Material Properties Of Articular Cartilage Research Articles

Image-Based Optimization of Articular Cartilage Material Properties for the Entire Joint Structure in Porcine Hips

Image-Based Optimization of Articular Cartilage Material Properties for the Entire Joint Structure in Porcine Hips

Effect of mineral diets on the development of cartilage material properties

Vitamin D and minerals, including zinc (Zn) and manganese (Mn), are vital in the development of bones, but their roles in the development of articular cartilage material behavior are not well understood. In this study, articular cartilage material properties from a hypovitaminosis D porcine model were evaluated. Pigs were produced by sows fed vitamin D deficient diets during gestation and lactation, and the offspring were subsequently fed vitamin D deficient diets for 3 weeks during the nursery period. Pigs were then assigned to dietary treatment groups with inorganic minerals only or inorganic plus organic (chelated) minerals. Humeral heads were harvested from pigs at 24 weeks of age. Linear elastic modulus and dissipated energy were measured under compression to 15% engineering strain at 1 Hz. Anatomical location within the humeral head affected elastic modulus. Diet significantly affected linear modulus and dissipated energy. The largest modulus and highest energy dissipation was in the inorganic zinc and manganese group; the lowest modulus and the least energy dissipation was in the organic (chelated) zinc and manganese group. Pairwise results between the control group and all vitamin D deficient groups were not statistically significant. Overall, these results suggest that mineral availability during rapid growth subsequent to a vitamin-D deficiency during gestation and lactation had minimal effects on articular cartilage material properties in young growing pigs. Though not statistically significant, some of the numerical differences between mineral sources suggest the potential importance of mineral availability during cartilage formation and warrant further study.

Anisotropic properties of articular cartilage in an accelerated in vitro wear test

Many material properties of articular cartilage are anisotropic, particularly in the superficial zone where collagen fibers have a preferential direction. However, the anisotropy of cartilage wear had not been previously investigated. The objective of this study was to evaluate the anisotropy of cartilage material behavior in an in vitro wear test. The wear and coefficient of friction of bovine condylar cartilage were measured with loading in directions parallel (longitudinal) and orthogonal (transverse) to the collagen fiber orientation at the articular surface. An accelerated cartilage wear test was performed against a T316 stainless-steel plate in a solution of phosphate buffered saline with protease inhibitors. A constant load of 160 N was maintained for 14000 cycles of reciprocal sliding motion at 4 mm/s velocity and a travel distance of 18 mm in each direction. The contact pressure during the wear test was approximately 2 MPa, which is in the range of that reported in the human knee and hip joint. Wear was measured by biochemically quantifying the glycosaminoglycans (GAGs) and collagen that was released from the tissue during the wear test. Collagen damage was evaluated with collagen hybridizing peptide (CHP), while visualization of the tissue composition after the wear test was provided with histologic analysis. Results demonstrated that wear in the transverse direction released about twice as many GAGs than in the longitudinal direction, but that no significant differences were seen in the amount of collagen released from the specimens. Specimens worn in the transverse direction had a higher intensity of CHP stain than those worn in the longitudinal direction, suggesting more collagen damage from wear in the transverse direction. No anisotropy in friction was detected at any point in the wear test. Histologic and CHP images demonstrate that the GAG loss and collagen damage extended through much of the depth of the cartilage tissue, particularly for wear in the transverse direction. These results highlight distinct differences between cartilage wear and the wear of traditional engineering materials, and suggest that further study on cartilage wear is warranted. A potential clinical implication of these results is that orienting osteochondral grafts such that the direction of wear is aligned with the primary fiber direction at the articular surface may optimize the life of the graft.

Estimation of depth-dependent material properties of biphasic soft tissues through finite element optimization and sensitivity analysis

A knowledge of material properties of soft tissue, such as articular cartilage, is essential to assess its mechanical function. It is also increasingly more evident that the inhomogeneity of the tissues plays a significant role in its in vivo functioning. Hence, efficient and reliable tools are needed to accurately characterize the inhomogeneity of the soft tissue mechanical properties. The objective of this research is to propose a finite element optimization procedure to determine depth-dependent material properties of articular cartilage by processing experimental data. Cartilage is modeled as a biphasic continuum with a linear elastic solid phase. The optimization method is based on a sensitivity analysis where the sensitivity of the finite element results to a variation in the material properties is analytically evaluated. The elastic modulus and permeability of the tissue are assumed to vary either linearly or quadratically through the thickness of the cartilage layer. After adopting some initial estimates, these material properties are updated iteratively based on their sensitivities to the current results, and the difference between the actual experimental data and computational experimental data. The optimization method has been tested in two common experimental configurations of cartilage and found to be efficient to estimate the material properties.

