (Leroux et al., 2001) or by replacement ofthe femoral trochlea with a hemiarthroplasty implant(LaBerge et al., 1993) are other used physical knee OAmodels. Hip animal models are rare and performed bychemical induction, for instance by injection of papain(Bentley, 1971; Scheck and Sakovich, 1972) or by pelvicosteotomy (Heinegard, 1987). As the analysis is mainlyrestricted to biochemical or histological characterisationof 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 differences in cartilagethickness and PG distribution compared to control group(Hyttinen et al., 2001). However, a significant increasedOA occurrence from 21% in the control group to 73% inthe knockout mice was detected by the presence of superfi-cial fibrillation. Indentation stiffness revealed a cartilagesoftening by 45%.

Histological evaluation after transection of the anteriorcruciate ligament in dogs revealed mild alterations, includ-ing chondrocyte proliferation, mild surface disruption,chondrolysis and focal reduction of safranin-O staining(Altman et al., 1984). The total PG content showed onlylittle change, whereas PG aggregates were reduced in size.Biomechanical analysis revealed a small increase in unre-laxed Gu and relaxed shear modulus Gr of 37% and 22%,respectively, in the early group and an increase of nearly50% ofGu in the late group (1016 weeks after transec-tion). Another study showed similar histological alterationsat numerous sides on the surface of tibial cartilage but nochange in cartilage thickness compared to control (Settonet al., 1994). But aggregate and shear modulus both werelowered by 44% and 25% after 6 and 12 weeks, respectivelyin zones covered by the meniscus whereas they were low-

ered by 30% and 26%, respectively after 6 weeks and by

27% and 22%, respectively compared to control in uncov-ered regions. Hydraulic permeability increased only after12 weeks by 70% and 26% in covered and uncoveredregions, respectively. Water content increased from 74.2%to 83.4% 12 weeks after transection of the ACLT incovered and from 84.1% to 89.0% in uncovered regions

(Table 2).An increase in water content was also observed on pos-terior and distal sides of the medial femoral condyle in asubsequent study (Setton et al., 1995). Equilibrium com-pressive stiffness Es and equilibrium shear modulus Geqdecreased 6 weeks after transection of the ligament butdid not differ between 6 and 12 weeks. On posterior sides,shear and compressive stiffness decreased by more than 80and 72%, respectively, whereas distal sides showed a reduc-tion of 53% and 70%, respectively. The magnitude of thecomplex shear modulus G* from dynamic shear tests alsodecreased after 6 weeks by an average value of 56% com-bined for both sides, whereas thickness did not change sig-

nificantly. Statistical analysis revealed a weak correlationof the complex shear modulus with water content(r= 0.55) and a strong correlation between the equilib-rium shear and compressive properties (r= 0.75) (Table 2).

Transection of the ACLT in cats increased the meanthickness of femoral and patellar cartilage between 48%and 102%, whereas tibial cartilage showed no significantchanges (Herzog et al., 1998). In contrast to other pub-lished data, differences neither in the Youngs modulusnor in the permeability could be observed between experi-mental and contralateral sites. Only the total contact areaof the patellofemoral joint increased due to the increased

cartilage thickness. Cartilage of medial femoral condylesfrom ACLT transected rabbit knees showed an increasedwater content of approximately 775% after 9 weeks (Sahet al., 1997). A trend towards a decrease in GAG contentper wet weight of the sample was observed. All femoralcondyles displayed gross morphological changes fromfibrillation to erosion of the surface, but no thicknesschanges could be detected. The aggregate modulus wasreduced by 18% and showed a positive correlation with tis-sue GAG content of control (r= 0.66) and OA-like sam-ples (r= 0.62) (Table 2). Pooling of the osteoarthritic andthe healthy group revealed a negative relationship betweenaggregate modulus and water content of tissue (r=0.38).Analysis of the distinct groups revealed a weak correlationamong normal specimens but none in OA samples.

Bilateral (on both knee joints) lateral meniscectomy ini-tiates experimental osteoarthritis in the ovine femoro-tibialjoint (Appleyard et al., 2003) as well as in the patellar car-tilage (Appleyard et al., 1999). Histological signs of OAchanges were mainly detected in central and lateral regionsof the patellar cartilage surface whereas the thickness wasnot changed. An average decrease of initial Gi, relaxedGr, and unloaded shear modulus Gu of 34, 32, and 22%,respectively, was shown, while permeability was increasedby 72%. Proteoglycan content was increased (+52%) in

the outer regions of the meniscectomized lateral compart-



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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%.

