3D bioprinting and scaffold-free strategies for fabrication of multi-cellular tissues or organoids

The biofabrication of multi-cellular tissues or organoids (MTOs) has been challenging in regenerative medicine for decades. Currently, two primary technological approaches are being explored: scaffold-based strategies utilizing three-dimensional (3D) bioprinting techniques and scaffold-free strategies employing bioassembly techniques. 3D bioprinting techniques include jetting-based, extrusion-based, and vat photopolymerization-based methods, and bioassembly techniques include Kenzan, fluid-based manipulation and microfluid, bioprinting-assisted tissue emergence, and aspiration-assisted technology methods. Scaffold-based strategies primarily concentrate on the construction of scaffold structures to provide an extracellular environment, while scaffold-free strategies primarily emphasize the assembly methods of building blocks. Different biofabrication technologies have their advantages and limitations. This review provides an overview of the mechanisms, advantages, and limitations of scaffold-based and scaffold-free strategies in tissue engineering. It also compares the strengths and weaknesses of these two strategies, along with their respective suitability under different conditions. Moreover, the significant challenges in the future development of convergence strategies, specifically the integration of scaffold-based and scaffold-free approaches, are examined in an objective manner. This review concludes that integrating scaffold-based and scaffold-free strategies could overcome the problems in the biofabrication of MTOs. A novel fabrication method, the BioMicroMesh method, is proposed based on the convergence strategy. Concurrently, the development of a desktop-scale integrated intelligent biofabrication device, the BioMicroMesh system, is underway. This system is tailored to the BioMicroMesh method and incorporates cell aggregate spheroids preparation, 3D bioprinting, bioassembly, and multi-organoid co-culture functions, providing an objective perspective on its capabilities.