Functional effects of an interpenetrating polymer network on articular cartilage mechanical properties.

Depletion of glycosaminoglycans (GAGs) and degradation of collagen network are early hallmarks of osteoarthritis (OA). Currently, there are no chondroprotective therapies that mitigate the loss of GAGs or effectively restore the collagen network. Recently, a novel polymeric cartilage supplement was described that forms a charged interpenetrating polymer network (IPN) reconstituting the hydrophilic properties of the extracellular matrix (ECM). To investigate the mechanism by which this hydrophilic IPN improves articular cartilage material properties, a finite element (FE) model is used to evaluate the IPN's effect on the fibrillar collagen network, nonfibrillar matrix, and interstitial fluid flow. Bovine osteochondral plugs were degraded with chondroitinase ABC to selectively decrease GAG content. Samples were mechanically tested before and after IPN treatment using unconfined testing geometry and stress-relaxation protocol. Every measurement was modeled separately using a fibril-reinforced poroviscoelastic FE model. Measurement replication was achieved by optimizing the following model parameters: initial and strain-dependent fibril network modulus (Ef0, Efε, respectively), nonfibrillar matrix modulus (Enf), initial permeability (k0) and strain-dependent permeability factor (M). Based on the FE model results, treatment of native and GAG depleted cartilage with the hydrophilic IPN increases the ECM stiffness and impedes fluid flow. The IPN did not alter the stiffness of fibrillary network. Cartilage permeability and the strain-dependent permeability factor decreased with increasing IPN w/v%. The IPN reconstitutes cartilage material properties primarily by augmenting the hydrophilic ECM. This reinforcement of the solid phase also affects the fluid phase reestablishing low permeability.

Micromechanical properties of canine femoral articular cartilage following multiple freeze-thaw cycles

Tissue material properties are crucial to understanding their mechanical function, both in healthy and diseased states. However, in certain circumstances logistical limitations can prevent testing on fresh samples necessitating one or more freeze-thaw cycles. To date, the nature and extent to which the material properties of articular cartilage are altered by repetitive freezing have not been explored. Therefore, the aim of this study is to quantify how articular cartilage mechanical properties, measured by nanoindentation, are affected by multiple freeze-thaw cycles. Canine cartilage plugs (n = 11) from medial and lateral femoral condyles were submerged in phosphate buffered saline, stored at 3–5°C and tested using nanoindentation within 12h. Samples were then frozen at −20°C and later thawed at 3–5°C for 3h before material properties were re-tested and samples re-frozen under the same conditions. This process was repeated for all 11 samples over three freeze-thaw cycles. Overall mean and standard deviation of shear storage modulus decreased from 1.76 ± 0.78 to 1.21 ± 0.77MPa (p = 0.91), shear loss modulus from 0.42 ± 0.19 to 0.39 ± 0.17MPa (p=0.70) and elastic modulus from 5.13 ± 2.28 to 3.52 ± 2.24MPa (p = 0.20) between fresh and three freeze-thaw cycles respectively. The loss factor increased from 0.31 ± 0.38 to 0.71 ± 1.40 (p = 0.18) between fresh and three freeze-thaw cycles. Inter-sample variability spanned as much as 10.47MPa across freezing cycles and this high-level of biological variability across samples likely explains why overall mean “whole-joint” trends do not reach statistical significance across the storage conditions tested. As a result multiple freeze-thaw cycles cannot be explicitly or statistically linked to mechanical changes within the cartilage. However, the changes in material properties observed herein may be sufficient in magnitude to impact on a variety of clinical and scientific studies of cartilage, and should be considered when planning experimental protocols.

