Dynamic Hydrogels and Polymers as Inks for 3D Printing - ACS

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Dynamic Hydrogels and Polymers as Inks for 3D Printing Pejman Heidarian, Abbas Kouzani, Akif Kaynak, Mariana Paulino, and Bijan Nasri-Nasrabadi ACS Biomater. Sci. Eng., Just Accepted Manuscript • DOI: 10.1021/acsbiomaterials.9b00047 • Publication Date (Web): 07 May 2019 Downloaded from http://pubs.acs.org on May 8, 2019

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ACS Biomaterials Science & Engineering

Dynamic Hydrogels and Polymers as Inks for 3D Printing Pejman Heidarian, Abbas Z. Kouzani, Akif Kaynak, Mariana Paulino, Bijan Nasri-Nasrabadi School of Engineering, Deakin University, Geelong, Victoria 3216, Australia *Corresponding Author:

Professor Abbas Z. Kouzani School of Engineering Deakin University Geelong, Victoria 3216 Australia Email: [email protected]

Abstract: Developing rationally designed dynamic hydrogels and polymers as inks for 3D printing is in the limelight today. They would enable us to precisely fabricate complex structures in high resolutions and modular platforms with smart functions (e.g., self-healing and selfrecovery), as well as tunable mechanical, chemical, and biological properties. In this paper, we explore recent developments in dynamic hydrogels and polymers as inks for 3D printing and discuss their properties and applications in tissue engineering, soft actuators, sensors, and flexible electronics. The main scope of the paper is to give a deeper understanding of the field in terms of chemistry, physics, and associated properties. Moreover, the challenges and prospects of hydrogel/polymer inks will be discussed. We envisage that 3D printed dynamic hydrogels and polymers will provide unprecedented opportunities in designing and fabricating smarter structures. Keywords: Dynamic linkages; Hydrogels; Polymers; 3D printing; Self-healing; Self-recovery

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Introduction Development of hydrogels and polymers capable of responding to damage is indeed a panacea for fabricating more durable products, e.g. flexible electronics, biomedicine, and external coatings, because breaks in materials usually take place before any noticeable cracks at the failure point. 1 Inspired by the innate ability of living systems, dynamic linkages between polymer chains can impart healable feature to polymers at the molecular level, by which polymer chains are able to partially or fully heal their segments and regain their initial mechanical strength after damage inflicted on them, e.g. cavity or crack formation. As a result, products with better multiscale architectures and enhanced binding affinity at the interface of polymer chains can be achieved. 1-4 In this regard, the networks of hydrogels and polymers can be classified either as static dealing with the structural integrity of materials or as dynamic coping mostly with self-healing and self-recovery properties. 5-6 In static hydrogels and polymers, network formation is based on covalently non-reversible crosslinks among polymer chains that form irreversible, static bridges (Fig. 1A). 6-7


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Fig. 1. Schematic of (A) static polymer chains with covalently cross-linked networks, and (B) dynamic polymer chains with flexible, dynamic networks. In contrast, dynamic crosslinks are reversible crosslinks among polymer chains imparting dynamic properties to polymers (Fig. 1B): self-recovery and self-healing. Here, self-recovery is ascribed to the viscoelastic properties of polymers and refers to the ability of them to repair their internal damage and recover their original shape after rheological deformations. In other words, it shows time-dependent recovery upon relaxation that is a very important feature for polymer processing. However, self-healing is related to the ability of materials to rejoin to its original shape or condition at the molecular level after being damaged. The most common example of self-healing properties is to cut a hydrogel in half and then allow it to rebond again. 1, 8 Dynamic crosslinks are either chemical (covalent) via dynamic covalent bonds or physical (non-covalent) via physical interactions. 6 The most common examples of covalent bonds include: cyclohexenes, 9 sulfur-sulfur bonds, 10 photoresponsive cycloadducts, 11 imine, and 12 oxime. 13 Hydrogen bonding, metal–ligand coordination, host–guest recognition, electrostatic interaction, hydrophobic interaction, π–π interaction, and van der Waals force are also the common examples of reversible, non-covalent interactions that are also known as supramolecular interactions arising physically the dynamic behaviors of polymer chains. 6, 14 Compared to static hydrogels and polymers, dynamic counterparts often display fast structural recovery after being processed, so they can be employed as suitable inks for 3D printing. 1, 3, 8, 15 It has also been reported that physically cross-linked dynamic hydrogels or polymers via supramolecular interactions are weaker and more sensitive to mechanical shears than chemically cross-linked dynamic peers, leading supramolecular-based hydrogels and polymers to bettershaped- 2D or 3D structures. 6 For more specific information regarding dynamic hydrogels and polymers, we refer the reader to some most recent reviews. 1-2, 6, 8, 14, 16-18 3 ACS Paragon Plus Environment


The programmed configuration of polymer chains/segments within a predefined path using 3D printers is now paving the way for creating highly regulated hydrogels and polymers with precisely-controlled properties and boosted functionalities. 3 However, the main challenge of polymer processing is that when polymers are subjected to any processing methods the properties of products would reduce with increasing the speed of process because speed usually triggers the rheological phenomena of polymers. Furthermore, weak interlayer adhesion between the 3D-printed polymers is another main challenge that directly influences the mechanical properties of the product. Moreover, when static inks are printed, their polymer chains can only disentangle into a certain path. This eventually results in poor printability and structural destruction. 19 As such, there is a continuous need for developing new inks with proper mechanical properties, printability, and printing fidelity for 3D printing to augment the utility of 3D printed subjects. 20 Dynamic inks are interestingly able to overcome the aforementioned challenges and known to allow for: increase of print speeds without deterioration of the properties of objects, and improvement of interlayer adhesions between “weld lines” in objects. 15 In fact, dynamic polymers are able to disrupt during the applying shear forces (e.g. extrusion through a nozzle), and then rapidly re‐form upon removal of the stress (e.g. on the substrate after printing) 20 Furthermore, employing dynamic inks in 3D printing can open up an avenue for fabricating objects whose production using conventional methods is complex and limited. 19 Therefore, using dynamic inks for 3D printing can facilitate the fabrication of highly tunable hydrogels and polymers that are structurally controlled, mechanically tailored, and capable of being used in a wide range of applications. Furthermore, the advancement of 3D printing is strongly contingent upon the development of ink formulations. 21-22 In this paper, we review the most recent and 4 ACS Paragon Plus Environment

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important results associated with the preparation of dynamic hydrogels and polymers (elastomers, thermoplastics, and thermosets) formed by different 3D printers, and highlight their applications. We also give a summary of the findings to date and discuss the characteristics of the printed dynamic inks. Finally, the challenges in printing dynamic hydrogels and polymers, as well as their perspectives, are discussed. 3D Printing Technology 3D printing, unlike conventional fabrication methods that are either time or material-consuming, can provide a programmed layer-by-layer deposition of pre-defined objects with controlled thickness. 4 3D printing is, in fact, a computer-controlled process to precisely fabricate 3D designed objects with complex geometries. Currently, there exist many attempts to fabricate complex biological structures from hydrogels by means of 3D printing. As an example, alginate, 23

fibrin, 24 and gelatin 25 thus far have been used to fabricate 3D printed hydrogels. There exist

several methods by which hydrogel and polymer-based inks can be printed: inkjet, extrusion, laser-assisted bioprinting, and stereolithography. 26 Inkjet 3D printing of objects is suitable for inks having low viscosity and low thermal conductivity to prevent clogging and heat damage of cells. In this method, there is a need for a thermal or piezoelectric actuator, acting as a driving force, to well deposit inks layer-by-layer in a designed pattern. 27 Low cost, high printing speeds (up to 10,000 drops /s), and high spatial resolution (50-300 μm) of inkjet 3D printing can be considered as the most significant features of inkjet 3D printing, but the main downside is the limited range of viscosity for 3D printing (3.512 mPa.s). 26 Furthermore, compared with extrusion-based printing, inkjet 3D printing cannot print a filament under continuous flow and has inherently low cell densities. 28-29