Table 2Properties of articular cartilage in animal models of osteoarthritis

Author Sample Parameters Correlations

Appleyard et al. (2003) Sheep G* h GAGdry Water G*GAGdryneg (lat NOC)

NOC 2.67 (1.92) 0.30 (0.18)to to G*HYPRO

0.19 (0.12) 1.23 (0.29) pos (all)Lateral #4570% "26135% #27% "5% G*WaterMEN neg (MEN)

G* hneg (all)

LeRoux et al. (2000) Canine E Geq AIOD EAIODr= 0.870*

Medial #50% #50% # 20% GeqAIRMEN Medial Medial r= 0.626**

12 wk

Oakley et al. (2004) Sheep G* h Total TB Birefring. G*birefring.q= 0.44

Medial #50% TM "3040% #4050% #1530% G*hMEN #30% TL MFC, LFC all regions q=0.47

16 wk #46% P G*Total TBq= 0.42

Sah et al. (1997) Rabbit HA j GAGwet Water HAGAG

r= 0.66***

NOC 0.75 (0.28) 0.631 (0.28) 27.6 (9.8) 70.3 (4.1) (healthy)ACLT 0.61 (0.21) 0.644 (0.35) 24.6 (8.9) 75.2 (4.0) r= 0.62**

(OA)

HAWaterr=0.35*

(healthy + OA)

Setton et al. (1994) Canine HA j h Water jWaterr= 0.75***

NOC (healthy + OA)Cov. 0.56 (0.19) 2.4 (1.3) 0.85 (0.17) 74.2 (4.8) HAWaterUnc. 0.49 (0.19) 5.0 (1.7) 1.7 8 (0.4) 84.1 (2.0) r=0.25*

ACLT 6 wk (healthy + OA)Cov. 0.31 (0.10) 2.6 (0.4) 0.85 (0.11) 79.5 (2.3)Unc. 0.34 (0.09) 5.8 (0.4) 1.5 (0.2) 89.5 (1.6)12 wkCov. 0.42 (0.10) 4.1 (1.0) 0.94 (0.24) 83.4 (3.3)Unc. 0.36 (0.07) 6.3 (1.0) 1.4 (0.3) 89.0 (1.1)

Setton et al. (1995) Canine E Geq jG*j Water Water jG*j:

r=0.55**

NOC (healthy/OA)Post. 0.29 (0.10) 0.22 (0.04) 0.79 (0.25) 78.0 (1.5)Dist. 0.14 (0.03) 0.13 (0.09) 0.44 (0.22) 73.8 (4.8)ACLT6 wk

Post. 0.04 (0.02) 0.07 (0.02) 0.26 (0.07) 79.9 (1.3)Dist. 0.04 (0.01) 0.06 (0.03) 0.25 (0.08) 79.7 (0.9)12 wkPost. 0.05 (0.03) 0.06 (0.01) 0.24 (0.11) 81.1 (0.9)Dist. 0.05 (0.03) 0.06 (0.04) 0.31 (0.19) 80.3 (1.4)

Mean (SD), *P< 0.05, **P< 0.01, ***P< 0.001.ACLT = anterior cruciate ligament transection, birefring. = superficial 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 [10

15 m4/N s]; Water = water content [%].



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Total collagen content was not different from controlgroup, but a gradual decrease was evident from outer toinner regions in lateral and medial compartments. Carti-lage thickness increased between 26% and 135% in the lat-eral 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 modulusG* decreased by 4570% in the lateral tibial compartment,whereas it remained unaffected in the medial compartment.A strong negative correlation between the sGAG contentand the dynamic effective shear modulus G* of the entireand the lateral plateau solely in non-operated controlgroup was shown (Table 2). In contrast, the water contentand shear modulus showed only a strong negative correla-tion in meniscectomized knees. All samples showed astrong negative correlation between shear modulus G*and thickness and between shear modulus and collagencontent. In dogs no change in total thickness was shown12 weeks after total medial meniscectomy (LeRoux et al.,

