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Pharmacology & Pharmacy
4D printing (4DP) is an evolution of 3DP where additive manufacturing printing techniques are employed. In other words, adapting 3DP processes for 4DP of shape memory polymers (SMPs) or smart materials requires minor adjustments. In order to produce the desired shape-changing materials as per estimation or for optimal application, an air circulation system may be incorporated into 3DP’s traditional fused deposition method (FDM) technology. This would cool the SMP below its Tg and, after these small alterations, previous 3DP methods such as stereolithography apparatus (SLA), digital laser writing and inkjet printing can also be employed.
- shape memory polymer
- 4D printing
- medical devices
- additive manufacturing
1. Additive Manufacturing (AM)
The process of layer-by-layer printing of a computer-aided design (CAD) model is known as AM [45]. This process involves significantly less mechanistic involvement and yields higher levels of precision. Frequently, additive manufacturing is juxtaposed with computer numerical control (CNC) machining, which is a material removal method, otherwise known as a subtractive manufacturing process. Therefore, the subtractive approach generates a significant amount of waste materials. On the contrary, AM is more design-flexible, cost-effective and environmentally benign. The fabrication method of 4DP is identical to that of 3DP using CAD software, employing the initial step of AM to create a CAD design of the desired object [46]. The file is then saved using the standard tessellation language file extension (STL file). Before the object is produced, stages such as proper settings, landscape, portrait printing, cartridge filling and thickness selection must be completed. The following sections depict the various layering techniques.
1.1. Digital Light Processing (DLP)
Digital light processing (DLP) is based on the technique of vat polymerization [47]. In this procedure, a vat of liquid resin is polymerized or cured under a light source [48]. Under UV light provided by a light curing unit (LCU) or laser source, the drop of resin is cured. The laser then converts the liquid into a solid substance, layer by layer, forming the product.
1.2. Direct Ink Writing (DIW)
The process of regulating the orientation of an anisotropic filler inside a polymer matrix is required for direct ink writing. Because of this, tension is generated, which is then successively modulated via ink writing for each pixel. In the biomedical area, DIW printers have been used to print high-strength biodegradable scaffolds and for tissue engineering. Printing extremely flexible and self-healing shape memory elastomers were accomplished through the use of a UV-assisted DIW technique. Because of the self-healing capabilities of these elastomers, they could be potentially employed as components in biomedical repair systems.
1.3. Digital Laser Writing (DLW)
DLW is employed to create samples with dimensions beyond a few microns and at the submicron range. This approach is appropriate for manufacturing at the microscopic level and enables the 3DP of complex and intricate shapes with accurate dimensions at the scale of micrometers to nanometers [49]. The DLW polymerization method is designed on the basis of the polymerization threshold model, where resins are transparent to the near-infrared spectrum and the spontaneous absorption of two or more photons results in the formation of the desired materials. Self-healing shape memory polymers that are extremely extensible have been printed using the UV-assisted DLW process. Moreover, biodegradable scaffolds with great strength have been created using this method. The technique has wide applications in tissue engineering [50].
1.4. Direct and Binder 3DP
Both direct 3DP and binder 3DP utilize the same inkjet printing technology. In direct 3DP, polymer and wax are utilized in place of ink and the liquid material is released through the up-and-down movement of the nozzle. These liquid polymers and waxes quickly solidify and form a layer of solid material. Rapid prototyping and multi-jet modelling are also advantages of this type of additive manufacturing (MJM) [51]
In binder-based 3DP, the printer extrudes two distinct substances, a fine powder and a liquid binder [52]. Each layer is composed of a combination of these two distinct substances. Consequently, one of the primary benefits of binder 3DP is that different materials can be selected throughout the manufacturing of the same product design. Furthermore, thick and porous graphene-based devices were created in research using direct and binder 3DP technologies. The device was capable of retaining 80% of its capability [53].
1.5. Selective Laser Sintering (SLS)
SLS requires the melting and sintering of plastics and metals [54]. In this process, the raw material is first heated with a laser to a temperature just below its melting point so that it could be melted, and then the molten substance is solidified [55]. In case of metal, however, melting can be used instead of sintering to produce the end product owing to the possibility of minimal porosity and voids during melting. Generally, it is used to print hearing aid implants, thus successfully establishing its application in printing medical devices.