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Extrusion-based 3D printers, on the other hand, are suitable for printing shear thinning inks within a high range of viscosity (6-30 ×107 mPa.s). 30 In extrusion-based printing, a filament is extruded continuously via a narrow nozzle, thus a high driving pressure or large extruding force must be applied to print an ink, which triggers some rheological phenomena of polymer chains, e.g. jamming. Therefore, during the extrusion of inks, careful consideration of rheology is of importance. In addition, a suitable solidification rate is required in order for inks to maintain their shape and structure. 26-27 The main demerits of extrusion-based printing are potential nozzle clogging, inferior resolution, and decreased cell viability due to shear stress. 30-31 Laser-assisted bioprinting technology is a technique capable of printing objects, either in a solid or liquid phase, in high resolution, 29 moderate speed, 32 and within a viscosity range of 1-300 mPa.s. 26-27, 29 The main shortcoming of this method is cell death as a result of inducing laser irritation. 33 Laser-assisted bioprinting can print objects under the resolution of 10 μm. 34 Stereolithography, similarly to laser-assisted printers, also employs light to polymerize lightsensitive inks in a layer-by-layer deposition and usually results in high resolution (50-100 μm), 35-36

high speed (5 kHz), 37 and low cost. 36 Stereolithography is, in fact, a nozzle-free technique

that takes the advantage of a UV light source for depositing biological materials, e.g. peptides, living cells, and DNA in a 3D-designed pattern. 26 As such, stereolithography allows the printing of inks in a large viscosity range (100–10000 mPa.s). 38 Since employing UV light for creating radicals during the polymerization of monomers or crosslinking of polymer chains is important, damage to cells may occur during the photocuring. 36, 39 Table 1 summarizes a comparison of different 3D printing methods. Table 1. A comparison of 3D printing methods. Comparison

Inkjet 26-29

Extrusion 26-27, 30-31

Laser-assisted 22, 26-27, 32-34, 40


Stereolithography 26, 35-39

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Merits

Suitable for inks with low viscosity and low thermal conductivity, high printing resolution, high speed

Suitable for inks with high viscosity and low thermal conductivity, able to print a filament under continuous flow, high cell densities

High resolution, able to print objects either in solid or liquid phase

High accuracy, nozzlefree, printing time independent of the complexity

Demerits

Limited range of viscosity for 3D printing, unable to print a filament under continuous flow, low cell densities

Inferior resolution, potential nozzle clogging, decreased cell viability due to shear stress, triggered rheological phenomena during printing

Cell death and thermal damage as a result of inducing laser irritation, expensive

Cell death during photocuring

Resolution

50–300 μm

200–1000 μm

10 μm

50–100 μm

Viscosity

3.5–12 mPa.s

6–30 × 107 mPa.S

1-300 mPa.s

100–10000 mPa.s

Speed

Fast

Low

Medium

Fast

Cost

Low

Moderate

High

Low

Dynamic Hydrogels in 3D Printing Hydrogels are solid polymers at the macroscopic scale, with liquid characteristics at the molecular level 41 capable of immobilizing large amounts of water via surface tension and capillary forces. 6 Viscoelasticity and water-rich nature endow hydrogels high compositional and structural versatility allowing them to be used for numerous applications, e.g. biomedical devices, 42 soft electronics, 43-44 sensors, 45 and actuators. 2-3, 6, 46 However, the rather brittle, opaque, and limited structural complexity of them, plus their large equilibrium volume swelling have always been considered as their main shortcomings. Moreover, static hydrogels are not capable of imitating the hierarchical complexity of the biological tissues due to having static and uniform microenvironments. 1, 3 Currently, there have been many efforts to develop dynamic hydrogels as ink for 3D printing. Here, we recite recent innovations in employing dynamic hydrogels to fabricate 3D printed hydrogels. 7 ACS Paragon Plus Environment


3D Printing of Dynamic Hydrogels for Tissue Engineering and Biomedicine Applications As a general rule, ideal hydrogel-based inks for 3D printing are those whose monomer/polymer solutions are extrudable and 3D-printable enough. Furthermore, their gelation must be quick enough on the printing substrate after being printed for self-supporting a layer-by-layer object, and the deposited multilayer stacks must bind together tightly to prevent delamination. 47 Therefore, dynamic hydrogels have great potential for being employed in 3D printing. 3D printing of dynamic hydrogel-based inks is very interesting for tissue engineering applications as it can provide a suitable platform for growing tissues under cytocompatible conditions. 20 Additionally, in comparison with other assembly techniques, e.g. molding and porous scaffolds, it is feasible to fabricate scaffolds with very flexible resolution within the range of 10 to 10,000 μm. 36 However, the successful use of such hydrogels in 3D printing completely depends on the precise control over the polymer rheology (enough fluidity during the extrusion) and gelation mechanism (enough structural integrity while deposited to support subsequent layers). 4, 47 As an example, premature gelation leads to an inhomogeneous 3D-printed structure and high viscosity results in cell death for cell-laden hydrogels. 1, 48 3D printing of dynamic hydrogels was for the first time performed by Highley et al. who reported the fabrication of a physically dynamic hydrogel by means of a syringe needle coupled to a thermoplastic extrusion-based printer. 20 A shear-thinning hydrogel-based ink was directly printed into a cytocompatible hydrogel as a self-healing “support”. Here, both hydrogels were based on the modified hyaluronic acid (HA) polymer, having supramolecular assembly through host–guest complexes with high biocompatibility and amenability to chemical modification. HA was also modified by either β-cyclodextrin (β-CD, the host) or adamantane (Ad, the guest) functional groups (Ad–HA and CD–HA, Fig. 2A). By means of this modification, Ad–HA and 8 ACS Paragon Plus Environment

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CD–HA is capable of interacting with each other via supramolecular interactions of host–guest complexes between Ad and β-CD moieties. 20, 49-50 Here, host–guest writing process was feasible into any position of printing of the ink into the support, and the supramolecular crosslinking was able to bestow stability to the ensuing printed hydrogel via intermolecular host–guest bonds (Fig. 2B). The optimized formulation used in this study resulted in the formation of stable hydrogels. Furthermore, the bulk of hydrogels bore the motion of needle during the printing without deformation and revealed shear-yielding and100% self-recovery behavior. The dynamic nature of the support rapidly healed around the printed area and recovered the mechanical integrity of the samples after applying mechanical stress. They also patterned multicellular structures by means of the host–guest writing process by incorporating cells into the support hydrogel at a final concentration of 5 million cells per mL. They labeled the population of mesenchymal stem cells (MSCs) with a green CellTracker dye and a population of 3T3 fibroblasts (3T3s) with a red CellTracker dye, allowing to visually track the populations of cells after printing an MSC-loaded ink into 3T3-loaded support (Fig. 2C). Results showed that the hydrogel was highly cytocompatible with the cultured cells with more than 90% cell viability, and after several days in culture, minimum loss in viability was observed. As a result, the incorporation of cells did not influence the printing process. 20



Fig. 2. Modification of HA by either β-cyclodextrin (β-CD, the host) or adamantane (Ad, the guest) functional groups (A), host–guest printing of the ink into the support (B), visually tracking of MSCs with a green CellTracker dye and 3T3 fibroblasts with a red CellTracker dye. Reproduced with permission from ref. 20. Copyright 2015 John Willey. Due to the reversible physically cross-linked interactions, HA-based hydrogels have inherently low mechanical strength despite having self-recovery and self-healing properties. 20 This might limit their functionality in applications that need strength for long-term stability. As such, HAbased hydrogels were rationally designed via supramolecular interactions of host–guest complexes as a shear-thinning and self-healing hydrogel, where their weak mechanical strengths were improved by forming double-network hydrogels via the entanglement of the