2000). However, thickness of the cartilage superficial zoneat medial points decreased (59%) but not at intermediateand lateral points of the central tibial plateau. Loss inGAG content was detected only in medial intermediateregion. Close to these positions, equilibrium compressiveEs and equilibrium shear modulus Geq decreased signifi-cantly by approximately 50% of control values but not inlateral tibial plateau. A strong correlation (r= 0.857)between the GAG content and the compressive moduluswas shown for the meniscectomized but not for controlsamples (Table 2). As soon as 2 weeks after the medialmeniscectomy 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 onthe lateral tibial plateau (Hoch et al., 1983). Surprisinglyafter 6 months, both regions regained their initial uronicacid content. This recovery trend was also apparent forthe Youngs modulus calculated from indentation tests.Youngs modulus of medial tibial cartilage decreased by72% after 2 weeks and increased to near normal after 6months. This observation was confirmed by the strong cor-relation between Youngs modulus and uronic acid con-tent. Four months after medial meniscectomy in sheeplarge histological damage was observed on the medial sur-faces, followed by patello-femoral and lateral surfaces(Oakley et al., 2004). The intensity of superficial collagenbirefringence decreased for all surfaces by 1530%.Changes in PG, measured by toluedine-blue staining, weremost severe in the medial compartment with a reduction of4050% compared to control. Cartilage thickness, however,increased uniformly by 1520% after 4 weeks and by thesame magnitude between 4 and 16 weeks in all regions ofthe joint. Biomechanical assessment revealed a 46% reduc-tion in dynamic shear modulus G* of patellar cartilage anda 50% reduction in medial tibial cartilage. Furthermore areduction by 30% of G* in the contralateral (lateral) partof the tibial articular cartilage was detected which was

not found in previous studies. Strong correlations between

G* and collagen birefringence, toluedine-blue staining, andthickness were observed (Table 2). A multivariate analysisrevealed that collagen organisation contributed twice asmuch to dynamic shear modulus as the PG content. Oakleyet al. proposed that for the maintenance of cartilage stiff-ness, collagen integrity was more important than PG

content.A specific OA animal model is the joint immobilisationof canine knees (Leroux et al., 2001). Cast immobilisationfor 4 weeks resulted in a 75% lower equilibrium shear mod-ulusGeqcompared to control group and in a 53% differencecompared to the contralateral leg. Differences of the equi-librium modulus Es were not significant. In addition, nodifferences in biochemical properties were found. However,it was concluded that these findings are consistent with amild form of cartilage degeneration. Further informationabout the effect of immobilisation on the mechanical, bio-chemical and morphological properties of articular carti-lage can be found inVanwanseele et al. (2002).

In conclusion cartilage from OA animal models showedan 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 significant changes of collagencontent were reported, but a variation in collagen birefrin-gence 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 superficial zone in someregions was observed (LeRoux et al., 2000). Except onegroup (Herzog et al., 1998), all of the recent publicationsof OA-like animal models reported at least in temporarily

decreased mechanical properties (Hoch et al., 1983). Fur-thermore, correlations between mechanical parametersand biochemical parameters, as well as structural parame-ters (LeRoux et al., 2000; Oakley et al., 2004) and cartilagethickness (Appleyard et al., 2003; Oakley et al., 2004) wereshown.

3.3. Spontaneous occurring OA-like changes in vivo

For spontaneously occurring OA-like cartilage it is com-mon practice to examine the surface visually for classifica-tion of the sample as neither the stimulus nor the durationof degeneration, nor the degenerative environment areknown. A few groups (Brocklehurst et al., 1984; van Val-burg et al., 1997) found a good correlation between thefindings from histology and visual appearance in autopsyspecimens. However, several other authors showed thatvisual surface properties are not reliable to distinguishbetween healthy and degraded tissue (LaBerge et al.,1993; Orford et al., 1983; Panula et al., 1997; Stockwellet al., 1983; Vignon and Arlot, 1981). India ink stainingof the articular surface in vitro could indeed improve theexpressiveness, since the ink particles are entrapped in sur-face irregularities and adhere to fibrillated cartilage (Col-lins and McElligott, 1960). But an intact non-stained

cartilage surface can cover heavily fissure lamellae, whereas



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the surface of structural healthy cartilage can show aslightly rough surface (Clark and Simonian, 1997). Neitherthe absence of visual surface disruption nor the on bonecartilage compliance or thickness measurements necessar-ily constitute sensitive indicators of the biomechanicalhealth of cartilage (Broom and Flachsmann, 2003). How-

ever, due to the lack of more suitable and more reliablemethods the (arthroscopic) cartilage classification in vivoand the pre-classification in the following in vitro sectionsof OA-like cartilage are commonly performed visually.

