4D printing of smart scaffolds for bone regeneration: a systematic review

As a novel emerging technology, four-dimensional (4D) printing allows the stimulation of 3D-printed materials in order to change shape, color, functionality, etc, over time. This systematic review is conducted to evaluate the purpose, materials, physiomechanical, and biological properties of 4D-printed scaffolds used for bone tissue engineering. An electronic search was conducted following the PRISMA 2020 guidelines in PubMed, Scopus, Web of Science, and Google Scholar online databases limited to English articles until April 2024. Studies in which scaffolds were fabricated through 3D printing methods responding to external stimulation were included. The quality ofin vitroandin vivostudies was evaluated through the modified CONSORT checklist and SYRCLE's risk of bias tool. The full text of 57 studies were reviewed, and 15 studies met the inclusion criteria. According to the analyzed studies, most scaffolds responded to temperature changes showing shape memory effect. Polyurethane and poly(lactic acid) were the most common shape memory polymers (SMPs), and the most common fabrication method used was fused deposition modeling. A comprehensive systematic review of the studies from the past 10 years demonstrated several findings: (1) Shape memory, drug delivery, and shape morphing are three general purposes of 4D printing for bone regeneration. (2) Smart materials used for 4D printing mostly consist of SMPs. (3) Temperature changes account for the majority of stimulation used for 4D printing. (4) incorporating 4D printing principles does not negatively impact on the physiomechanical properties of the designed scaffold. (5) The 4D-printed scaffolds show a higher osteogenic differentiation capacity than their identical 3D-printed structures in terms of bone regeneration.