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P. 382

CHA PTE R

Impact of Mechanobiological Perturbation

in Cartilage Tissue Engineering

,†
,†
,†
Zheng Yang* , Yingnan Wu* , Lu Yin* , Hin Lee Eng* ,†
*NUS Tissue Engineering Program, Life Sciences Institute, National University of Singapore, Singapore
†
Department of Orthopaedic Surgery, National University of Singapore, Singapore

19.1 INTRODUCTION

Articular cartilage at the diarthrodial joints serves a critical mechanical role with a smooth, lubricated surface,
allowing joint articulation that withstands cyclic loading deformation while minimizing wear. Cartilage is a highly
hydrated tissue, with high content of water drawn in by the highly negatively charged sulfated proteoglycans
(PG), embedded within the fibrillar type II collagens (Col II), endowing the cartilage with its high compressive
strength. Despite its simple appearance, articular cartilage exhibits significant heterogeneity, comprising of superficial,
middle (transitional), and deep zones with distinct chondrogenic phenotypes (Fig. 19.1). The density, morphology, and
metabolic activity of the cells, as well as the composition and structural arrangement of the extracellular matrix (ECM)
components, vary greatly across these zones [1, 2]. The superficial zone (constituting the top 10%–15% of total cartilage
thickness) contains flattened chondrocytes with collagen fibrils aligned parallel to the articulating surface. Chondro-
cytes in the superficial zone produce superficial zone protein (SZP, also known as proteoglycan 4 (PRG4) and lubricin),
which acts as a lubricant for efficient gliding motion during joint movement [3]. The middle zone (40%–50% of total
cartilage thickness) contains more rounded chondrocytes, thicker collagen fibrils with random orientation. The deep
zone (30%–40% of total cartilage thickness) is made up of large, spherical chondrocytes in a columnar arrangement,
embedded in a dense extracellular matrix rich in proteoglycans (PGs), with thick collagen fibrils aligned perpendic-
ularly to the articulating surface. While PG concentration increases along the cartilage depth, collagen content (per wet
weight) does not change significantly, but displays depth-dependent increases in collagen hydroxylysine and hydro-
xylysyl pyridinoline cross-links [4]. The presence of other minor collagens isoforms such as type IX and XI and cartilage
oligomeric matrix protein (COMP) play critical roles in the regulation of fibril size, inter fibril cross-linking, and inter-
actions with PGs [5, 6], conferring the characteristic compressive strength and dimensional stability of the articular
cartilage tissue.
The mechanical property and function of the articular cartilage are defined by the ECM composition and organi-
zation. On the other hand, mechanical signals experienced by the tissue chondrocytes play a key role in cartilage
homeostasis and in shaping stem cell chondrogenic differentiation [7]. Understanding how chondrocytes and mesen-
chymal stem cells (MSCs) respond to mechanical signals is a major focus of research that has important implications for
cartilage tissue engineering and regeneration. Mechanical signals can be derived passively from the base properties of
the materials to which cells adhere or actively from extrinsically applied mechanical deformations. Interaction with
ECM molecules through membrane proteins such as integrins and adhesion molecules, perturbation of ion channels,
and cytoskeletal components are believed to play key roles in the complex mechanotransduction mechanisms that
govern how cells sense and transmit mechanical signals. This chapter will summarize our current understanding
of how mechanical cues control chondrocytes and direct MSCs towards the chondrogenic lineage, including (i) the
influence of extracellular substrate mechanics (stiffness and topography) in regulating cell shape/cytoskeleton tension
and (ii) the effects of various extrinsic mechanical signals (e.g., compression, hydrostatic pressure, tension, and fluid

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