Armstrong and Mow (1982) were the first ones whoextensively investigated the spontaneous variations of themechanical properties with age and OA of human autopsy

patellae. Histologicalhistochemical grading according toMankin et al. (1971)revealed a broad variance of this scorebetween 1 and 12 (Table 3). The thickness of 103 samples inthe age between 16 and 85 years was diversified between1.69 and 5.17 mm, whereas water content varied from72.8% to 88.4%. Biomechanical analysis displayed a mean

aggregate modulus of 0.79 MPa and a mean permeabilityof 4.7 1015 m4/(N s). A linear relationship between theinverse of permeability, the so-called frictional drag, andthe water content was shown (r=0.50) (Table 3). Thestrongest correlation was the linear decrease of aggregatemodulus with increasing water content (r=0.73). Sinceno correlation between biomechanical parameters and the

Table 3Properties of articular cartilage during spontaneous occurring osteoarthritis

Author Sample Parameters Correlations

Armstrong and Mow (1982) Human autopsy HA j Water Mankin HAWater

r=0.73***

0.131.91 0.519.5 72.888.4 112 1/jWaterLateral facet of patella r=0.50***

Mean Mean Mean Mean HA*Mankin0.79 (0.36) 4.7 (3.6) 78.63 (3.86) 6.33 (2.58) r=0.25*

Nieminen et al. (2004a) Bovine patellar Es Edyn Uronic Water EeqUS speedrs= 0.790**

Intact 0.32 (0.15) 7.06 (4.83) 10.2 (3.5) 79.9 (2.4) EdynUS speedModerate 0.26 (0.13) 2.12 (1.58) 6.7 (1.5) 81.6 (1.2)Advanced 0.08 (0.08) 0.54 (0.36) 4.1 (1.2) 84.1 (2.6) rs=0.898**

Nissi et al. (2004) Bovine patellar Es Edyn Uronic T1,Gd EeqT1,Gdr= 0.625*

T1,GdUronicIntact 0.40 (0.11) 9.74 (2.83) 12.17 (2.01) 405 (47) r= 0.624*

Moderate 0.24 (0.12) 1.63 (0.48) 6.24 (0.79) 376 (25) EeqBulk[Gd]Advanced 0.06 (0.03) 0.44 (0.20) 3.95 (1.19) 316 (64) r=0.609*

Rivers et al. (2000) Human HA j sGAGwet Water OA:CMC HAsGAG

r= 0.803*

Non-OA 0.82 (0.20) 4.04 (2.91) 21.5 (4.4) 72.5 (3.7) HAWater(OA) 0.52 (0.22) 2.92 (1.00) 16.4 (6.5) 74.8 (3.8) r=0.426*

jsGAGr= 0.360*

Non-OA:jWaterr=0.315*

Saarakkala et al. (2003) Bovine patellar E Edyn Edyn_ultra Water EdynMankinr=0.777*

EdynWaterIntact 0.28 (0.12) 7.5 (5.6) 9.2 (5.8) 80.3 (2.0) r=0.686*

Discolor. 0.23 (0.11) 1.5 (0.6) 2.4 (0.3) 82.0 (1.3) EdynUronicSuperfic. 0.27 (0.12) 1.2 (0.6) 2.1 (1.0) 83.6 (3.0) r= 0.876*

Deep 0.06 (0.04) 0.5 (0.3) 1.5 (0.3) 83.5 (2.0) EMankinDefects r=0.674*

EWaterr=0.586*

EUronic

r= 0.717*

Mean (SD), *P< 0.05, **P< 0.01, ***P< 0.001.CMC = carpometacarpal, Discolor. = slightly discoloured surface; Mankin = Mankin score, Superfic. = superficial defects; Bulk [Gd] = GD-DTPAcontent;Edyn= dynamic Youngs modulus [MPa]; Edyn_ultra= equilibrium Youngs modulus form ultrasound indentation device [MPa]; E= equilibriumYoungs modulus [MPa]; HA= aggregate modulus [MPa];j= hydraulic permeability [10

15 m4/N s]; sGAG = sulphated glycosaminoglycan content

[mg/g]; T1,Gd=T1relaxation in presence of Gd-DTPA, Uronic = uronic acid content [lg/ml].



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visual or any of the histological appearances could bedetected,Mankin et al. (1971)concluded that these proper-ties might be a poor indication for the functional character-isation of the material in the intact joint.

