A review of graded scaffolds made by additive manufacturing for tissue engineering: design, fabrication and properties

Abstract The emergence of tissue engineering (TE) has provided new vital means for human body tissue/organ repair. TE scaffolds can provide temporary structural support for cell attachment, growth, and proliferation, until the body restores the mechanical and biological properties of the host tissues. Since native tissues are inhomogeneous and in many situations are graded structures for performing their unique functions, graded scaffolds have become increasingly attractive for regenerating particular types of tissues, which aim to offer a more accurate replication of native interactions and functions. Importantly, the advances introduced by additive manufacturing (AM) have now enabled more design freedom and are capable of tailoring both structural and compositional gradients within a single scaffold. In this context, graded TE scaffolds fabricated by AM technologies have been attracting increasing attention. In this review, we start with an introduction of common graded structures in the human body and analyse the advantages and strengths of AM-formed graded scaffolds. Various AM technologies that can be leveraged to produce graded scaffolds are then reviewed based on non-cellular 3D printing and cell-laden 3D bioprinting. The comparisons among various AM technologies for fabricating graded scaffolds are presented. Subsequently, we propose several types of gradients, structural, material, biomolecular and multi-gradients for scaffolds, and highlight the design methods, resulting mechanical properties and biological responses. Finally, current status, challenges and perspectives for AM in developing graded scaffolds are exhibited and discussed.