1.6. Stereolithography Apparatus (SLA)
SLA is based on the vat photopolymerization strategy which uses a laser beam and a vat of liquid plastic photopolymers [56]. By using a laser beam, a layer of photopolymer is hardened and then, to create the final result, a layer-by-layer process is conducted. The basic components of SLA include a tank of liquid photopolymer resin or plastic, a high-powered UV laser, a platform and a computer interface for controlling the thickness and movement of the interface and laser. The SLA 3DP technique can be divided into several steps: (1) A CAD. stl file, which must be prepared for the component design, then this stl [unit] file is imported into slicer software, which will convert it into G-code for the machine’s required movement instructions; (2) When the procedure starts, the laser strikes the photosensitive resin, solidifying the liquid. Here, a computer-controlled mirror directs the laser to the specified coordinates; (3) After all of the layers have been applied, the model is removed from the platform and cured in a UV oven. This post-print curing helps the objects to achieve maximum strength and become more stable [57].
One of the key features of SLA is its capacity to generate high-resolution objects of varying sizes; objects ranging in size from submicron to decimeters can be made by using this technique. While the majority of AM (Additive manufacturing) methods are capable of producing structural features on the scale of 50–200 microns [58], the precision of SLA-printed SMPs is between 0.1 mm–1 μm [59].
1.7. Fused Filament Fabrication (FFF)
FFF is also known as fusion deposition modelling or melt material extrusion (MME). It is the most affordable and widely accessible 3DP and 4DP technology [60]. Here, a spool of filament is inserted into the 3D printer and feed is supplied through an extrusion head nozzle in the material extrusion equipment. Then by using a pump, the filament goes to the heated nozzle where the desired temperature of the nozzle melts the filament. The extrusion head moves in predetermined directions, releasing molten material onto the surface to solidify. After finishing the first layer, the printer adds a second layer. This procedure of printing cross-sections is continued, layer-by-layer, until the entire object has been produced. This method is the most common because of its scalability and it is used to make a variety of 4DP products, such as bone samples for material behaviour testing in polymer laboratories, robot grippers, etc. [61]. FDM is an intriguing manufacturing method in the domain of tissue engineering due to its capacity to create porous polymer scaffolds [42].
2. 4DP Stimuli
In 4DP, the final product generated after the manufacturing changes its size, shape, color, etc., when stimulated or coming in contact with external media called stimuli. As a result, stimuli are required to initiate the transition in time, which is the fourth dimension of 4DP. The stimuli may therefore be water, heat, light, electrical currents, etc. The fourth dimension is the parameter that changes over time, such as size, shape, color, property, function, etc. The following are some examples of commonly used stimuli [59]
2.1. Water or Solvent
It has been established that water, moisture, or liquid are crucial stimuli for accomplishing smart transformation. Temporally or spatially, liquid-responsive materials undergo a transformation in the form of surface expansion. Water-responsive hydrogel film transforms its shape, because of which it has varied applications. It has been reported that poly- (ethylene glycol) diacrylate hydrogel films exhibit reversible bending when exposed to moisture [31]. Similarly, multiple-layered poly-glycerol sebacate strips exhibited a similar reversible deformation when exposed to organic solvent vapor [32]. Using a polyethene glycol-based hydrogel, self-folding cylindrical scaffolds for cell encapsulation were made [62]. However, the liquid-responsive hydrogel has a delayed response time, a short life cycle and lower mechanical qualities as a result of expansion, swelling and potential degradation/hydrolysis owing to prolonged interaction with water. To address this, the swelling of the hydrogels must be designed to account for anisotropy. A group of researchers blended cellulose fibrils with hydrogen ink, which aligned primarily because of the generation of shear forces caused by the interaction of the print bed and hydrogen ink [63]. This alignment resulted in transverse swelling becoming four times that of the longitudinal swelling, enabling the programming of the 4D-printed structure [64]. In biomedical applications, liquid-responsive materials are primarily employed for cell encapsulation, controlled drug delivery, and reversible activation of smart valves.