Cartilage samples from osteoarthritic human thumb car-pometacarpal joints revealed significant differences in water

content, sGAG content, aggregate modulus, and perme-ability compared to healthy samples (Rivers et al., 2000).Whereas collagen content stayed constant, the proteogly-can content decreased by 24%, and the water contentincreased by 2.3% in OA samples. Biomechanical analysisdemonstrated reduction of the aggregate modulus in OAcartilage by 36%. In contrast to other studies, an increasedpermeability of 28% was observed. The competing effect ofthe increase of j with extracellular matrix loss and thedecrease of matrix compaction during indentation mayexplain these findings. Correlation between aggregate mod-ulusHAand the biochemical parameters water, and sGAGcontent were observed for OA joints but not for non-OA

joints (Table 3). All correlations between the biochemicalcomposition and the biomechanical parameters were foundto be stronger in OA than in healthy joints.

Bae et al. (2003) measured the functional indentationstiffness on anterior regions of cadaveric human lateraland medial femoral condyles by means of a handheldindentation device. This stiffness parameter varied mark-edly between the normal group without OA-typical macro-scopic surface appearance and the degenerated samplegroups. India ink staining and histopathology scoring dis-played identical results. Only little variations between thenormal samples from different age groups were observed.

Averaged cartilage thickness did reveal only negligibleeffects between normal aging and degeneration. Correla-tion between indentation stiffness and reflectance scorefrom India ink stained surfaces (R2 = 0.35), histopathologyoverall score (q2 =0.44), and histopathology surfaceirregularity score (q2 =0.34) were observed. Humanautopsy samples of OA femoral cartilage displayed a lowerthickness compared to normal (Roberts et al., 1986). Fur-thermore, the PG content, the mechanical compressiveand tensile properties were lower in the OA samples. How-ever, no correlation between the mechanical property andthe PG content was found. Bank et al. performed instanta-neous deformation (ID) tests on samples from femoralheads and condyles of OA patients of total joint replace-ment surgery and from normal cadaveric joints (Banket al., 2000). The percentage of instantaneous deformation(% ID), parallel and perpendicular, showed a linear posi-tive correlation with the percentage of degraded collagen(r= 0.81 and r= 0.87, respectively) but not with fixedcharge density. They confirmed that the decreased ID stiff-ness is strongly related to the amount of degraded collagennetwork. Ding et al. (1998) classified the early-stage OAsamples as macroscopically degenerated and fibrillated car-tilage and confirmed this histologically. Medial proximaltibial cartilage showed a mean Mankin score of 4.9 (37)

and was denoted as osteoarthritic. They found a distinct

difference in the stiffness of the cartilage and of the sub-chondral bone of OA compared to healthy samples. Carti-lage with slight fissures on its superficial zone showed areduced stiffness by 29% compared to age-matched sam-ples. Mean thickness of OA cartilage was 2.3 mm, whichwas thinner than lateral comparison and age-matched sam-

ples. The stiffness of osteoarthritic cartilage did correlateneither with bone the stiffness or cartilage mean thickness.However, a correlation between cartilage and bone wasshown in the normal age matched and lateral comparisongroups. Apparently healthy tibial cartilage from patientswith diagnosed unicompartimental OA and from cadaverswas on average 22% thinner and 71% softer than controlcartilage from normal knees (Obeid et al., 1994).

In addition to the commonly used biochemical, biome-chanical or histological methods, ultrasound and MRproperties were investigated to assess articular cartilage(Nieminen et al., 2004a). They classified the cartilage sam-ples with early OA changes according to Mankin score into

three groups. Equilibrium Esand dynamic Youngs moduliEdynwas respectively 18% and 70% lower in moderate and87.5% and 90%, respectively, in advanced degenerated car-tilage compared to healthy samples. Cartilage thicknessincreased by approximately 20% with OA progression. Adecrease of 60% in uronic acid content and of 40% inhydroxyproline content was shown, whereas the water con-tent increased from 79.9% to 84.1% with OA progression.Linear correlation between Mankin score and ultrasoundspeed (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 relatedto all biochemical and biomechanical parameters (Table3). Saarakkala et al. (2003) assessed the cartilage qualityusing an ultrasound indentation instrument and uncon-fined compression tests. Dynamic modulus Edynof sampleswith superficial defects decreased by 85%, whereas staticYoungs modulus remained unchanged. The mechanicalproperties were impaired by concurrent increase of tissuewater content and decrease of uronic acid content (Table3). Cartilage dynamic and equilibrium modulus were posi-tively 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 gadolin-ium-diethylene triamine pentaacetic acid (Gd-DTPA)enhancedT1and T2 imaging techniques for the assessmentof biomechanical properties of healthy (Kurkijarvi et al.,2004; Nieminen et al., 2004b) and spontaneous degeneratedbovine cartilage (Nissi et al., 2004). BulkT1relaxation timein the presence of Gd-DTPA as well as Gd-DTPA contentshowed a linear correlation with Youngs modulus in ahigh magnetic field strength MRI machine in healthy sam-ples (Nieminen et al., 2004b). As T2 relaxation time ishighly related to the three-dimensional collagen architec-

