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

the osseous layer was optimized by incorporating HA into triggered fibrocartilaginous commitment characterized
the GelMA matrix, thereby enhancing the compressive by collagen type I dominance. Pore sizes around 200 μm
modulus for bone formation. promote the maintenance of a spherical cell morphology,
facilitating cell–cell interactions, whereas, larger pore sizes
3.2. Microarchitectural gradient encourage cell attachment, reducing intracellular contact.
Native cartilage exhibits a gradient in microarchitectural Conversely, smaller pores may not provide sufficient
patterning, encompassing variations in geometry, porosity, space for ECM production. It has been reported that
stiffness, and density, which are essential for maintaining spherical-shaped BMSCs correlate with higher expression
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its mechanical properties, as described in Section 3.2. of chondrogenic molecular markers and are more likely to
Meanwhile, the porous structure plays a crucial role in undergo chondrogenic differentiation.
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cell adhesion, metabolism, and proliferation, which are
critical for spatial organization and tissue regeneration in Sun et al. further revealed that pore size modulates
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tissue engineering. Conventional fabrication techniques— BMSCs differentiation by activating the Hypoxia-inducible
such as solvent casting, freeze-drying, electrospinning, factor 1α/Focal Adhesion Kinase (HIF1α/FAK) signaling
and gas foaming—can produce well-structured scaffolds, axis. A layered-mesh structured, BMSCs-laden PCL
yet they lack precise microstructural control. Key factors scaffold was fabricated, in which the superficial small-
include pore size, shape, distribution, and density. In pore zone (SPZ, 150 μm) provides lubrication and shear
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contrast, 3D printing offers a highly adaptable approach resistance, while the deep large-pore zone (LPZ, 750
for designing scaffolds that closely replicate the native μm) enhances elasticity and maintains structural rigidity.
cartilage microarchitecture. The SPZ exhibited high HIF1α expression, promoting
Previous studies have demonstrated that neo-tissue chondrogenesis and maintaining a hyaline cartilage
regeneration predominantly initiates at the defect periphery, phenotype, whereas the LPZ favored osteogenesis and
whereas central regions often exhibit compromised increased vascularization (Figure 3).
regeneration capacity due to reliance on cellular migration 3.3. Biochemical gradient
through the scaffold matrix. Proper microstructures In scaffold-based osteochondral defect repair, biomimetic
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(e.g., pores or channels) provide mechanical support strategies for cell-free scaffolds involve in situ tissue
and guidance for cell migration, while simultaneously regeneration through precise coordination of MSC
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facilitating nutrient transportation and bioactive factor recruitment, differentiation, and maturation. For cell-laden
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release. Gu et al. developed a biomimetic bilayer scaffold scaffolds, directing cells to undergo specific differentiation
using digital light processing (DLP)-based 3D printing. at various layers is equally crucial for successful repair. Thus,
The upper cartilage layer features a “lotus and radial” pore biochemical factors, functioning as chemoattractants, need
distribution that facilitates the transverse migration of to be applied in a spatially distributed manner to regulate
chondrocytes and cartilage progenitor cells at superficial cell behavior and optimize tissue regeneration. 95
layers. The bottom osseous layer exhibits a “lotus” pore
structure, guiding BMSCs to vertically migrate to the Biochemical gradient strategies involve adding growth
defect site, thus creating a native tissue-like cell distribution factors or small molecules to induce cell differentiation.
pattern. In vitro experiments demonstrated a preference These can be incorporated directly into the material for
for cell migration along the delicate “lotus and radial” pore bioprinting or delivered through carriers such as exosomes
structure (Figure 2), resulting in nearly a fourfold increase or nanoparticles. Additionally, decellularized ECM
in cell migration compared to non-porous scaffolds. (dECM) is used to create biochemical gradients.

Microarchitectural features of biomaterials also regulate Growth factors are a large family of cytokines that
cell differentiation. 89,90 Events such as cell–cell interactions, regulate cell migration, adhesion, proliferation, and
adhesion molecule binding, gap junction formation, differentiation. For cartilage, transforming growth factor
and cytoskeletal reorganization, significantly impact (TGF)-β1, IGF-1, fibroblast growth factor-2 (FGF-2),
chondrogenic differentiation. 91,92 Larger pore sizes promote and BMP-2 support maturation and formation, while
the aggregation and proliferation of MSCs, facilitating BMPs, IGF-1/2, TGF-β, and FGFs are primarily involved
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chondrogenic condensation. Li et al. demonstrated that in bone regeneration. These growth factors are spatially
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pore sizes in 3D-printed silica hybrid scaffolds critically distributed and function in a coordinated manner,
regulate human BMSCs (hBMSCs) lineage commitment: working synergistically to promote tissue development
pores of ~100 μm resulted in poor matrix formation, and repair. Ding et al. developed a hydrogel scaffold
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~220 μm promoted hyaline cartilage formation through covalently functionalized with bioactive TGF-β1 binding
predominant collagen type II deposition, while ~500 μm peptides (TBP) to recruit endogenous TGF-β1, thereby
Volume 11 Issue 4 (2025) 9 doi: 10.36922/IJB025120100