The structure and mechanical properties of articular cartilage are highly resilient towards transient dehydration

Articular cartilage is a mechanically highly challenged material with very limited regenerative ability. In contrast to elastic cartilage, articular cartilage is exposed to recurring partial dehydration owing to ongoing compression but maintains its functionality over decades. To extend our current understanding of the material properties of articular cartilage, specifically the interaction between the fluid and solid phase, we here analyze the reversibility of tissue dehydration. We perform an artificial dehydration that extends beyond naturally occurring levels and quantify material recovery as a function of the ionic strength of the rehydration buffer. Mechanical (indentation, compression, shear, and friction) measurements are used to evaluate the influence of de- and rehydration on the viscoelastic properties of cartilage. The structure and composition of native and de/rehydrated cartilage are analyzed using histology, scanning electron microscopy, and atomic force microscopy along with a 1,9-dimethylmethylene blue (DMMB) assay. A broad range of mechanical and structural properties of cartilage can be restored after de- and rehydration provided that a physiological salt solution is used for rehydration. We detect only minor alterations in the microarchitecture of rehydrated cartilage in the superficial zone and find that these alterations do not interfere with the viscoelastic and tribological properties of the tissue. Statement of SignificanceWe here demonstrate the sturdiness of articular cartilage towards changes in fluid content and show that articular cartilage recovers a broad range of its material properties after dehydration. We analyze the reversibility of tissue dehydration to extend our current understanding of how the material properties of cartilage are established, focusing on the interaction between the fluid and solid phase. Our findings suggest that the high resilience of the tissue minimizes the risk of irreversible material failure and thus compensates, at least in part, its poor regenerative abilities. Tissue engineering approaches should thus not only reproduce the correct tissue mechanics but also its pronounced sturdiness to guarantee a similar longevity.

Influences of the depth-dependent material inhomogeneity of articular cartilage on the fluid pressurization in the human knee

The material properties of articular cartilage are depth-dependent, i.e. they differ in the superficial, middle and deep zones. The role of this depth-dependent material inhomogeneity in the poromechanical response of the knee joint has not been investigated with patient-specific joint modeling. In the present study, the depth-dependent and site-specific material properties were incorporated in an anatomically accurate knee model that consisted of the distal femur, femoral cartilage, menisci, tibial cartilage and proximal tibia. The collagen fibers, proteoglycan matrix and fluid in articular cartilage and menisci were considered as distinct constituents. The fluid pressurization in the knee was determined with finite element analysis. The results demonstrated the influences of the depth-dependent inhomogeneity on the fluid pressurization, compressive stress, first principal stress and strain along the tissue depth. The depth-dependent inhomogeneity enhanced the fluid support to loading in the superficial zone by raising the fluid pressure and lowering the compressive effective stress at the same time. The depth-dependence also reduced the tensile stress and strain at the cartilage–bone interface. The present 3D modeling revealed a complex fluid pressurization and 3D stresses that depended on the mechanical contact and relaxation time, which could not be predicted by existing 2D models from the literature. The greatest fluid pressure was observed in the medial condyle, regardless of the depth-dependent inhomogeneity. The results indicated the roles of the tissue inhomogeneity in reducing deep tissue fractures, protecting the superficial tissue from excessive compressive stress and improving the lubrication in the joint.

Mineralization of articular cartilage in the sprague-dawley rat: characterization and mechanical analysis

The formation of mineralized deposits in human articular cartilage is a common occurrence [1–4]; however, the relationship between mineral deposition and material properties of the articular cartilage is not well understood nor the relationship between mineral deposition and the development of degenerative joint disease. Several different crystalline structures have been identified in articular cartilage and synovial fluid including monosodium urate, calcium pyrophosphate dihydrate (CPPD), and basic calcium phosphates (BCPs). These distinct mineral phases are associated with specific pathologies and mechanisms of crystal formation such as the development of monosodium urate in gout and CPPD in pseudogout. Less is known regarding the deposition of BCPs, a class of compounds including carbonate-substituted hydroxyapatite (cHA), tricalcium phosphates (TCP), octacalcium phosphate (OCP), and whitlockite, in articular cartilage. The presence of BCP calcification of articular cartilage in humans has been associated with decreased joint function [1, 3], aging [2] and severity of osteoarthritis [1, 3]. Commonly used methods of crystal detection such as polarized light microscopy of synovial fluid and conventional radiography of the joint can be insensitive to the detection of BCP crystals and more sensitive techniques such as microradiography or electron microscopy of articular cartilage sections are required to detect areas of BCP mineralization [3, 5, 6]. It is not yet known how regions of mineralization may influence the tribological properties (friction, wear, and lubrication) of the articulating surfaces and the material and structural properties of articular cartilage. Animal models with which to study the mechanisms of mineralization of articular cartilage are limited.

