Top-Down and Bottom-Up Biofabrication of Biomimetic Cartilage Scaffolds for Regenerative Applications

Articular cartilage (AC) is a highly specialized, load-bearing tissue whose extracellular matrix (ECM) composition and zonal organization are essential for its exceptional biomechanical performance. However, due to its avascular and aneural nature, AC possesses very limited intrinsic repair capacity, making functional regeneration a longstanding clinical challenge. Although current biomaterials and scaffold-based strategies can reproduce aspects of gross architecture and mechanical properties, they often fail to replicate the anisotropic collagen type II organization and biochemical complexity required for durable joint function [1].

To address these limitations, we present a biofabrication strategy that combines advanced 3D printing technologies, genetically engineered cells with enhanced cartilage-like ECM production capacity and devitalization methods. Two complementary fabrication approaches were employed: digital light processing (DLP) printing for rapid, high-resolution construct generation, and coaxial extrusion printing to deposit multi-material core–shell filaments integrating structural and bioactive components.

To enhance biochemical fidelity, bioinks were supplemented with devitalized ECM (dECM) derived from CRISPRa-edited adipose-derived stem/stromal cells engineered to upregulate proliferation as well as aggrecan and collagen type II expression, key structural components of cartilage [2]. This strategy provides a scalable and reproducible source of cartilage-specific ECM without exogenous growth factors while maintaining bioactivity through mild devitalization [3].

Poly(ethylenglycol)-diacrylate-Gelatine-Methacryloyl (PEGDA-GelMA)-based bioinks enriched with lyophilized dECM were processed using both printing techniques to generate anisotropic scaffolds replicating the different zones of cartilage, especially in regard to collagen type II organization. Thorough characterization demonstrated high print fidelity, suitable mechanical properties, and improved support for synovial mesenchymal stem/stromal cell (sMSC) viability and function (Figure 1).

By integrating top-down (DLP) and bottom-up (coaxial extrusion printing) fabrication with engineered dECM, this approach advances the development of biomimetic scaffolds that more closely recapitulate the hierarchical organization of native AC, offering a promising translational pathway for functional cartilage regeneration.

[1] doi :10.1039/9781782623663

[2] doi: 10.1016/j.actbio.2024.11.007

[3] doi: 10.1016/j.mtbio.2025.101735