ture, the combination of these parameters can lead to use-



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ful information on mechanical, biochemical and structuralparameters on healthy and spontaneously degeneratedarticular cartilage. Nissi et al. (2004) presented similarparameters on normal, early and advanced degeneratedbovine patellar cartilage samples. It was assumed that theadvanced degenerated group corresponded most probably

to the initial stage of cartilage degeneration. Youngs mod-ulus and dynamic modulus decreased by 85% and 95%,respectively, PG content lowered by 67% and collagen con-tent per wet weight by 50% in advanced OA samples. Thisresulted in increased superficial T2and in decreased super-ficial and bulk T1parameters in the presence of Gd-DTPAwith OA progression (Table 3). Samples were also slightlythicker than normal samples.

The results from spontaneous osteoarthritic changesin vivo were comparable to animal models in terms ofdecrease in mechanical properties and GAG content, andincrease in water content. However, structural and mor-phological differences were reported more frequently. Par-

ticularly human cadaveric samples displayed a reduction incartilage thickness compared to the reported increasedthickness of the bovine samples. This is probably due tothe more advanced OA progression of the human cadavericsamples. Furthermore, a significant reduction in total colla-gen content of up to 50% (Nissi et al., 2004) and in theamount of degraded collagen was reported (Bank et al.,2000). Mechanical parameters were correlated with bio-chemical properties as well as with the Mankin score ( Arm-strong and Mow, 1982; Saarakkala et al., 2003), ultrasonicparameters (Nieminen et al., 2004a), and MR parameters(Nissi et al., 2004).

4. Summary and conclusion

The progression of osteoarthritis is generally dividedinto three broad stages, namely the proteolytic breakdownof the cartilage matrix, the fibrillation and erosion of thecartilage surface, and the beginning of the synovial inflam-mation (Martel-Pelletier, 2004). Due to the limited regener-ative capability of AC, the progression of this degenerativejoint disease has to be detected before irreversible morpho-logical changes become manifested. Early diagnosis of OAwill enable an early treatment, the reduction of pain anddisability and thus the improvement of the quality of lifeof the patient.

As shown in numerous studies, the values of themechanical compressive parameters (E, HA, Edyn) of artic-ular cartilage in the early pre-osteoarthritic stage arereduced between 20% and 80% (Fig. 2) compared tohealthy tissue. These early changes (mild, moderate andadvanced) might remain undetected using common clinicalmethods such as plain radiographs or arthroscopy due tothe lack of cartilage loss and the marginal superficialchanges (Nissi et al., 2004). Several studies showed thatthe Youngs modulus is already 20% lower in early OAsamples compared to the healthy samples. Consequently,

pre-osteoarthritic changes might be detected in this moder-

ate degenerative stage using the cartilage static moduli

(HA, E). Moreover, the decrease of the dynamic YoungsmodulusEdynis even more pronounced in the early degen-erative stage. Therefore, the use of this material parametercould enable the detection of mild pre-osteoarthritic carti-lage changes.

This review showed that measuring the cartilage staticand dynamic modulus has the potential to identify earlydegenerative changes in articular cartilage. The accuracy(or measurement error) of a mechanical testing device hasto be adequate to detect changes of 10% in stiffness in orderto detect reliably the degeneration of articular cartilageeven in the early osteoarthritic stage. Improvement of thepreviously validated arthroscopic indentation devices, asrecommended byBrommer et al. (2006), or the numericalanalysis of MR-controlled patellofemoral compression testin vivo, as already performed in vitro byHerberhold et al.(1999), might allow for such measurements in clinical prac-tice. Such methods might enable to classify pre-OA carti-lage based on its mechanical properties and consequentlyon its functional quality and might enable to track earlydegenerative cartilage changes.

Acknowledgement

We would like to thank the International Society of Bio-

mechanics ISB for financial support and Mr. T. Fischbachfor the help with the manuscript.

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Es

Edyn

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0

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



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