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supramolecular network with a covalently formed HA network able to support printed objects for injectable therapeutics and 3D-printing. 51-52 Here, similar to what Highley et al. performed, 20 the functionalization of HA was first performed with either adamantane via controlled esterification (as the guest moieties) or with β-cyclodextrins through amidation (as the host moieties), but in order to impart mechanical strength to the printed object, they employed a secondary covalent cross-linking by incorporating methacrylates into the CD-HA and Ad-HA derivatives. After printing the object, they employed UV photo-cross-linking to covalently stabilize the methacrylated hydrogel. 51-52 The patterned multicellular structures through the printing of human MSCs-loaded ink into the 3T3 fibroblasts-loaded support hydrogel showed higher cytocompatible with more than 95% cell viability after 24 h compared to Highley et al. research with 100% self-recovery. This enhancement can be attributed to the better mechanical strength of the printed pattern. 51 Zhang and co-workers are also among the first who conducted research to develop dynamic hydrogels for 3D printing. 53 They synthesized triblock supramolecular polymers from poly(isopropyl glycidyl ether)-block-poly(ethylene oxide)-block-poly(isopropyl glycidyl ether) ABA through the controlled ring-opening polymerization to prepare dynamic inks exhibiting dual stimuli-responsive behavior for temperature and shear response. The thermoreversible behavior was driven from the poly(isopropyl glycidyl ether) block showing lower critical solution temperature (LCST) behavior, and facilitating the load of ink into the printer syringe. Based on the rheological results, the ensuing hydrogel displayed rapid and reversible modulus response to shear stress making them suitable for being employed as ink for 3D printing such that the dynamic ink was easily printed and maintained its integrity. Their results indicated that



the 3D printed dynamic inks have great potential for being used for tissue engineering scaffolds and other biomaterial applications. 53 Dynamic hydrogels, owing to their similarity to extracellular matrices, can be deemed as attractive scaffolds, so employing them in treating bone defects via 3D printing appears to be interesting. However, the lack of enough strength and precision in fabricating complex geometric scaffolds for loading support for bone regeneration has remained an ongoing challenge. 54 Zhai et al. developed a nanocomposite hydrogel using a supramolecular polymer, poly(N-acryloyl glycinamide) (PNAGA), reinforced by nanoclay. 47 Nanoclay is a bioactive and biocompatible inorganic multifunctional cross-linker suitable for fabricating high performance hydrogels. 55 In PNAGA, dual amide motifs available in the side chain of the polymer would form stable hydrogen bonded cross-linking domains, thereby enhancing the mechanical strength and swelling stability of the hydrogel. 56 Nanoclay-incorporated NAGA monomer was easily extruded due to the enhanced interlayer binding and shear thinning behavior and quickly recovered and formed an uncollapsed structure thanks to its self-healing capability. This structure was then polymerized with a UV light to fabricate a bioscaffold with high strength and excellent swelling stability. The scaffold exhibited high reliability in bearing external load and retaining its microstructural integrity, which is an important property for bone regeneration in vivo: the swollen scaffold withstood easily hand folded and compressed via the wheel of a car and recovered rapidly in macroscopic shape and microstructure. The ensuing scaffold was used for treating animal bone defects, and rat osteoblast (ROB) cells were seeded on the ensuing scaffold. Based on the results, the release of silicon ions and magnesium ions, two bioactive ions of nanoclay, promoted the osteogenic differentiation of ROB cells with better proliferation rate and a stronger osteogenic differentiation tendency on both the molecular and genetic levels.


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Furthermore, the incorporation of PNAGA-clay scaffold in the tibia defect of rats could efficiently elicit the new formation of bone. 47 3D extrusion-based printing of dynamic hydrogel inks has continued to prepare novel scaffolds suitable for tissue engineering, but as mentioned earlier, viscosity is important during the extrusion of such inks because it must be low enough for allowing extrusion, and at the same time must be high upon deposition to form a stable structure able to hold its shape over time. 47 On the other hand, high viscosity may come at the cost of cell viability because the applied shear forces may damage cells, and meeting this need is a major challenge during the printing of cellincluded hydrogels—bioinks. 57 One strategy to reduce cell damage appears to be the inclusion of dynamic hydrogels because cells are more able to spread within a dynamic network than a static counterpart. 58 Currently, hydrazone chemistry was employed in HA hydrogels with the capability of forming hydrazone bonds (Fig. 3). 59 Hydrazone bonds are, in fact, dynamic covalent bonds formed between a nucleophilic hydrazide and an electrophilic aldehyde, able to protect cells during the extrusion. 60 Here, covalently modified HA hydrogels with dynamic and shear-thinning behaviors were fabricated via hydrazide (HA-HYD) or aldehyde (HA-ALD) groups and encapsulated with fibroblasts to evaluate the effect of extrusion force on their cell viability. During the preparation of the dynamic 3D-printed scaffold, a double-network approach was obtained through a photocrosslinkable interpenetrating network via a thiol-ene reaction incorporated with the original hydrogel. 59



Fig. 3. Synthesis of HA (HA‐HYD) and HA (HA‐ALD) via an amidation reaction and formation of dynamic network. Reproduced with permission from ref. 59. Copyright 2018 John Willey.

Based on the results, photo-stiffening improved the Young modulus (300%) and yield strain of (200%) the ensuing scaffold. Furthermore, the encapsulated fibroblasts on the printed hydrogel revealed more than 85% viability compared to the non-printed counterpart (95%), revealing that with increasing shear force, cell viability decreases. Self-healing assessment of hydrogels showed that for a sample cut in half, healing at the interface can be completed after 10 min, with no separation. 59 Similarly, the cell viability of cell-encapsulated dynamic hydrogels as bioink suitable for 3D printing was investigated in another research by Wei et al. 61 Here, they employed polysaccharide-based polymers for fabricating dynamic hydrogels. The utilized


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monoamine oxidase B to deaminate benzylamine-functionalized polyethylene glycol (PEG), and after deamination, the corresponding benzaldehyde functionalized PEG was cross-linked with amine-containing polysaccharides (glycol chitosan or gelatin) through Schiff bonds for the formation of dynamic hydrogels. The cell viability of NIH-3T3 cells encapsulated in dynamic hydrogels after printing showed 95.5% cell viability after 48 h culture, indicates that the ensuing dynamic hydrogels are able to protect cells during the extrusion with high efficiency. Furthermore these hydrogels, after being cut in half, healed at the interface at room temperature after incubating for 12 h. 61 The reprocessability and thermoplasticity are two significant properties for fabricating future personalized bioscaffolds. Wang et al. designed a novel reprocessable, self-healable ink with high strength—tensile strength of 1.2 MPa, stretchability of 1300%, and compressive strength of 11 MPa—and great potential for treating degenerated soft supporting tissues as an injectable hydrogel scaffold. 62 To prepare the hydrogel, the copolymerization of N-acryloyl glycinamide and 1-vinyl-1,2,4-triazole was performed in the absence of any chemical crosslinkers: the hydrogen bond interactions between dual amide motifs in the side chain of N-acryloyl glycinamide cross-linked the hydrogel network. Here, the hydrogels showed antibacterial and anti-inflammatory properties indicated by in vitro cytotoxicity assay and histological staining and in vivo implantation. The self-healing of hydrogels after being cut in half was completed in 45 min at 55 °C such that they were able to bear stretching and a 100 g weight. The tensile test indicated that the healed samples had a self- recovery efficiency of 90%. An extrusion-based printer was also employed to evaluate the thermoprocessability of the ensuing hydrogel, where results showed the successful printability of this novel hydrogel. The reprocessability of the printed hydrogel was also examined by slicing the printed samples into small fragments,