8C-09 FEMを用いた生体関節軟骨の円筒圧子による物性評価(OS-2(2) 臨床応用を目指した骨・関節力学(2))

8C-09 FEMを用いた生体関節軟骨の円筒圧子による物性評価(OS-2(2) 臨床応用を目指した骨・関節力学(2))

Effects of increased chronic loading on articular cartilage material properties in the Lapine tibio-femoral joint

Methods of producing relevant and quantifiable load alterations in vivo with which to study load-induced cartilage degeneration analogous to osteoarthritis are limited. An animal model was used to investigate the effects of increased chronic loads on articular cartilage. Mature rabbits were randomized into one of three experimentally loaded groups and a fourth unoperated control group. A mechanical-loading device was skeletally fixed to the hind limb of animals in the loaded groups. Engaging the device resulted in an additional load of 0%, +22% or +44% body weight to the medial compartment of the experimental knee, while allowing normal joint function. Following a 12-week loading protocol, a creep-indentation test and needle probe test were used to determine the biphasic material properties and thickness of the cartilage at four locations of each femoral and tibial condyle of the experimental and contralateral limbs. Analyses of covariance were performed to compare outcome measures across the treatment groups. The effect of increased load was site and load-level specific with alterations of material properties and thickness most prominent in the posterior region of the medial compartment of the tibia. At this site, permeability increased 128% and thickness increased 28% in the +44% body weight group relative to the 0% body weight group. This model of altered chronic loading initiated changes in the material properties to the articular cartilage at the sites of increased load over 12-weeks that were consistent with early degenerative changes suggesting that increased tibio-femoral loading may be responsible for the alterations. This work begins to elucidate the chronic-load threshold and the time course of cartilage degeneration at different levels of altered loading.

Use of microindentation to characterize the mechanical properties of articular cartilage: comparison of biphasic material properties across length scales

Small scale mechanical testing techniques offer new possibilities for defining changes in mechanical properties that accompany the morphological, histological, and biochemical abnormalities of osteoarthritis (OA). The goal of this study was to investigate the use of microindentation in characterizing the biphasic material properties of articular cartilage. Direct comparisons of the biphasic properties (E, k and nu) determined using microindentation were made to those determined on the same specimens using standard macroscale testing techniques. Deep-zone bovine articular cartilage specimens (n=10) were tested in macroscale confined and unconfined compression. For microindentation testing, the biphasic properties were determined by conducting finite element simulations of the microindentation experiments for different combinations of values of biphasic properties and identifying the combination yielding the best match to each microindentation curve. Paired t-tests were performed to compare each of E, k and nu between the macro- and microscale. The microscale values for E, k and nu were 0.74 (0.53, 0.95)MPa, 0.66 (0.022, 0.110)x10(-16)m(4)/Ns, and 0.16 (0.08, 0.24), respectively. A significant difference between the macro- and microscale measurements was observed for k (P<0.0001), but not for E or nu (P=0.88, 0.16). The agreement in Young's modulus and Poisson's ratio between the results of the microindentation and macroscale tests supports the use of microindentation for characterization of some of the biphasic material properties of articular cartilage. The observed differences in permeability between macro- and microscales are consistent with evidence in the literature of a length-scale dependence to this property.

Oxygen, nitric oxide and articular cartilage

Molecular oxygen is required for the production of nitric oxide (NO), a pro-inflammatory mediator that is associated with osteoarthritis and rheumatoid arthritis. To date there has been little consideration of the role of oxygen tension in the regulation of nitric oxide production associated with arthritis. Oxygen tension may be particularly relevant to articular cartilage since it is avascular and therefore exists at a reduced oxygen tension. The superficial zone exists at approximately 6% O2, while the deep zone exists at less than 1% O2. Furthermore, oxygen tension can alter matrix synthesis, and the material properties of articular cartilage in vitro. The increase in nitric oxide associated with arthritis can be caused by pro-inflammatory cytokines and mechanical stress. Oxygen tension significantly alters endogenous NO production in articular cartilage, as well as the stimulation of NO in response to both mechanical loading and pro-inflammatory cytokines. Mechanical loading and pro-inflammatory cytokines also increase the production of prostaglandin E2 (PGE2). There is a complex interaction between NO and PGE2, and oxygen tension can alter this interaction. These findings suggest that the relatively low levels of oxygen within the joint may have significant influences on the metabolic activity, and inflammatory response of cartilage as compared to ambient levels. A better understanding of the role of oxygen in the production of inflammatory mediators in response to mechanical loading, or pro-inflammatory cytokines, may aid in the development of strategies for therapeutic intervention in arthritis.

