Multi-Material 3D and 4D Bioprinting of Heterogeneous Constructs for Tissue Engineering.

Additive manufacturing (AM), which is based on the principle of layer-by-layer shaping and stacking of discrete materials, has shown significant benefits in the fabrication of complicated implants for tissue engineering (TE). However, many native tissues exhibit anisotropic heterogeneous constructs with diverse components and functions. Consequently, the replication of complicated biomimetic constructs using conventional AM processes based on a single material is challenging. Multi-material 3D and 4D bioprinting (with time as the fourth dimension) has emerged as a promising solution for constructing multifunctional implants with heterogeneous constructs that can mimic the host microenvironment better than single-material alternatives. Notably, 4D-printed multi-material implants with biomimetic heterogeneous architectures can provide a time-dependent programmable dynamic microenvironment that can promote cell activity and tissue regeneration in response to external stimuli. This paper first presents the typical design strategies of biomimetic heterogeneous constructs in TE applications. Subsequently, the latest processes in the multi-material 3D and 4D bioprinting of heterogeneous tissue constructs are discussed, along with their advantages and challenges. In particular, the potential of multi-material 4D bioprinting of smart multifunctional tissue constructs is highlighted. Furthermore, this review provides insights into how multi-material 3D and 4D bioprinting can facilitate the realization of next-generation TE applications. This article is protected by copyright. All rights reserved.