2.2. Temperature
Shape-memory polymers alter their shape when subjected to a dynamic mechanical force at a higher temperature. When such materials are subjected to a changing load, heated above the Tg and cooled, they deform into a transitory metastable shape. Additionally, when adequate transformation energy is employed during the application, the temporary shape deforms and then returns to the desired shape [41]. Consequently, such desirable viscoelastic and recovery properties of polymer have applications in bio-printed parts, such as self-conforming replacements for minor bone defect implants. These temperature-responsive bio-implant materials have been developed by a number of researchers, with approximately 98% form restoration [50]. For 4D printed bio-structure, when temperature stimuli are applied to a shape-changing material, the material’s shape and size change, and when the stimuli are removed the material returns to its initial shape [65,66].
In general, the biomedical efficacy of thermo-responsive polymeric materials is governed by their thermal characteristics, such as their Tg. In most cases, the components are pre-formed at a temperature that is higher than the Tg, which will cause the printed components to contract and become denser. These components are then cooled below their Tg to keep them small and compact for minimally invasive surgical procedures. When implanted into a body with a temperature greater than the Tg, these printed components regain their original, ideal form [67,68,69]. However, this approach is only applicable to substances whose Tg is below or equal to body temperature. Alteration or fabrication of biocompatible materials with a lower Tg or multi-responsiveness, where the material simultaneously responds to many stimuli, is required to broaden the base of such materials [70].
2.3. Light
Light irradiation, curing and polymerization generated diverse shape and size transitions in polymeric substances [38]. Using the FDM printing technique, polyurethane-based material was manufactured and it was discovered that the size of the plate returned to its original cubic structure when illuminated with 87 mW/cm2 of light [71]. Light has also been utilized to achieve selective drug release from the capsule, for instance, capsule printing in a core-shell configuration, with an aqueous core loaded with the desired drug and the poly(lactic-co-glycolic) acid shell encapsulating plasmonic gold nanorods. By irradiating these capsules with a laser of a specified wavelength corresponding to the nanorods’ resonance wavelength, the capsule may be ruptured. Such rupturing might result in the sequential release of selected drugs, which is particularly significant for cancer therapy and the treatment of multiple-drug resistance [72].
The application of light as a stimulus has created a new opportunity for the development of bio-responsive medical equipment. However, more study is needed to address concerns regarding the possible toxicity of photo-activated materials, the production of heat during photothermal conversion, and the diminution of shape transformation due to the oxygen inhibiting action of the NOA65 composite [73]. Furthermore, when a photo polymerization method (such as SLA or DLP) is utilized to manufacture a light-responsive structure, photo-activated materials are restricted only to responding to specified wavelengths of light. To prevent undesirable conformation or structural transitions during printing, these specified wavelengths must not be within the wavelength range employed during the UV/laser printing procedure. If utilized as an internal implant, it is also important to examine the mode for triggering light stimulation. For instance, if an external light stimulus is delivered, then its penetration depth must be adequate and safe for substantial alteration to occur [74].
2.4. pH
Localized acidification around cancerous or inflammatory regions and the variation in pH along the gastrointestinal tract have encouraged the adoption of pH-responsive materials to attain regulated anticancer drug delivery and organ-specific drug release, respectively. Due to the protonation of ionizable groups or degradation of acid-cleavable bonds [75,76,77], pH-responsive materials are capable of swelling, contracting, dissociating, or degrading in response to changes in external pH. When there is a shift in pH, materials that are pH-responsive undergo a globule-to-coil transition. This occurs when polymer chains either stretch into a coil shape owing to the electrostatic repulsion of charged functional groups, or form a globule structure when the charge of the functional groups is neutralized [78,79]. It is well known that, for drug release applications, a wide range of pH-sensitive synthetic polymers has been used.
However, 4DP was used to create the required systems for drug delivery with specialized designs and precise dimensions, both of which are impossible to achieve using conventional manufacturing processes. This was made possible through the utilization of 4DP technology. For instance, a hydrogel based on acrylic acid has been created and printed in order to produce tablets that are capable of causing rapid drug release in high pH conditions [80]. This tablet showed gastric resistance qualities as well as a drug release pattern that is pH sensitive which makes them a potentially useful approach for enteric drug delivery applications [81].
This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics15010116
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