Estimation of the mechanical property of meniscus using ultrasound: Examinations of native meniscus and effects of enzymatic digestion

We previously developed a novel ultrasound assessment system featuring wavelet transform to evaluate the material properties of articular cartilage. We aimed in this study to demonstrate the feasibility of quantitative evaluation of meniscus using ultrasound and to elucidate the relationships between its acoustic, mechanical, and biochemical properties. Meniscal disc specimens from mature pigs were assessed by ultrasound and compression testing, and their correlation was analyzed. A positive correlation was found between the ultrasound signal intensity and apparent Young's modulus (r=0.61). Subsequently, the porcine meniscal discs were treated with various enzymes and then characterized by ultrasound, by compression tests, by biochemical analyses, and by histology and immunohistochemistry. The signal intensity was decreased not by hyaluronidase but by collagenase treatment. Hyaluronidase-treated menisci showed a discrepancy between acoustic and mechanical properties, suggesting that the ultrasound reflection could not detect a reduction in proteoglycan content. Also, ultrasound signal intensity could only reflect superficial layers of the material. Several limitations exist at present, and further studies and improvements of the device are required. However, given the noninvasive nature and the requirement of only small equipment, this ultrasound assessment system will be an instrumental diagnostic tool for meniscal function in both research and clinical fields.

Extraction of Mechanical Properties of Articular Cartilage From Osmotic Swelling Behavior Monitored Using High Frequency Ultrasound

Articular cartilage is a biological weight-bearing tissue covering the bony ends of articulating joints. Negatively charged proteoglycan (PG) in articular cartilage is one of the main factors that govern its compressive mechanical behavior and swelling phenomenon. PG is nonuniformly distributed throughout the depth direction, and its amount or distribution may change in the degenerated articular cartilage such as osteoarthritis. In this paper, we used a 50 MHz ultrasound system to study the depth-dependent strain of articular cartilage under the osmotic loading induced by the decrease of the bathing saline concentration. The swelling-induced strains under the osmotic loading were used to determine the layered material properties of articular cartilage based on a triphasic model of the free-swelling. Fourteen cylindrical cartilage-bone samples prepared from fresh normal bovine patellae were tested in situ in this study. A layered triphasic model was proposed to describe the depth distribution of the swelling strain for the cartilage and to determine its aggregate modulus H(a) at two different layers, within which H(a) was assumed to be linearly dependent on the depth. The results showed that H(a) was 3.0+/-3.2, 7.0+/-7.4, 24.5+/-11.1 MPa at the cartilage surface, layer interface, and deep region, respectively. They are significantly different (p<0.01). The layer interface located at 70%+/-20% of the overall thickness from the uncalcified-calcified cartilage interface. Parametric analysis demonstrated that the depth-dependent distribution of the water fraction had a significant effect on the modeling results but not the fixed charge density. This study showed that high-frequency ultrasound measurement together with triphasic modeling is practical for quantifying the layered mechanical properties of articular cartilage nondestructively and has the potential for providing useful information for the detection of the early signs of osteoarthritis.

Compressive Properties of Mouse Articular Cartilage Determined in a Novel Micro-Indentation Test Method and Biphasic Finite Element Model

The mechanical properties of articular cartilage serve as important measures of tissue function or degeneration, and are known to change significantly with osteoarthritis. Interest in small animal and mouse models of osteoarthritis has increased as studies reveal the importance of genetic background in determining predisposition to osteoarthritis. While indentation testing provides a method of determining cartilage mechanical properties in situ, it has been of limited value in studying mouse joints due to the relatively small size of the joint and thickness of the cartilage layer. In this study, we developed a micro-indentation testing system to determine the compressive and biphasic mechanical properties of cartilage in the small joints of the mouse. A nonlinear optimization program employing a genetic algorithm for parameter estimation, combined with a biphasic finite element model of the micro-indentation test, was developed to obtain the biphasic, compressive material properties of articular cartilage. The creep response and material properties of lateral tibial plateau cartilage were obtained for wild-type mouse knee joints, by the micro-indentation testing and optimization algorithm. The newly developed genetic algorithm was found to be efficient and accurate when used with the finite element simulations for nonlinear optimization to the experimental creep data. The biphasic mechanical properties of mouse cartilage in compression (average values: Young's modulus, 2.0 MPa; Poisson's ratio, 0.20; and hydraulic permeability, 1.1 x 10(-16) m4/N-s) were found to be of similar orders of magnitude as previous findings for other animal cartilages, including human, bovine, rat, and rabbit and demonstrate the utility of the new test methods. This study provides the first available data for biphasic compressive properties in mouse cartilage and suggests a promising method for detecting altered cartilage mechanics in small animal models of osteoarthritis.

