Temperature is one of the most commonly used stimuli in 4D printing. Thermo-responsive shape memory implants are designed to transform their shape to their final morphology after implantation at body temperature. Initially, according to the target geometry, the temperature of the scaffold is elevated above the transition temperature (T_trans) for shape programming of the implant. T_trans in semi-crystalline polymers and amorphous polymers is equal to the melting temperature (Tm) or glass transition temperature (Tg), respectively. At T_trans, the scaffold deforms to a temporary shape appropriate for implantation. This temporary shape is fixed by cooling down to a temperature below T_trans which will recover to the permanent shape after implantation by heating above T_trans (Kuang et al., 2019). Therefore, to avoid causing frostbite or scald to the tissues, the challenge is to keep T_trans between 20 and 37°C as this is required for the shape programming temperature range. In a recent study, it has been indicated that synthesized poly(glycerol dodecanoate) acrylate (PGDA) is an appropriate material that can be 4D printed with T_trans 20–37°C. Shape memory vascular stents with mechanical and geometrical adaptability were printed out of PGDA and then photo-crosslinked. Next, they were programmed to a temporary compact shape for delivery above T_trans, and then after deployment by heating above the T_trans, the stored energy was released and the stent recovered the target shape. Interestingly, with the same approach, 4D printed vascular grafts were developed and implanted into a mouse aorta. By ligating the two ends of the vessel, the blood of the target vessel was drained to cool down the section and keep the temperature lower than the body temperature. After implantation and by allowing blood flow inside the graft, the shape of the graft was recovered to the final and permanent morphology. The 4D printed vascular stents and grafts exhibited a high recovery ratio of 98% at 37°C, cycling stability, and rapid recovery time which can open new horizons for the next generation of vascular implants. This is a great advantage compared to the commercially available vascular stents and grafts which have fixed dimensions and mechanical properties (Zhang et al., 2021). 4D printed, curved films (aligned to the heart curvature) with a thickness smaller than 300 µm were also fabricated from soybean oil epoxidized acrylate (SOEA) by a photolithographic-stereolithographic-tandem strategy (PSTS) printing technique. These shape memory films seem appropriate for the application in cardiac tissue engineering increasing cardiomyogenic differentiation of stem cells. The aim of these 4D printed films is to optimize the integration within damaged heart tissue and to minimize the invasiveness of the surgical delivery and subsequent trauma by in situ shape change which can potentially improve patient comfort in the future. The thin films were stimulated to bend or roll by being warmed up at body temperature. In this study, UV crosslinking resulted in generating the internal strength during a photolithography process. The UV exposure attenuated through the thickness of gel production resulting in a crosslink density gradient. Differential swelling and a bending moment occur which initiates self-folding (Miao et al., 2018). In another approach, 4D printed vascular grafts were fabricated from a composite ink prepared by photho-curable resin [aliphatic urethane diacrylate (AUD) and n-butyl acrylate (BA)], semi-crystalline polycaprolactone (PCL) and nanoparticles such as fumed silica (Figure 3). The rheology of the composite ink was tuned by nanoparticles to achieve printability and self-healing (structural restoration and functional recovery) and shape memory behaviors after direct-ink-write (DIW) printing. Due to the self-healing behavior, the 4D printed vascular grafts could heal microcracks and even notched gaps by the entanglement of PCL chains (restoration of the mechanical properties) between urethane chains. By thermal stimulation, shape memory behavior can also help to close large cracks (Figures 3–E). These self-healing properties are especially important after implantation of vascular grafts in which the graft can be damaged or perforated during the operation. In this case, self-healing can prevent constant bleeding and further surgical repair. Moreover, the shape memory-self-healing vascular grafts can eliminate the need for surgical suturing which is a time-consuming approach. In this study, the in vitro monitoring was performed with red colored water (Kuang et al., 2018). In another approach, biodegradable 4D printed vascular stents were fabricated from a photocrosslinkable ink from a star polymer composed of a β-cyclodextrin (βCD) core and 21 PCL arms with an acrylate end group. Interestingly, the 4D printed stents demonstrated appropriate mechanical functions, such as tensile strength, elasticity, and burst pressure comparable to the human great saphenous vein. The stents were also designed to deliver sustained paclitaxel release. The aim of these stents was to be implanted small in size (diameter of 5 mm) to reduce the surgical damage and recover the target shape after deployment upon a thermal stimulus (Zhou et al., 2021).

Light can change the structure of photoresponsive materials by various mechanisms. Common processes are photocrosslinking (photoinduced crosslinking) and photodegradation (or photocleavage) which is a temporal or spatial reduction of the crosslinking by light exposure (Kloxin et al., 2009; Guvendiren and Burdick, 2012). Also, light-induced stereoisomerism, a form of isomerization induced by photoexcitation (Van Oosten et al., 2009), and light-induced hydrophobicity (change of wettability in response to light) (Ter Schiphorst et al., 2016) are of importance. In addition, photothermal effects characterized by photoexcitation of the material resulting in the production of thermal energy can change the structure of materials (Wang et al., 2020).