followed by immersing them with shaped molds into a water bath for 1 h for inducing gel–sol transition. After being cooled, the hydrogel reshaped into flower-like and butterfly-like structures. 62 The methods used thus far to prepare the 3D printed dynamic hydrogels are based on supramolecular interactions, mainly because of their easier printing process, and research on printing covalently cross-linked dynamic hydrogels for tissue engineering is very rare. However, recently, Kabb et al. developed polymers containing coumarin groups to fabricate covalently cross-linked dynamic hydrogels appealing for cell-culture. 48 To do so, they radically copolymerized a hydrophilic comonomer—N, N-dimethylacrylamide (DMA)—with vinyl monomers having coumarin functionality that eventually resulted in a linear, water-soluble hydrogel that is curable with UV light. The ensuing dynamic hydrogel was then employed for 3D printing via an extrusion-based printer to prepare a dynamic scaffold for cell culture. In the next step, human mammary epithelial cells (MCF-10A) were seeded on the scaffolds. Cell viability of the cell-incorporated sample was 80%, where after being cured under long-wave UV irradiation, cell viability percentage reduced to 10%, indicating that UV irradiation results in cell death. As a result, while the as-printed hydrogel has great potential for being used in biomedical applications because of low cytotoxicity, employment of UV irradiation for curing can result in cell death. As such, unlike supramolecular polymers, this dynamic hydrogel was not able to be employed for cell-encapsulated inks. 48 3D Printing of Dynamic Hydrogels for Sensing Application Wearable strain sensors able to transduce mechanical deformation into electrical signals are in the limelight today for their applications in sports, 63 robotics, 64 health monitoring, 65 electronic


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skin, 66 among others. To fabricate such sensors, the conventional approach is to employ metallic strain sensors, albeit because of the limited stretchability of metals, they are not able to sustain strains higher than 5%. 67 Therefore, it is still an ongoing challenge to prepare strain sensors having high stretchability and strain sensitivity. 67 3D printable self-healing hydrogels with applications in sensing devices are another novel area of interest to develop 3D printed dynamic hydrogels, suitable for next-generation wearable sensors and health-monitoring systems. To develop such sensors, stretchable and self-healable double network hydrogels were fabricated based on ionically cross-linked κ-carrageenan and covalently cross-linked polyacrylamide (PAAm). 68 Here, the coordination between the anionic groups of κ-carrageenan and K+, as well as hydrogen bonding can be considered as the main mechanism for the dynamic behavior of the hydrogel. The ensuing hydrogel was used for the first time as an ink to print complex 3D structures with superb mechanical properties and remarkable strain sensitivity appealing for producing sensitive strain sensors in robotics and human motion detection. The hydrogel after being cross-linked exhibited a superb fracture energy of 6150 J·m−2 that is much higher than the value reported for articular cartilage (∼1000 J·m−2). 1 The cut hydrogels healed well via the reversible interactions when they were brought together and heated above the gel-sol transition temperature (90 °C) for 20 min (Fig. 4A1-A2 and B1-B2). As depicted in Fig. 4C, the healed sample was able to bear a weight of 250 g without further collapse, proving the outstanding selfhealing capability of κ-carrageenan/PAAm double-network hydrogel. A light-emitting diode (LED) indicator was also employed to evaluate the self-healing behavior of the double-network hydrogel, used as the conductor. The LED was lit when the hydrogel was healed (Fig. 4D1-D3). Furthermore, the tensile strength and elongation at break of the healed hydrogel increased with increasing healing time at 90 °C. The successful 3D printing of hydrogel-based inks in different



patterns—hollow triangular prism and hollow cube—confirmed that the hydrogel can be used as an ideal ink for 3D printing with proper strength capable of supporting its weights during the printing, as well as high deformability and toughness after UV exposure. The 3D printed double network hydrogel was then employed as a wearable strain sensor to monitor multifarious motions of the human body. Based on the results, the fabricated strain sensor responded to the thumb finger motions rapidly. Moreover, no visible damage was observed when the index finger was bent repeatedly, making κ-carrageenan/PAAm hydrogel a promising sensor to prepare stretchable and wearable electronic skin. 68

Fig. 4. (A) Cut and healed self-healable hydrogels with a cylindrical shape structure able to bear its weight without collapse. (B) Cut and healed self-healable hydrogels with a sheet shape structure. (C) Self-healed sheet-shaped sample with the ability to bear a weight of 250 g. (D) Circuit contains an LED indicator connected by undamaged, cut, and self-healed hydrogel sheets. Reproduced with permission from ref. 68. Copyright 2017 American Chemical Society. Darabi et al. also employed dynamic conductive hydrogels having both covalent and noncovalent interactions. First, they grafted polypyrrole (PPy) onto double-bond decorated chitosan 18 ACS Paragon Plus Environment

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(DCh) to prepare a stable conductive compound. Next, they radically polymerized acrylic acid (AA) monomers to DCh-PPy in the presence of ferric irons and N, N″-methylenebis-acrylamide (MBA), as the covalent cross-linker. This graft polymer, because of having reversible physical and chemical interactions, exhibited 100% mechanical recovery in 2 min as well as 90% electrical recovery in 30 s. Here, ionic interactions between COOH groups of PAA and NH groups of PPy and ferric ions (Fe3+), and interactions between -OH and -NH2 groups in chitosan are responsible for providing strong supramolecular interactions via ionic interactions and hydrogen bonding in the hydrogel, thus creating self-healing and self-recovery properties and stabilizing the ensuing hydrogel (Fig. 5B). Furthermore, the chemical cross-linking of PAA and MBA imparts mechanical strength to the hydrogel. As shown in Fig. 5A, hydrogels, after being cut in half, were completely healed after 2 min thanks to the dynamic interactions of the functional groups between PAA and PPy (ionic interactions) and chitosan and PAA (hydrogen bonding). Based on the findings of this study, the increase of MBA results in a dramatic decrease in the dynamic properties of the hydrogel in such a way that the ensuing hydrogel lost its selfhealing behavior after loading 40% of MBA Fig. (5C). Furthermore, the electrical recovery of the hydrogel after recovery was 96% in 1 min. Mechanical studies of the hydrogels also revealed an ultra-stretchable behavior capable of deforming up to more than 1500% of its initial length. The conductive self-healing hydrogel was then printed for the preparation of wearable sensors via an extrusion-based method. The hydrogel exhibited a shear-thinning behavior due to the breaking down of the dynamic network during the printing and exhibited self-healing behavior after being printed. To examine the potentiality of the 3D printed dynamic hydrogel in wearable devices, a wireless human motion detector was prepared using smartphones, and relative resistance change of the respiratory, pulse and muscle motions were monitored. Based on the



results, the prototype 3D printed sensor had superb sensing performance pairing with selfhealing behavior compared to conventional sensing counterparts. 69

Fig. 5. (A) Visual tracking of the self-healing capability of the hydrogel. (B) Mechanism of selfhealing. (C) Mechanical self‐recovery efficiency. (D) Electrical self-recovery efficiency. Reproduced with permission from ref. 69. Copyright 2017 John Willey. Conductive dynamic hydrogels were also prepared by doping a supramolecular copolymer of poly(N-acryloyl glycinamide-co-2-acrylamide-2-methylpropanesulfonic) (PNAGA-PAMPS) crosslinked by multiple hydrogen bonds with poly (3,4-ethylenedioxythiophene)-poly (styrenesulfonate) (PEDOT/PSS) colloidal particles that are negatively charged and are able to improve the stability in the aqueous media and the specific conductivities of the hydrogels (Fig. 20 ACS Paragon Plus Environment

