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

such as MEW, 45,163 enhance the structural stability during Cell-laden scaffolds can demonstrate dual angiogenic
both the processing and implantation stages. 145 modulation through both direct angiogenic differentiation
and paracrine signaling mechanisms. Qin et al.
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5.2. Cell-free versus cell-laden strategies established a pre-vascularized scaffold by encapsulating
Over the past decade, notable progress has been achieved human umbilical vein endothelial cells (HUVECs)
in cell-free scaffold-mediated in situ osteochondral within Li-Mg-Si (LMS) ceramic-incorporated GelMA
regeneration. However, critical unresolved challenges scaffolds. This design significantly enhanced angiogenic
persist, including: (1) structural incompatibility functionality, evidenced by robust neovascularization
between scaffolds and defect topography, (2) inadequate through both HUVEC-derived capillary network
recruitment of endogenous host cells, and (3) suboptimal formation and amplified VEGF secretion. Notably, the
remodeling of neo-formed tissues. The limited diffusion endothelial paracrine profile concurrently stimulated
164
capacity of oxygen and nutrients within conventional neurogenic precursor proliferation and bone marrow
scaffolds, compounded by progressive peripheral stromal cell osteogenic differentiation, thereby establishing
mineralization, establishes a diffusion barrier that restricts a multifunctional regenerative microenvironment.
cellular infiltration to superficial regions. This results
165
in preferential survival of cells localized near the scaffold Cellular regulation of angiogenesis demonstrates zonal
63
surface, while deeper regions remain sparsely populated. specificity in osteochondral regeneration. Zhang et al.
Bioprinting with cell-laden materials offers a promising engineered an anisotropic bilayer scaffold by spatially
alternative by enabling precise spatial deposition of pre- embedding ACPCs in chondral layers and BMSCs in
seeded cells within scaffolds. However, a fundamental osseous layers. During regeneration, ACPCs maintained
limitation persists in maintaining the long-term viability avascularity through paracrine secretion of anti-
and functional persistence of encapsulated cells, angiogenic factors (e.g., endostatin, chondromodulin-1)
particularly under sustained physiological stresses. 166 and transcriptional downregulation of pro-angiogenic
factors (e.g., VEGF, EGF). Meanwhile, osteogenic-phase
Ongoing research should focus on biomaterial BMSCs promoted vascular invasion via sustained release of
optimization to achieve biomimetic cell alignment, density, angiogenic signals (e.g., ANGPT1, VEGFA, endomucin),
and ECM patterns to better resemble native tissue. which stimulated endothelial cell proliferation, chemotaxis,
and lumenogenesis through ERK1/2-MMP9 pathway
5.3. Vasculature in osteochondral regeneration activation. Similarly, Liang et al. engineered GelMA-
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During in vivo osteochondral regeneration, angiogenesis alginate core-shell microcapsules for dual encapsulation
serves as a prerequisite for osteogenesis, as neo- of human dental pulp stem cells (hDPSCs) and HUVECs.
vasculature provides indispensable metabolic support for Compared to monoculture groups containing either
bone-forming cells. Inadequate vascularization results hDPSCs or HUVECs alone, co-cultured groups exhibited
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in hypoxic microenvironments and cellular necrosis. elevated proliferation rates. Notably, 3D capillary-like
Oxygen diffusion constraints restrict metabolically active networks formed in all hDPSC-containing co-culture
osteoblasts/osteocytes to within 100–200 μm of functional microcapsules, regardless of cell ratio, with significant
capillaries to sustain viability and biosynthetic activity. increases vasculogenesis markers after 14 days of culture
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Cartilage, however, must preserve avascularity to avoid (e.g., percentage vascular area, branch length, branch
pathological ossification and complications, necessitating number, and junction points). In contrast, hDPSC-
precise spatial regulation of vascularization in scaffold- deficient groups showed no vasculogenesis at day 14,
based osteochondral regeneration. Current approaches demonstrating the essential role of intercellular interactions
focus on dual-pathway control: pro-angiogenic growth during vascularization. Given the persistent challenge of
factors such as VEGF and bFGF 169,170 are selectively vascularizing osteochondral interfaces, scaffolds designed
incorporated into subchondral regions to stimulate with a cell heterogeneity strategy offer a promising way to
vascular infiltration, while anti-angiogenic compounds address this critical limitation in tissue engineering.
(e.g., suramin and bevacizumab) 171,172 are embedded
within cartilaginous zones to inhibit ectopic vessel 5.4. Inflammatory microenvironment in vivo
formation. Besides this biochemical strategy, a physical Osteochondral defects are often accompanied by
barrier—typically a semipermeable membrane engineered inflammatory alterations in the local microenvironment.
to block endothelial cell migration while permitting The persistent presence of an inflammatory environment
metabolic exchange—is interposed between osteochondral is a major obstacle to cartilage repair, as it may limit the
layers to anatomically restrict vascular encroachment into recruitment of endogenous cells to the site, ultimately
cartilage layers. 167 leading to the failure of in situ cartilage regeneration.
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Volume 11 Issue 4 (2025) 20 doi: 10.36922/IJB025120100