Light which is controllable by specific pattern and photo exposure energy can interact with photoresponsive polymers (Kuang et al., 2019). Photoresponsive materials convert light energy into mechanical forces in response to a wide range of wavelengths (Wei M. et al., 2017). Near-infrared (NIR) light-sensitive 4D printed cardiac patches have been developed to fabricate scaffolds with a reprogramming capacity. The aim was to adjust them to the curvatures of the heart after myocardial infarction (MI) making them an interesting product for commercialization with appropriate personalized capacities. DLP printing was used to print a photo crosslinkable NIR light-sensitive ink material, composed of polyethylene glycol diacrylate (PEGDA) and graphene nanoplatelets. The 4D printed cardiac patches revealed the capacity for spatiotemporal transformation by photothermal stimulation. In the photothermal process, the NIR light remotely controls the shape changing of the nanocomposite structure in which graphene nanoparticles absorb the heat from NIR and raise the temperature (Wang et al., 2021b). The 4D cardiac patches were also printed from GelMA and a PEGDA-based photocurable bioink by beam-scanning stereolithography (SL) printing technique (Figure 4) and implanted in a mouse model. The aim was to achieve the same heart’s curvature by self-morphing of these patches. In addition, the patches were designed to switch between the wavy and mesh pattern based on the systolic and diastolic cycles (Figures 4–D). This switching was induced by a light-induced internal stress (affecting the physicochemical properties of the hydrogel by photo crosslinking) resulting in a solvent-induced material relaxation (reversible shape transformation by solvent swelling). Human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) indicated a high engraftment onto the patches after 3 weeks (Figures 4–J). In vivo results revealed a firm attachment of the patches to the epicardium and vascular infiltration obtained after 3 weeks of implantation in a chronic MI model in mice (Figure 4) (Cui et al., 2020).

Electric and magnetic fields alter the structure of a material by their initiated thermal effects. Materials sensitive to the electric field are usually polyelectrolyte hydrogels that react by swelling, shrinking, erosion, or bending upon the electric stimulus. Doping hydrogels with conductive polymers such as polypyrrole and polythiophene is another approach to obtain hydrogels responsive to the electric field. Carbon-based nanoparticles such as carbon nanotubes and graphenes are alternative options to make materials electro-sensitive (Ashammakhi et al., 2018).

Magnetic field responsive materials are containing ferromagnetic or paramagnetic micro or nanoparticles. Due to the high surface-to-volume ratio, nanoparticles display different properties than bulk materials (Patade et al., 2020). Self-heating is one of the properties that magnetic nanoparticles exhibit based on their particle size. This property is due to loss of hysteresis and magnetic relaxation (Kobayashi et al., 2010; Nakamura et al., 2012). According to the Néel-Brown model, the applied magnetic energy is converted into heat, also called self-heating, which allows the adaptation of the used material (Wang et al., 2021a). This approach has been used for the construction of biodegradable patient-specific left atrial appendage occluders (LAAO). The LAAOs were 4D printed from PLA and a Fe₃O₄ magnetic nanocomposite. The usage of magnetic nanoparticles enabled the self-heating remote controllable 4D transformation. The 4D printed LAAOs were programmed to exhibit a straight shape with a small cross-section area to temporarily facilitate the implantation. Two types of LAAOs, single-layer and double-layer, were developed based on a bio-inspired hex88 network pattern with the closest stress-strain response to LAA. Interestingly, the transformation time of double-layered LAAOs was shorter than single-layered LAAOs. This might be due to the higher concentration of magnetic nanoparticles and the lower degree of freedom in the double-layered LAAOs. In this study, the magnetism-induced recovery in a magnetic field took a longer time compared with heat-induced transformation in a hot water bath. This can be explained by the fact that nanoparticles as self-heaters can only transfer the heat within the LAAO structure, while in heat-inducing transformation the whole LAAO was immersed in the liquid and therefore the heat transfer was faster. The most important advantage of these smart LAAOs, compare to commercial nitinol-based occlusion implants, is the biodegradability which together with the potential for being customized and adapted to the patient’s tissue deformation minimizes undesirable complications such as corrosion and allergy (Lin et al., 2021). Self-expandable biodegradable vascular stents were also 4D printed from a UV-crosslinkable ink composed of PLA and Fe₃O₄ magnetic nanoparticles. These personalized stents were fabricated by DIW printing at 80°C (above Tg) and are able to re-expand the blood vessels with minimum invasiveness (Wei H. et al., 2017).

Transformation of moisture responsive materials can be stimulated by water. Poly(ethylene glycol) (PEG) and hydrogels are the most common moisture responsive materials suitable for 4D printing. For example, a humidity responsive and thermo-responsive nanocomposite was developed from PCL, PEG, and cellulose nanocrystals (CNCs) nanofillers. Immersion of this nanocomposite strip inside water at 37°C caused shape recovery by swelling and water absorption (Liu et al., 2015). It is necessary to control the swelling of these materials in the transition process to keep the optimal integrity of the 4D printed scaffold (Amukarimi and Mozafari, 2021).

Since pH is adjustable and considered a significant parameter in different parts of the human environment, pH responsive polymers and hydrogels are applicable for 4D printing. The pH responsive polymers are classified into two groups, the ones with acidic or basic groups (Amukarimi and Mozafari, 2021). PH sensitive materials adapt to pH variations by swelling and de-swelling based on the chemical groups of the polymer such as amine and carboxylic acid, which release or absorb protons (Morouço et al., 2020).

Ions are the common stimulus to change the swelling ratio of hydrogels. Hydrogel networks can directly interact with ions or are affected by osmotic pressure gradients due to ion concentration imbalance (Imrie and Jin, 2022). Biodegradable hollow tubes applicable as vascular grafts were 4D printed from methacrylated alginate and hyaluronic acid hydrogels. The reversible shape transformation was programmed by sensitivity to Ca²⁺ ions due to the presence of carboxylic groups in the chains of the polymeric matrix. By this approach, it was possible to create blood vessels with a small diameter of 20 µm which is unique to this technique. Another capacity of this fabrication approach is its ability to keep the shear forces in the lower range for the fabrication of small diameters (Kirillova et al., 2017).