Material properties of articular cartilage in the rabbit tibial plateau

The material properties of articular cartilage in the rabbit tibial plateau were determined using biphasic indentation creep tests. Cartilage specimens from matched-pair hind limbs of rabbits approximately 4 months of age and greater than 12 months of age were tested on two locations within each compartment using a custom built materials testing apparatus. A three-way ANOVA was used to determine the effect of leg, compartment, and test location on the material properties (aggregate modulus, permeability, and Poisson's ratio) and thickness of the cartilage for each set of specimens. While no differences were observed in cartilage properties between the left and right legs, differences between compartments were found in each set of specimens. For cartilage from the adolescent group, values for aggregate modulus were 40% less in the medial compartment compared to the lateral compartment, while values for permeability and thickness were greater in the medial compartment compared to the lateral compartment (57% and 30%, respectively). Values for Poisson's ratio were 19% less in the medial compartment compared to the lateral compartment. There was also a strong trend for thickness to differ between test locations. Similar findings were observed for cartilage from the mature group with values for permeability and thickness being greater in the medial compartment compared to the lateral compartment (66% and 34%, respectively). Values for Poisson's ratio were 22% less in the medial compartment compared to the lateral compartment.

Cartilage mechanics in the guinea pig model of osteoarthritis studied with an osmotic loading method

Objective: To determine the material properties of articular cartilage in the Hartley guinea pig model of spontaneous osteoarthritis. Methods: Cartilage-bone samples from the medial femoral condyle and tibial plateau of 12 month-old guinea pig knees were subjected to osmotic loading. Site-matched swelling strains and fixed charge density values were used in a triphasic theoretical model for cartilage swelling to determine the modulus of the cartilage solid matrix. The degree of cartilage degeneration was assessed in adjacent tissue sections using a semi-quantitative histological grading scheme. Results: Decreased values for both moduli and surface zone fixed charge density were associated with increasing grades of cartilage degeneration. Decreases in moduli reflect damage to the collagen matrix, which give rise to greater swelling strains. Conclusion: Histological evidence of cartilage degeneration was associated with impaired cartilage mechanics in the aging Hartley guinea pig.

Osmotic loading to determine the intrinsic material properties of guinea pig knee cartilage

Few methods exist to study cartilage mechanics in small animal joints due to the difficulties associated with handling small tissue samples. In this study, we apply an osmotic loading method to quantify the intrinsic material properties of articular cartilage in small animal joints. Cartilage samples were studied from the femoral condyle and tibial plateau of two-month old guinea pigs. Swelling strains were measured using confocal fluorescence scanning microscopy in samples subjected to osmotic loading. A histochemical staining method was developed and calibrated for quantification of negative fixed charge density in guinea pig cartilage. Site-matched swelling strain data and fixed charge density values were then used with a triphasic theoretical model for cartilage swelling to determine the uniaxial modulus of the cartilage solid matrix. Moduli obtained in this study (7.2 MPa femoral condyle; 10.8 MPa, tibial plateau) compare well with previously reported values for the tensile moduli of human and other animal cartilages determined from uniaxial tension experiments. This study provides the first available data for material properties and fixed charge density in cartilage from the guinea pig knee and suggests a promising method for tracking changes in cartilage mechanics in small animal models of degeneration.

Some highlights in the emergence of modern concepts of osteoarthritis

The present-day concept that osteoarthritis may be amenable to biological modification rather than a hopeless expression of old age or injury has historical roots in the period of 1935 through the early 1970s. One root was the structural and chemical delineation of the connective tissues: discovery of the proteoglycans and multiple molecular species of collagen. Another was the recognition of the ability of mature articular chondrocytes to replicate themselves rather than being terminally differentiated. A third was the elucidation of the engineering physiology of the joint: the role of matrix hydrophilia to the material properties of articular cartilage and biolubrication. Each root has direct relevance to ongoing therapeutic approaches to degenerative joint disease. The early epidemiological studies of Kellgren and Lawrence evolved into new techniques for testing their validity in clinical practice. Along the way there was a rich 2-way interaction between scientists and clinicians in arriving at these ideas. Semin Arthritis Rheum 31:71-107. Copyright © 2001 by W.B. Saunders Company