Speaker
Description
Tissue engineering (TE) aims to regenerate damaged or diseased tissues by replicating their native structure, composition, and function. This goal is particularly challenging in the context of musculoskeletal tissues—such as articular cartilage, meniscus, ligaments, and tendons—whose unique biomechanical functions are tightly linked to their extracellular matrix (ECM) architecture. Damage to these tissues can accelerate joint degeneration and lead to conditions like osteoarthritis. While traditional TE approaches have attempted to seed stem or progenitor cells into scaffolds or hydrogels to stimulate ECM deposition, these methods often fall short in producing functional tissues with biomimetic collagen architectures, thereby limiting their clinical relevance.
This has led to increasing interest in scaffold-free approaches that rely on the innate ability of cells to self-organize via cell-cell and cell-matrix interactions. These strategies draw inspiration from developmental biology and regenerative processes, where tissues form through the orchestrated fusion and organization of cellular microtissues (μTs) or organoids. Under the right in vitro conditions, stem cells can generate tissue-specific μTs that replicate important structural and functional traits of native tissues. The ultimate goal is to combine these biological building blocks to fabricate large, organized grafts, which requires biofabrication methods that not only preserve cellular phenotype but also guide tissue remodeling and ECM organization.
Developmentally, tissues form within the mechanical and geometrical context of their neighboring structures, which exert compressive, tensile, or shear forces. Such mechanical inputs significantly influence morphogenesis and cell behavior. In vitro, these cues can be mimicked by introducing geometrical constraints and substrate stiffness, which affect cell proliferation, migration, and differentiation. For example, mesenchymal stem cell (MSC) differentiation is strongly regulated by physical confinement and mechanical tension, with stiff substrates encouraging osteogenesis. These mechanical cues offer an additional layer of control over tissue development and can be strategically used to guide the formation of biomimetic tissue constructs.
3D bioprinting has emerged as a powerful tool for spatially organizing cells and biomaterials to recreate the anatomical features of native tissues. Recently, this technology has been adapted for printing cellular aggregates, μTs, and organoids. However, challenges remain, particularly in achieving high-fidelity placement and fusion of microtissues, both of which are crucial for the engineering of large-scale, functional grafts. Moreover, the influence of the bioprinting process on long-term tissue phenotype and structure remains underexplored.
To overcome these limitations, this study employs a 4D bioprinting approach using extrusion-based bioprinting within a methacrylated xanthan gum (XG-MA) support bath with varying stiffness (20-60 kPa). This platform enables high-density microtissue patterning while allowing dynamic control over the bath's physical properties—such as rheology and stiffness—to modulate microenvironmental cues post-printing. By tuning these properties, the platform not only improves print fidelity but also directs microtissue fusion, differentiation, and ECM (re)modeling enabling the biofabrication of highly aligned musculoskeletal tissues, such as articular cartilage, meniscus and ligament. The integration of spatiotemporally controlled mechanical signals into the bioprinting workflow represents a significant advancement toward engineering anatomically scaled, functionally anisotropic musculoskeletal grafts with long-term regenerative potential.
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