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6). 70 The ensuing hydrogels showed high mechanical strength (0.22–0.58 MPa tensile strength and 1.02–7.62 MPa compressive strength), and remarkable stretchability (817–1709%), plus with 2.2 S m−1 conductivity. Furthermore, thanks to the dynamic responsiveness of hydrogen bonding, the cut hydrogel showed self-healing behavior with 80–85% healing efficiency when dipped for 3 h into a 90 °C water bath. Here, the self-healed hydrogel can bear bending and stretching and owing to its thermoplasticity and suitable viscosity, it can be printed while quickly solidifying at room temperature to fix its structure. With the inclusion of activated charcoal powder with the hydrogel, a supercapacitor with a high capacitive performance was prepared, able to bear a certain range of voltage/current change rates. Based on the findings of this study, this hydrogel has remarkable potential as a flexible electrode material, biosensor or electroactive scaffold material for soft tissue engineering. 70



Fig. 6. Schematic and chemical structure of PNAGA-PAMPS hydrogel crosslinked by dual amide hydrogen bonds and doped with PEDOT/PSS. Hydrogel cut in half (i), was healed by heating (ii) and withstand stretching and bending (iii, iv). Reproduced with permission from ref. 70. Copyright 2017 Nature Publishing Group. 3D Printing of Dynamic Hydrogels for Protective Coating Application Benzaldehyde-functionalized poly[2-hydroxyethyl methacrylate) (PHEMA) because of its alcohol groups can exhibit self-healing behavior after being cross-linked with ethylenediamine (EDA) through the fast reaction kinetics and dynamic covalent essence of imine chemistry—the attachment of benzaldehyde units to the alcohol groups of PHEMA takes place via carbodiimide coupling reactions. Currently, such formulation was employed to prepare covalently cross-linked


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dynamic inks with the capability of being employed as suitable protective coatings for phone screens. 71 Based on the finding of this study, when the hydrogels were broken at about 400% strain, a recovery of about 97% of the moduli to their initial values was achievable. The printability of the ensuing PHEMA hydrogel was also assessed via an extrusion-based 3Dprinter. By doing so, the values of storage modulus, yield stress, and zero shear viscosity were in the range of 84–3558 Pa, 46–829 Pa, and 801–15 335 Pa.s, respectively—a post-printing stage with EDA was also employed in order to reinforce the ensuing printed object. They also showed that if the hydrogel is mechanically damaged, only after 30 min of contacting the damaged parts, their interfaces self-healed at room temperature through the formation of a scar, and after 1 h, the self-healed area could bear the hydrogel weight again without failure. Since the 3D-printed hydrogels had a dynamic response to their chemical environment, they used this hydrogel to fabricate self-rolling rectangular platforms able to spontaneously form a cigar-like shape from its planar sheet structure and unfold in its original, rectangular shape upon introducing DMF solvent. Based on their results, the 3D-printed hydrogels have great potential to prepare protective coatings with smart and dynamic behavior. 71 Dynamic Cryogels in 3D Printing Thus far, in order to impart mechanical strength to printed objects, the inclusion of an external component or stimulus has been a feasible way, such as chemical or physical cross-linking by covalent or ionic cross-linkers, 4, 72 secondary cross-linking via UV light,73-74 thermally induced gelation, 53 and evaporation induced curing. 75 Recently, Nadgorny et al. 71 engineered a new method to fabricate self-healing, 3D-printable oxime hydrogels, without the incorporation of external components to bestow mechanical strength to soft printed objects. To do so, poly(nhydroxyethyl acrylamide-co-methyl vinyl ketone) (PHEAA-co-PMVK)-based hydrogels were 23 ACS Paragon Plus Environment


first prepared as a multi-functional platform, wherein PMVK, owing to its ketone groups, is able to form oxime cross-links, thus forming stable dynamic hydrogels chemically cross-linked with bifunctional hydroxylamine. 76 After being printed, thermally induced phase separation (TIPS) treatment was employed as a post-printing treatment to not only facilitate hydrogen bonding but also to tune the mechanical strength of the ensuing 3D-printed objects. Here, PHEAA—a waterbased polymer—eliminates the need for organic solvents, and because of having ample amide and hydroxyl groups, it is capable of forming hydrogen bonds during the TIPS, thereby arising physically cross-linked (supramolecular) interactions, by which a 3D printed cryogel with selfhealing behavior and double dynamic network can be achieved. 77 Furthermore, by means of this method, there is no need for employing additional chemicals or UV equipment as a post-printing reinforcement. Based on the rheological results, the ensuing oxime hydrogel at the optimized formulation showed shear thinning behavior, and its apparent viscosity significantly dropped with increasing temperature, which is essential for extrudability of polymers through an extruder at more moderate pressures. The print of oxime hydrogel also indicated the fabrication of stable filamentous strands that are suitable for layer by layer deposition. By doing so, the printed hydrogel showed fast self-recovery to its original shape, without collapsing. Furthermore, based on the rheological analyses, the network of oxime hydrogel collapsed at very high strains (2200%), and its storage modulus sharply declined, but thanks to the dynamic response of the hydrogel, immediate and full recovery of storage modulus was observed. As such, it was found that cryogelation did not influence the self-healing properties of the ensuing hydrogels. They also observed that with increasing the number of cryogelation cycles, the storage modulus of the oxime hydrogels significantly augments. As an example, storage modulus increased up to about 500% after 5 cycles when freezing was conducted at -20 °C. Likewise, storage modulus


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increased up to about 1900% after the same number of cycles when freezing was conducted at 10 °C. As a result, the mechanical strength of oxime hydrogels was easily tunable using cryogelation. Here, the increased mechanical strength can be ascribed to the formation of supramolecular interactions via hydrogen bonding through cryogelation, thus inducing secondary dynamic linkages to the network of the ensuing self-healing system. 77 Fig. 7 depicts the schematic of the Dynamic cryogels for 3D printing, as well as the morphology and chemical structure of the ensuing cryogels. 71

Fig. 7. Schematic of the method used to print doubly dynamic self-healing cryogels, plus with the morphology and chemical structure of the ensuing cryogels. Reproduced with permission from ref. 71. Copyright 2018 The Royal Society of Chemistry.



Dynamic Elastomers in 3D Printing The same as dynamic hydrogels, dynamic elastomers can be employed in many applications, e.g. next generation tires, dampers, biomaterials, soft robotics, wearable electronic devices, and sensors, because of their ability to recover their mechanical properties after damage. 78 Currently, dynamic elastomers have been employed in 3D printing. Here, we explore recent studies in employing dynamic hydrogels to fabricate 3D printed elastomers. 3D Printing of Dynamic Elastomers for Tissue Engineering Application Hart et al. designed a nanocomposite hydrogel based on silica nanoparticle-reinforced poly(caprolactone)-derived supramolecular polymers, with hydrogen bonding/π−π stacking motifs, as inks for inkjet printing of hybrid scaffolds for regenerative medicine. MTT assays indicated that the ensuing ink does not induce cytotoxic effects. Here, cell attachment, examined by immunohistochemistry and confocal microscopy, was not affected by the inclusion of hydrogen bonding/π−π stacking motifs. Therefore, the ensuing 3D printed ink exhibited promising results for being used as scaffolds for regenerative medicine. 79 However, neither selfheling nor self-recovery properties of the resulting supramolecular polymers were not investigated. Fig. 8 shows the schematic of 3D printing supramolecular polymer reinforced by silica nanoparticles—blue dots stand for silica nanoparticles and red/black chains exhibit supramolecular polymer chains, where the red ends are hydrogen bonding end-groups. 79


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Fig. 8. Schematic of 3D printing supramolecular polymer (red/black chains) reinforced by silica nanoparticles (blue dots). Reproduced with pernission from ref. 79. Copyright 2016 American Chemical Society.

