Adaptive and intelligent scaffolds: Transforming tissue engineering through material and structural innovations

There is an ongoing evolution towards active scaffold technology with dynamic properties that enable interaction between the scaffold and the biological microenvironment. In this mini-review, we present an updated view on recent developments in smart scaffolds. Specifically, we emphasize the significance of integrating responsive and smart materials with innovative designs and biofunctionalization techniques. Recent breakthroughs in developing mechanoactive, electroactive and stimuli-responsive scaffolds that harness various biological stimuli to convert them into proregenerative factors are discussed. These advancements include 3D/4D printing of bio-piezoelectric constructs and the ability to tune stiffness for applications in bone and neural tissue engineering. In addition, recent advancements in scaffold fabrication technologies such as additive manufacturing, melt electrowriting, and coaxial extrusion are emphasized as they provide precise control over the scaffold structure. Biofunctionalization, as another major topic in scaffold research, is considered, particularly regarding spatiotemporal delivery of biochemical cues and interface engineering for regulating angiogenesis, osteogenesis, and immunomodulation. Emerging topics, such as computational design of scaffolds, optimization of multiphasic interface, and vascularization by means of scaffolds, are also addressed. It should be noted, however, that despite impressive recent progress in this area, there are several challenges related to scaling up and establishing clinical relevance of novel technologies. Finally, current knowledge gaps in standardization of in vivo evaluation of smart scaffold performance as well as regulatory hurdles are pointed out.