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International Journal of Bioprinting                              Review of 4D-printed smart medical implants



                                                               that underwent 4D cyclic mechanical loading proved
                          References                           to have an influence on fibroblast-to-myofibroblast
                                                               transdifferentiation
                                                                                 . Moreover, Douillet et al. presented
                                                                              [120]
                                                               a novel model via laser-assisted bioprinting (LAB) to make
                                 [122]
                                           [124]
                                      [109]
                                    [121]
                                              [126]
                            [90]
                                                               a replication of fibroblast dynamic remodeling in vitro [121] .
                                                               This method can be utilized to understand better cellular
                                                               behaviors and interactions with the extracellular matrix
                          Possible applications  Cartilage-like tissue  Cartilage-like tissue  Soft tissue engineering  Mimicking microvessels  Scaffolds for tissue engineering  Culture substrates  (ECM). Except for these studies that affect cells through
                                                               the regulation of internal networks, some researchers use
                                                               cell-laden 4D bioprinting to form cartilage-like tissue
                                                                                                         [90,122]
                                                                                    , which are quite meaningful to
                                                               and vascularized tissue
                                                                                 [123]
                                                               tissue/organ regeneration applications.
                                                                  The cell-seeding scaffolds refer to culturing cells on
                                    Stress-release contraction  printed scaffolds directly. Dynamic platforms or scaffolds
                                                               are prepared via 4D printing of biomaterials (Figure 6A
                                                               and B), and it is demonstrated that their time-dependent
                                                                                                   and regulates
                                                               deformation influences cell morphology
                                                                                               [124]
                                                                                                         ,  and
                                                               cell  behaviors,  including  adhesion,  proliferation
                                                                                                      [125]
                          Stimuli  Solvent  Solvent  Solvent  Temperature  Temperature  differentiation in spatiotemporal control [126] , and further
                                                                                 [127]
                                                               controls cell functions
                                                                                   . Cui et al. encapsulated human
                                                               umbilical vein endothelial cells (HUVECs) in self-folded
                                                               microtubes that deformed by swelling difference of two
                                                               layers to mimic microvessels, which resembled the ECM
                          Fabrication methods  Extrusion-based printing  Laser-assisted bioprinting  Inkjet printing  FDM, extrusion-based   printing, stereolithography  in body tissues and promoted cell adhesion, spreading,
                                                               and proliferation
                                                                               . They also predicted the application
                                                                             [109]
                                                               prospects of engineering tissues in this structure, as shown
                                                               in Figure 6C. These values offer instructive guidance for
                                            FDM
                             DIW
                                                               creating cell culture platforms and scaffolds resembling
                                                               native ECM functions.
                             Human mesenchymal stromal   Human umbilical vein   endothelial cells (HUVECs)  Neural stem cells (NSCs)  5.3. Tissue engineering
                                                               5.3.1. Bone scaffolds
                                                               4D printing has been widely applied to bone defects.
                                                               The 4D-printed bone scaffolds allow minimally invasive
                                                                                                           [23]
                                                               Mechanical properties, porosity, degradation rate, and
                          Cell  cells (hMSCs)  hMSCs  Fibroblasts  hMSCs  implantation and fit irregular bone defects perfectly .
                                                               biocompatibility of bioscaffolds are of great importance to
                                                               implantation in vivo for bone tissue engineering. Thermo-
                             Oxidized and methacrylate
                                                               responsive  SMP  composites  are  mostly  used  to  fabricate
                                                               bone scaffolds
                                                                                . For instance, Zhang et al. presented
                                                                          [116,128,129]
                      Table 1. 4D printing cellular scaffolds.  Ink compositions  Cell-laden scaffolds  alginate (OMA)  Hyaluronan, alginate  Collagen  Gel-MA, Gel-COOH-MA Cell-seeding scaffolds  Polyurethane  SMP  filaments via FDM printer with shape memory effect of
                                                               bone tissue-like structures printed by PLA/Fe O  composite
                                                                                                  3
                                                                                                    4
                                                                                                             .
                                                               both heat- and magnetic-induced actuation (Figure 7A)
                                                                                                          [116]
                                                               In addition, various bioactive substances have been
                                                               introduced to SMP scaffolds to enhance osteogenic
                                                                                                     ,  bioactive
                                                               activities,  such  as  hydroxyapatite  (HA)
                                                                                                [130,131]
                                                               glasses
                                                                       , and others. Furthermore, remote regulation of
                                                                    [132]
                                                               stem cell fate can be realized by 4D programming in bone
                                                               repair. You et al. utilized 4D printing technique to fabricate
                          Category
                                                               a multi-responsive bilayer morphing membrane consisting
                                                               implanted in the bone defect, the membrane can morph due
            Volume 9 Issue 5 (2023)                        324  of an SMP layer and a hydrogel layer (Figure 7B) [108] . Once
                                                                                       https://doi.org/10.18063/ijb.764
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