3D Printing of Dynamic Elastomers for Sensing Application To develop mechanical and electrical self-healing sensors using extrusion-based 3D printing, graphene nanosheet-reinforced polyborosiloxane (PBS) ink was prepared via solution casting on PDMS flexible substrates. Here, the dynamic nature of the ink comes from the supramolecular interactions of PBS, whose boron/oxygen dative bonds not only lead to spontaneous self-healing behavior at room temperature after being damaged but also result in temperature-dependent and chemical-activated mechanically adaptive properties (MAPs). Conductivity and mechanical properties were also supplied via graphene nanosheet. Here, the incorporation of graphene nanosheet changed the mechanical behavior of the supramolecular polymer and made it more ductile. A LED-integrated circuit also estimated about more than 99.4% electrical recovery after healing. The extrusion of ink also revealed that the liquefied polymer has a shear thinning 27 ACS Paragon Plus Environment


behavior, and is able to rapidly turn to a solid state after being extruded on a PDMS substrate and exposed to air, which is appealing for the 3D printing of self-supporting filaments. The extruded ink can form a well-adhered 3D self-supporting structure thanks to its rapid solidification. The 3D printed graphene nanosheet-reinforced PBS was then used as a gas sensor for sensing various chemical vapors consisting of methanol, water, dimethyl carbonate, diethyl ether, 1,4-dioxane, toluene, and hexane, among which the fastest response and recovery time was found to be at sensing diethyl ether vapor (0.92 and 1.15 min), and the most sensitive response was calculated for hexane and toluene mainly due to a more effective diffusion of their vapors into the asprepaid sensor. As a result, the ensuing sensor has great potential to detect different chemical vapors with moderate response time and high sensitivity and moderate response time. 80 3D Printing of Dynamic Elastomers for Soft Robotic Applications Soft robotics can be considered as a promising technology for creating next-generation machines with complex functions, but because of the current limitations of molding processes and lithography the fabrication of soft, 3D hierarchical structures is still an ongoing challenge. 81 Nonetheless, 3D printing is simplifying the preparation of such devices. Currently, a stereolithography-based 3D printer has been employed to rapidly fabricate high resolution, lowcost substrates with stiffness similar to organic tissues in complex, 3D architectures based on sunlight-responsive polymer networks: silicone (polydimethylsiloxane) and thiol-ene click chemistry. 82 Thiol-ene click chemistry is, in fact, a reaction compatible with photo-initiation that forms an alkyl sulfide from a thiol and alkene and allows photopolymerization through a low energy source. 83 The 3D printed device showed a wide range of ultimate stresses (13 < σult < 129 kPa), elastic moduli (6 < E < 287 kPa), and ultimate elongations (0.45 < ϒult < 4) suitable for soft robotics. Here, monolithic, synthetic antagonistic muscles containing a pair of fluidic elastomer 28 ACS Paragon Plus Environment

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actuators (FEAs)—a soft device able to bend when internal channels are pressurized by a fluid and expand—was fabricated using stereolithography-based 3D printing. The device operated by pressurizing or evacuating showed elongation, contraction, and bidirectional actuation over >180° with long life cycle antagonistic actuator pairs. Furthermore, unlike traditional FEAs, like balloons, failing permanently after being torn, this system showed rapid autonomic self-healing within 30 s via sunlight induced photopolymerization recovering actuation capability from such punctures. 82 It is worth noting that using sunlight as a stimulus for self-healing is of interest for particular outdoor applications because sun is a cheap, environmentally friendly, and low intensity source of light. 84 The combination of shape memory polymers with self-healing polymers to prepare 4D printable inks is also a novel concept for soft robotics developed for the first time by Invernizzi and coworkers. 85 Here, the concept of 4D printing means the ability to change the shape of 3D printed structures as a function of time. 86 To do so, 2-ureido-4[1H]-pyrimidinone (UPy), as a thermally triggered self-healing polymer and polycaprolactone (PCL) were co-crosslinked to prepare the 3D printable ink and was printed using the stereolithography technology. Mechanical analyses demonstrated that UPy/PCL ink had similar stiffness compared to PCL-based ones with a higher elongation at break. Furthermore, in terms of shape memory effect, the ensuing inks had better functionality than other printed PCL samples plus having dynamic properties. The selfhealing capability of samples was assessed by creating a deep scratch on the samples, followed by thermal treating of the area of damage at 80 °C for 1 h, where a healing efficiency of 50% was observed in this case. The recovery ratio, describing the extent to which a shape memory polymer memorizes its original shape, and the fixity ratio, defining the polymer capability to maintain a temporary shape, were found to be 98.6% and 99.8%. The possibility of using the



ensuing ink as a support material for robotic arms and hands was also explored by printing an L shaped structure to mimic the index finger and the thumb. As shown in Fig. 9, this sample was thermally healed after being partially cut and the deformed object starts recovering the original shape after heating. As such, these features could make them suitable for preparing 3D printed components used for human-machine interactions and soft robotics. 85

Fig. 9. Shape memory-assisted self-healing hydrogel: after being cut (A) and after healing under the thermal treatment of 1 h at 80 °C (B). The deformed sample (C) was heated at 70 °C, the recovery of the heated sample to its original shape (D–F). Reproduced with permission from ref. 85. Copyright 2018 Elsevier. In another research, shape memory-assisted self-healing elastomers as inks were 3D printed to prepare highly stretchable (up to 600%, Fig. 10C) well-structured subjects with high healing capacity and considerable potential toward further development of new 4D printed soft robotics devices. 87 A photocurable semi-interpenetrating polymer network (semi-IPN) elastomer made of aliphatic urethane diacrylate (AUD; containing 33 wt % of isobornyl acrylate) and n-butyl acrylate (BA incorporated with polycaprolactone (PCL) was printed through a heating syringe as 30 ACS Paragon Plus Environment

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the direct-ink-write (DIW) approach. During the preparation of ink, silica nanoparticles were also added to modify the rheology of the ensuing ink by bestowing the shear thinning effect to the uncured ink. Here, the presence of PCL up to 20 wt.% also improved Young’s modulus (~3.5 MPa) and fracture stress (~5MPa), mainly because of increasing the crystallinity of inks. Furthermore, the small PCL crystals were able to retard the propagation of microcracks in the network of elastomer, thus improving the fracture toughness of the prepared semi-IPN. The printed Archimedean spiral was stretchable over 300% of its initial length. Based on the findings of this study, in dog bone samples, the tensile stress-strain curves of in various orientations (0°, 45°, and 90°) nearly overlap, and the fracture strains of all printed samples were between 500600%, with in-plane isotropic properties. Additionally, fracture strain, fracture strength, and Young’s modulus in all three printing angles have a small deviation. To evaluate the self-healing behavior of the as-prepared samples, a scratch with 3 mm long and 30 μm wide was applied to the surface of the printed object. Here, the polymer showed thermally-triggered self-healing behavior and the scratch healed when it was treated in an oven at 80 °C for 20 min, followed by cooling down in the air without adding any chemicals (Fig. 10A-B, E). By doing so, healing efficiency was below 30%. Similarly, a notched strip with a visible gap was healed in the micro scale when it was treated in an oven at 80 °C for 20 min (Fig. 10D). Based on the results, after healing the scratch part of the mechanical strength was restorable because of PCL entanglements, but elongation at break of samples increased from 100% (in the virgin sample) to 160% (in the healed sample) after healing. Here, the hydrogen-bond between urethane and diffusion/entanglement of PCL chains were considered as the main contributing factors for the healing ability of the ensuing system. Shape memory behavior of the semi-IPN system could trigger the healing of large cracks with the closure of the large cracks, followed by the chain



diffusion and re-entanglement of PCL, acting as “locks” across the interface for rebonding the cracks. 87 As seen, the thermally triggered self-healing behavior formed by hydrogen bonding has not high efficiency. 85, 87

Fig. 10. Shape memory-assisted self-healing semi-IPN ink for 3D printing: (A) SEM of a sample before and after healing. (B) Optical micrograph of a sample to indicate the healed sample has an invisible scar. (C) Stress-strain curves for the neat notched and healed samples. (D) 3D printed Archimedean spiral sample. (E) evaluation of three different healing cycle at 80 °C for 20 min. Reproduced with permission from ref. 87. Copyright 2018 American Chemical Society. Dynamic Thermoplastics in 3D Printing As seen before, temperature can act as a stimulus to trigger the dynamic behavior of materials. 85, 87

