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International Journal of Bioprinting 3D-printed scaffolds for osteochondral defect

phosphatase (ALP), a key enzyme in mineralization, is specialized biomechanical functions that correlate with the
selectively enriched in these zones, underscoring their role compositional gradients and microstructural organizations
in cartilage maintenance and mineralization. 23 described in Section 2.1. The SZ, characterized by the

In the CCZ, osteogenesis factors like COL10A1, ALP, lowest compressive modulus, maintains joint flexibility
and Runx2 are most highly expressed. Runx2, a key through its unique architecture: fine fibers of collagen
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osteogenic transcription factor, drives the transition of types II/IX aligned parallel to the articular surface,
hypertrophic chondrocytes into osteoblast-like cells, coupled with densely packed, flattened disc-shaped
2
facilitating ossification. Vascular endothelial growth factor chondrocytes arranged horizontally, collectively create
(VEGF), a critical angiogenic factor, ensures vascular a low-friction interface that minimizes shear stress. The
invasion, necessary for bone formation. These gradients MZ exhibits transitional viscoelastic properties, enabled
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promote the mineralization and ossification of the cartilage by its randomly oriented thicker collagen bundles forming
matrix, thereby bridging cartilage and bone. a porous scaffold, where sparsely distributed spherical
chondrocytes facilitate stress redistribution and energy
In the SCB, factors like osteocalcin, osteopontin dissipation. The DZ achieves maximal compressive
(OPN), Receptor Activator for Nuclear Factor-κ B Ligand resistance through perpendicularly aligned hypertrophic
(RANKL), and matrix metalloproteinases (MMPs) are collagen fibrils relative to the articular surface,
concentrated, reflecting bone mineralization, remodeling, accompanied by spherical chondrocytes organized into
and resorption. 26,27 Osteocalcin and OPN are involved in columnar arrays parallel to the collagen orientation. The
bone matrix formation, while RANKL regulates osteoclast CCZ demonstrates ultimate stiffness through mineralized
differentiation for bone resorption. MMPs, key for collagen networks, firmly anchoring the cartilage to the
ECM turnover, are highly expressed in the SCB, where 6
active bone remodeling occurs. 28,29 The distribution of SCB while preventing mechanical delamination. This
osteochondral substances is listed in Table 1. hierarchical mechanical stratification, evolutionarily
conserved across mammalian articular cartilage systems,
2.3. Mechanical gradient enables efficient stress transmission through depth-specific
The mechanical properties of cartilage layers exhibit a structural adaptations, ensuring optimal joint functionality
depth-dependent pattern, with each stratum fulfilling and biomechanical stability.
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Table 1. Gradient distribution of biochemical factors in articular cartilage

Substance Function Distribution
Aggrecan Enhances cartilage strength and elasticity High in SZ; low in DZ
COL2A1 Provides cartilage structural integrity High in SZ; decreases toward CCZ
SOX9 Maintains chondrocyte phenotype Predominantly active in SZ; reduced in deeper layers
TGF-β Regulates cell proliferation and ECM synthesis High in MZ; lower in deeper layers
BMP2 Promotes chondrocyte-to-osteoblast differentiation Low in SZ and MZ; high in DZ and CCZ
COL10A1 Marker of cartilage mineralization Present in DZ; high in CCZ
ALP Promotes mineralization High in DZ and CCZ
VEGF Promotes angiogenesis High in DZ; present in CCZ
Runx2 Promotes cartilage-to-bone conversion Highest in CCZ
Osteocalcin Involved in bone mineralization Present in SCB; high in CCZ
OPN Involved in bone mineralization and cell adhesion High in SCB
RANKL Stimulates osteoclast differentiation High in SCB
MMPs Degrades ECM components; aids in tissue remodeling High in SCB
Abbreviations: ALP, alkaline phosphatase; BMP2, bone morphogenetic protein-2; COL2A1, collagen type II alpha-1 chain; COL10A1, collagen type
X alpha-1 chain; CCZ, calcified cartilage zone; DZ, deep zone; ECM, extracellular matrix; MMPs, matrix metalloproteinases; MZ, middle zone; OPN,
osteopontin; RANKL, receptor activator of nuclear factor-κB ligand; SCB, subchondral bone; SZ, superficial zone; TGF-β, transforming growth factor β;
VEGF, vascular endothelial growth factor.

Volume 11 Issue 4 (2025) 6 doi: 10.36922/IJB025120100