Mechanobiology-based strategies for the maturation of biofabricated cartilage constructs

Recent advancements in 3D bioprinting and biofabrication offer promising avenues for tissue engineering (TE) and regenerative medicine (RM), particularly in addressing musculoskeletal conditions such as articular cartilage lesions. Despite significant progress in generating bioartificial tissue substitutes ex vivo, achieving functional tissues with accurate histological structure and physiological function remains a considerable challenge. This is largely due to the absence of crucial physiological stimuli in vitro that normally govern cell characteristics and functionality in native tissues. Therefore, the application of biochemical, physical, and mechanical stimuli that accurately mimic the in vivo environment is essential for the maturation of 3D constructs into functional tissues. This review explores the latest developments in mechanobiology-based strategies, biomaterials, and bioreactor systems that are designed to produce functional cartilage tissue. We delve into various types of stimuli, including mechanical (e.g., compression, tension, shear, and hydrostatic pressure), biochemical (e.g., growth factors and nanoparticles), and electrical stimulation, and their profound influence on cell differentiation and extracellular matrix (ECM) synthesis. This article highlights the critical role of advanced biomaterials-such as thermoplastics and hydrogels (natural and synthetic, including collagen, gelatin, alginate, and nanocellulose)-in providing structural support and mimicking native tissue properties. Furthermore, we discuss the indispensable role of computational simulation methods, such as the finite element method (FEM), artificial neural networks (ANN), and molecular dynamics (MD), in predicting scaffold behavior, optimizing designs, and understanding complex biological interactions within engineered cartilage. Finally, the review examines the current bioreactor technologies, emphasizing the need for automated systems that are capable of precisely replicating the intricate anatomical configuration and physiological load distribution of human joints, as exemplified by innovative approaches such as the BMAP® Knee bioreactor, to accelerate the translation of engineered tissues from laboratory to clinic. This comprehensive overview aims to serve as a valuable resource for researchers navigating the multidisciplinary challenges and opportunities in cartilage tissue engineering and regenerative medicine.