The Diels–Alder reaction is also another synthetic strategy to thermally trigger the dynamic

behaviors of materials. The Diels–Alder reaction is currently used to fabricate 3D printed structures with higher self-healing efficiency than that of hydrogen bonding. 88Among all currently known methods, extrusion-based printing is the most versatile and inexpensive 32 ACS Paragon Plus Environment

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technique, but lacking enough adhesion at the interfilamentous junctions usually results in a reduced mechanical strength and inhomogeneous mechanical anisotropy. 89-90 To overcome this issue, organically modified clays 91 and thermotropic liquid crystalline polymers 92 have been employed as the modifiers during the extrusion-based 3D printing. However, the fabrication of 3D printable objects in large scale, able to vie well with conventional processing techniques (e.g. injection molding), is still an ongoing challenge because commercially 3D printed objects usually lose their overall mechanical strength. One possible strategy to overcome this limitation appears to be the employment of dynamic interactions. In the first attempt to address this problem, Davidson et al. proposed the incorporation of furan maleimide Diels-Alder (fmDA) reaction, which is thermally reversible and dynamic, in the formulation of inks to improve the interfilamentous adhesion in the extrusion-based printing. 93 In fact, they enhanced the fusion at the filament interface using a system able to thermally depolymerize while printing, and repolymerize during cooling with new covalent bonds between filament layers, thus improving the strength of the printed object. To do so, they synthesized and printed cross-linked polylactic acid (PLA) containing fmDA functional groups, showing an improvement in the strength of polymer along the z-axis up to 130%: tensile strength increased from 10 MPa in the neat PLA to 24 MPa in the fmDA-assisted PLA, proving the increase in the interfilament adhesion after inclusion of fmDA. Furthermore, toughness in the z-axis aligned prints augmented up to 460% from 0.05 MJ/m3 for the neat PLA to 0.28 MJ/m3 for the fmDA-assisted PLA. Therefore, adding Diels-Alder (fmDA) reaction was shown to improve the mechanical properties of the printed sample along the z-axis. 93 In another study, Appuhamillage et al. investigated the potential of Diels-Alder based dynamic covalent reaction blended with PLA and printed into dogbone samples for tensile test to prepare a reversible polymer system with approximately uniform



mechanical strength in all directions. Based on the tensile results, the ultimate strength and toughness enhanced about 290% and 1150% along the Z axis which is the interfilament junctions of the printed material. Therefore, with the incorporation of dynamic reactions into the neat PLA, isotropic samples were printed along the three representative print directions X, Y, and Z with the highest ultimate strength and toughness. In the end, the self-healing capacity of the ensuing 3D printed samples was examined: to do so, the broken ends of dog bones was heated at 120 °C for 5 s, then the area of damage was contacted and cured at 65 °C for 15 min. After this, their tensile tests were repeated. Based on the new tensile results, the sample containing dynamic covalent reactions showed 77% recovery, whilst the pristine PLA exhibited only 6% recovery, indicating that Diels-Alder based dynamic covalent reaction is able to remain active after thermal cycles and the printed thermal sensitive objects like PLA after exposing to high temperature will not lose their mechanical strength if they are blended with such dynamic reactions. 94 Dynamic Thermosets in 3D Printing Traditional thermosetting photopolymers are unprocessable in 3D printing due to the covalent nature of crosslink bonds. In addition, their accumulation is always a major source of pollution in the biosphere. Moreover, the high curing temperature of thermocurable thermosetting polymers reduces their viscosity, thus collapsing the 3D shape during the curing. 95 As a result, the 3D printing of thermocurable thermosetting polymers is difficult. Currently, thanks to the incorporation of dynamic interactions between polymer chains, it is feasible to develop 3D printed thermosets that offer solutions for the aforementioned issues. Shi et al. were among the first who studied the recyclable thermoset-based inks in extrusion-based 3D printing, with a dynamic-based epoxy. 96 In their study, they used nanoclay-assisted thermosetting vitrimer epoxy ink able to recycle into a new ink for reprinting. To do so, the unprinted ink, with a high34 ACS Paragon Plus Environment

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viscosity, was gradually cured and printed into complicated 3D structures at an elevated temperature. Afterward, the printed object was cured using an oven in two steps: locking the printed shape at a low-temperature, followed by curing at high temperature. For the second printing round, the printed vitrimer epoxy objects were completely dissolved in an ethylene glycol solvent at a high temperature for another printing round under similar printing conditions. This cycle was continued for at least four times with a very good printability, indicating that a vitrimer epoxy at an elevated temperature can be repolymerized into a new cross-linked network after being dissolved and results in a shape adaptation and surface welding, showing near 100% repairability recyclability, without requiring external pressure to weld interfaces. Based on the mechanical tests, the recycled printing parts after four cycles exhibited the same level of mechanical strengths, with a small amount of reduction in the ultimate strength. Based on the morphological studies, the peeled surface of the printed object during the 3D printing process was fully healed using vitrimer epoxy and the damage was fixed. 96 Due to the complicated preparation procedure proposed by Shi et al., 96 Zhang et al. proposed a simple two-step method for developing reprocessable thermosets suitable for UV curing-based 3D printing using a transesterification reaction between the hydroxyl and ester functional groups upon heating, thus forming dynamic covalent bonds and imparting reprocessability to the printed structures (Fig. 11A). 97 To do so, they first prepared a polymer solution by mixing 2-hydroxy-3phenoxypropyl acrylate (as the monomer), bisphenol A glycerolate (1 glycerol/phenol) diacrylate (as the cross-linker), diphenyl(2,4,6-trimethylbenzoly) phosphine oxide (as the photo initiator to trigger the UV polymerization), and zinc acetylacetone hydrate (as the catalyst) to accelerate the transesterification reactions (Fig. 11B). During the 3D printing, photopolymerization was performed by a patterned UV irradiation with opening the double bonds of acrylate functional



groups on both the monomer and crosslinker to form permanent covalent bonds, solidify the polymer solution layer-by-layer, and form a 3D structure. To impart reprocessability to the ensuing 3D printed thermoset, heating treatment to an elevated temperature was conducted to facilitate transesterification reactions between the ester and hydroxyl groups thereby forming dynamic covalent bonds capable of simultaneous breaking and reconnecting between the ester and hydroxyl groups. 97

Fig. 11. Schematic of 3D printing a reprocessable thermoset polymer. (A) General procedure of 3D printing (Stage I). Two cut printed 3D printed structures are welded together by heating and form a bendable structure (Stage II). (B) Chemical structures of crosslinker, monomer, initiator, and catalyst. (C) UV curing forming permanent covalent bonds (blue dots). (D) Thermaltriggered transesterification forming dynamic covalent bonds (red dots). Chemical structures of the permanent crosslinked network of Stage I (E) and dynamic covalent bonds of Stage II after 36 ACS Paragon Plus Environment

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heating (F, G). Scale bar: 1 mm. Reproduced with permission from ref. 97. Copyright 2018 Nature Publishing Group. Based on the mechanical analyses, the thermal treatment significantly augmented Young’s modulus of the as-printed objects from 7.4 MPa to ~900 MPa, resulting in highly stiffed objects. Here, the thermally treated objects have the self-healing feature based on the heat-triggered bond exchange reactions in which the dynamic crosslinking bonds are broken up and attacked by the adjacent hydroxyl functional groups, reforming new dynamic crosslinking bonds by connecting with the adjacent ester functional groups. This reaction eventually leads to a uniformly repaired object that can restore the mechanical performance of the original sample thanks to the existence of bond exchange reactions rendering the total number crosslinking reaction in the area of damage (Fig. 11C, D). Chemical structures of the permanent covalent bonds and dynamic covalent bonds are shown in Fig. 11E, F, and G. To illustrate this, self-healed printed strip showed ~100% of the stiffness, and 93% of strength compared to the virgin sample, indicating the high healing capability of ink to restore its mechanical performance after being damaged. In order to analyze the recyclability of the ensuing 3D structure, they were powdered and molded. After the thermal treatment, a thermosetting sheet was formed because of the bond exchange reactions. Based on the mechanical analysis the recycled samples after 3 cycles had a good overall mechanical performance, indicating the recycle process is repeatable and reasonably good. 97 Discussions Recent studies on dynamic hydrogels and polymers as inks for 3D printing reveal that by means of dynamic inks, it is feasible to fabricate smarter structures for tissue engineering, 20, 47-48, 51-53, 59, 61-62, 79, 82

soft robotics, 69, 85, 87, 98 protective coatings, 4 gas sensors, 80 reprocessable inks, 62, 96-97

reinforcing materials, 93-94 flexible electrode materials, 70 and wireless human motion detectors. 37 ACS Paragon Plus Environment


