Superficial zone chondrocytes can get compacted under physiological loading: A multiscale finite element analysis

Articular cartilage is a specialized tissue lining diarthrodial joints in the body, where it serves to reduce friction while sustaining contact forces for over 108 million cycles of loading in a 60-year lifespan. As with any mechanical system with moving parts, cartilage must experience some normal ‘wear and tear’ over normal activities of daily living. In some cases, this ‘wear and tear’ may progress to further degradation of the tissue, resulting in osteoarthritis (OA). Yet primary (idiopathic) OA is rare in individuals younger than 45. This counter-intuitive observation suggests that there must exist an intrinsic repair mechanism to compensate for this daily wear and tear in diarthrodial joints, and to maintain normal tissue function over many decades of life.

This routine damage initiates in the superficial zone (SZ) of cartilage tissue [1], [2], [3] where its resident chondrocytes have been shown to die even under normal physiologic loading conditions [4], [5], [6]. As such, it is probable that this expected repair mechanism is a SZ cell replenishment mechanism, most likely from the synovium lining [7], [8], [9]. However, the mechanism by which these SZ cells preferentially die has not yet been explained. The objective of the current study is to better understand mechanical factors that may lead to SZ chondrocyte death, as part of a broader effort to understand the mode of repair of normal ‘wear and tear’.

The SZ is known to exhibit lower compressive [10] and shear moduli [11] compared to the middle and deep zones (MZ, DZ) of the articular layer, likely resulting in excessive SZ compaction under physiological loading. Such compaction may wring out the interstitial fluid of SZ chondrocytes, significantly altering their fluid transport properties and possibly causing their death. Chahine et al. [12] showed that SZ chondrocytes died after sustained 12 h compaction of live cartilage explants by 50–80% strain. Using suitable control experiments they reported that this death was not a result of higher local compressive strains in the soft SZ, but instead the higher vulnerability of SZ chondrocytes to loading than their MZ and DZ counterparts.

Albro et al. [13] showed that chondrocytes can survive a volume loss of 50%, induced by hyperosmotic loading, for a short period of time (up to 1 h, at room temperature). However, lasting changes in cell volume can affect the ability of the cell to regulate its volume via ion channel transport, significantly affecting its homeostasis and viability [14]. A theoretical analysis by Ateshian et al. [15] demonstrated that chondrocytes under compression in situ experience fluid pressure differentials across the semi permeable cell membrane on the order of tens of kilopascals, causing water outflow and resulting in cell volume reduction greater than that of the extracellular matrix (ECM). Tissue compaction, especially of the pericellular matrix (PCM), and reduced cytoplasm permeability as fluid volume is lost, may also decrease diffusivity of glucose, insulin, other nutrients, and waste products between the cell and the synovial fluid, harming cell metabolism and potentially resulting in cell death. Further, SZ chondrocytes have been shown to be metabolically different and less phenotypically mature [16], [17], [18] than MZ and DZ chondrocytes, and may therefore be more sensitive to this loss of nutrients.

The evidence summarized above, though suggestive, is limited by experimental constraints that cannot examine field variables throughout the entire cellular environment. Computational models of the type proposed here provide access to data experiments cannot obtain. A few multiscale models of chondrocytes embedded in tissue have begun to investigate the mechanical role of the ECM and PCM on chondrocyte deformation under compressive loading [19], [20], [21], [22], [23], [24], [25]. As such, in this study we performed a multiscale finite element analysis of articular contact to understand the fate of a SZ chondrocyte, by tracking the temporal evolution of its interstitial fluid pressure, hydraulic permeability, and volume change under physiologic loading conditions. This deeper understanding of the mechanical loading environment of SZ chondrocytes, and the response of the chondrocytes to that load, will provide insight into potential repair mechanisms that maintain tissue viability despite regular loading, and may be used to inform and guide future experiments.

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