Nanocellulose has emerged as a promising biomaterial for cartilage tissue engineering due to its unique structural, mechanical, and biological properties. Derived from plant or bacterial sources, nanocellulose offers high tensile strength, tunable elasticity, and biocompatibility, making it suitable for replicating the extracellular matrix (ECM) of native cartilage. Its fibrous network mimics the collagen-rich environment of cartilage, providing structural support while promoting chondrocyte adhesion and proliferation.

Mechanical properties of nanocellulose can be tailored to match the compressive and shear resistance of natural cartilage, which typically exhibits a compressive modulus ranging from 0.1 to 2 MPa. By adjusting the concentration, crosslinking density, or composite formulation, researchers have achieved nanocellulose scaffolds with moduli within this range. For instance, bacterial nanocellulose (BNC) hydrogels reinforced with polymeric networks or mineral phases demonstrate enhanced load-bearing capacity, critical for weight-bearing articular cartilage applications. The anisotropic mechanical behavior of aligned nanocellulose fibers further allows directional reinforcement, closely resembling the zonal organization of cartilage tissue.

Chondrocyte compatibility is a key advantage of nanocellulose. Studies indicate that chondrocytes cultured on nanocellulose scaffolds maintain their rounded morphology and phenotypic stability, evidenced by sustained expression of collagen type II and aggrecan. Unlike synthetic polymers, nanocellulose does not induce dedifferentiation into fibroblast-like cells, a common challenge in cartilage regeneration. Bacterial nanocellulose, in particular, exhibits high water retention (up to 99%), creating a hydrated microenvironment that supports nutrient diffusion and waste removal, essential for chondrocyte viability.

In bioprinting applications, nanocellulose serves as a bioink component due to its shear-thinning behavior and post-printing stability. When combined with alginate or hyaluronic acid, nanocellulose-based bioinks exhibit improved print fidelity and shape retention, enabling the fabrication of complex, patient-specific cartilage constructs. The high viscosity of nanocellulose suspensions prevents cell sedimentation during printing, ensuring uniform chondrocyte distribution. Post-printing, ionic or photo-crosslinking further enhances the structural integrity of printed constructs without compromising cell viability.

Immune responses to nanocellulose are generally mild, with minimal induction of pro-inflammatory cytokines such as TNF-α or IL-6. Bacterial nanocellulose, owing to its high purity and absence of lignin or hemicellulose, elicits lower immune activation compared to plant-derived variants. However, surface modifications like oxidation or PEGylation can further reduce foreign body reactions. Long-term implantation studies in animal models reveal minimal fibrous encapsulation, suggesting good biocompatibility for in vivo applications.

Degradation profiles of nanocellulose are tunable based on chemical functionalization. Unmodified nanocellulose degrades slowly due to the lack of mammalian enzymes capable of cleaving β-1,4-glycosidic bonds. This slow degradation aligns with the prolonged mechanical support required for cartilage regeneration, typically spanning several months. For accelerated resorption, enzymatic pretreatment or oxidation introduces hydrolyzable bonds, enabling controlled breakdown coinciding with neocartilage formation. Degradation byproducts, primarily glucose oligomers, are non-toxic and metabolically inert, reducing risks of inflammatory cascades.

Comparative studies between bacterial and plant-derived nanocellulose highlight trade-offs in mechanical performance versus degradation rates. Bacterial nanocellulose exhibits higher crystallinity and purity, yielding superior tensile strength, while plant-derived nanocellulose offers more straightforward chemical modification routes. Hybrid approaches, such as blending both types, have been explored to balance these properties.

In preclinical models, nanocellulose scaffolds seeded with chondrocytes or mesenchymal stem cells (MSCs) demonstrate successful integration with host tissue, with histological evidence of glycosaminoglycan (GAG) deposition and collagen type II synthesis. Load-bearing animal studies reveal functional restoration of articular cartilage, with reduced fibrillation and improved surface smoothness compared to untreated defects.

Challenges remain in scaling up production and ensuring consistent quality for clinical translation. Standardization of purification protocols and sterilization methods is critical to avoid batch-to-batch variability. Nevertheless, the versatility, biocompatibility, and biomechanical adaptability of nanocellulose position it as a leading candidate for next-generation cartilage tissue engineering strategies. Future directions include optimizing vascular-free nutrient diffusion in thick constructs and integrating growth factor delivery systems to enhance chondrogenesis.

In summary, nanocellulose-based scaffolds offer a compelling solution for cartilage repair, combining mechanical resilience with biological functionality. Its compatibility with advanced fabrication techniques like bioprinting and its benign immune profile underscore its potential for clinical adoption. Continued refinement of material properties and degradation kinetics will further solidify its role in regenerative medicine.