69

As can be seen, studies especially in the area of tissue engineering, on such inks have been

growing during the last couple of years, and it is expected that this trend will continue. Here, we divide dynamic inks into two main categories: dynamic inks via supramolecular interactions and dynamic inks via covalent bonding, each has its own physical and mechanical properties with a range of recovery percentage and recovery time. Supramolecular-based inks consist of hydrogen bonding, 70 host–guest recognition, 20 ionic interactions, 69 hydrophobic interactions, 53 and π–π interactions. 79 Covalent bonding-based dynamic inks include Diels-Alder reaction, 94 thiol-ene chemistry, 82 photoresponsive cycloadducts, 48 imine, 4 and oxime 71. All these dynamic inks were printed using different 3D printers. As described earlier, 3D printing is a computer-aided process, by which objects with complex geometries are precisely designed and fabricated under considerable ease without wasting materials. Inkjet, extrusion, and stereolithography are the 3D printers used so far to print dynamic inks. As shown in Table 2, most of the printing exercises has been based on extrusion mainly because of its innate ability to print inks with a high range of viscosity. As an example, the range of viscosity required for printing benzaldehyde-functionalized poly(2-hydroxyethyl methacrylate), a dynamic covalent bonding-based ink, is between 405-21760 (Pa s) 4 or the viscosity of graphene nanosheet-reinforced polyborosiloxane is 2.32 × 1010 (Pa s), which is much higher than the pristine polyborosiloxane (3.96 × 107 (Pa s)), so it needs a stronger printer. 80 As shown, dynamic hydrogels and polymers have many benefits compared to their conventional counterparts for 3D printing mainly because of imparting healable, recoverable, and stable features to the printed structures—being reversible and regaining structural integrity after printing are appealing properties because 3D printed objects retain their well-defined architectures. However, there exist some challenges regarding the employment of dynamic 38 ACS Paragon Plus Environment

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hydrogels and polymers for 3D printing that are discussed below. One major challenge is to prepare a printable, dynamic ink from hydrogels with robust and time-independent printing performances. It is important for gels to rapidly form and to fully mature prior to printing. In addition, 3D-printing of covalently cross-linked hydrogels and polymers is more challenging than physically cross-linked counterparts because of the higher viscosity of covalent bonds, albeit covalently cross-linked hydrogels and polymers have higher stability and diverse functionality than supramolecular interactions. 71 Moreover, accurate control over the rheological properties, formulation and crosslinking degrees are also significant for finding the most suitable printable inks. As such, for hydrogels, a precise investigation of the rheology of gelation kinetics before printing is of importance to developing a suitable 3D-printable, dynamic ink. Another main challenge to formulate 3D printable dynamic inks is to find a formulation that exhibits synchronously self-healing and mechanical robustness: two properties that are generally in opposition. 1 To find such inks, one feasible way is to tune dynamic inks by means of the topological, nanocomposite, and double network systems. As an example, in the double network of PPy-g-DCh-g-PAA, MBA was used as the covalent cross-linker to impart mechanical strength to the system. Here, the system showed incredible electrical and mechanical recovery after healing, but when the concentration of the covalent cross-liker increased, a dramatic reduction in the self-healing capability was observed. 69 An overview of the 3D printed dynamic hydrogels and polymers is presented in Table 2 that consists of 3D printing methods, dynamic interaction types, tuning methods, self-healing efficiencies and recoveries, stimuli, and applications. As can be seen, the bulk of the list belongs to the inks whose dynamic interactions are based on supramolecular interactions, and are tuned via a double-network system. In this approach, inclusion of multiple reversible and irreversible 39 ACS Paragon Plus Environment


reactions is considered as the strategy to improve the mechanical strength of products. Based on the data tabulated in Table 2, inks tuned by double network systems exhibit a broad range of selfhealing efficiencies (30-100%) with instant to 3h recovery time. Nanocomposite and topological hydrogels also show an instant 100% recovery. Here, an amalgam of supramolecular interactions has been employed, among which host−guest interactions, 20 hydrophobic interactions, 53 ionic interactions, 69 showed instant 100 % recovery. Furthermore, different dynamic covalent bonds have also been used, including hydrazone bond with 100 % recovery in 0.16 h, 59 Schiff base with 100 % recovery in 12 h, 61 and Diels−Alder with 77 % recovery in 0.25 h. Additionally, multi-mechanisms have also been employed, e.g. ionic interactions and hydrogen bonding 68 with 91 % recovery in 0.33 h. As such, different designs are possible to fabricate dynamic inks with self-healing capability. As can be seen, the dynamic covalent interactions are slower than supramolecular interactions in terms of recovery. This means healing time decreases with increasing healing efficiency, and systems with better dynamic interactions exhibit faster recovery.


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1 Table 2. Overview of 3D printed dynamic hydrogels and polymers based on 2 crosslinking. 3 4 Polymer 3D Dynamic SelfHealin SelfRecovery Printing Interaction Tuning method Healin g Time Recove Time [h] 5 Method Type g [%] [h] ry 6 [%] 7 Extrusio Host−guest Topological hydrogel 100 Instant 8 Hyaluronic acid n interactions 9 functionaliz 10 ed with AD 11 and β-CD Hyaluronic Extrusio Host−guest Topological/double100 Instant 12 acid n interactions network 13 functionaliz 14 ed with AD and β-CD 15 16 100 Instant 17 Hyaluronic Extrusio Host−guest Topological/doublen interactions network 18 acid functionaliz 19 ed with AD 20 and β-CD Inkjet Hydrogen Nanocomposite 21 Silica nanoparticle bonding/π− elastomer 22 -reinforced π stacking 23 poly(caprol motifs 24 actone)-diol 25 26 27 100 Instant 28 Poly(isopro Extrusio Hydrophobi Copolymer hydrogel pyl glycidyl n c 29 ether)interactions 30 block31 poly(ethyle ne oxide)32 block33 poly(isopro 34 pyl glycidyl 35 ether) NanoclayExtrusio Hydrogen Nanocomposite 36 reinforced n bonding/ hydrogel physical 37 poly(Ncross38 acryloyl glycinamide linking of 39 ) nanoclay 40 ~100 0.5 100 Instant 41 Hyaluronic Extrusio Hydrazone Double-network acid n bond 42 modified 43 with 44 hydrazide (HA-HYD) 45 or aldehyde 46 (HA-ALD) 47 48 49 AldehydeExtrusio Schiff base Double-network ~100 12 100 Instant 50 functionaliz n 51 ed 52 poly(ethyle glycol) 53 ne (PEG) and 54 amino55 containing 56 57 58 41 59 ACS Paragon Plus Environment 60

supramolecular interactions and covalent Stimulus

Applicatio ns

Limitations

Refere nce

Autonomou s selfrecovery at RT

Tissue engineering

Low mechanical properties

20


Tissue engineering

UV photocross-linking might cause cell death for using the hydrogel as a bionink

51


Tissue engineering

52

-

Tissue engineering


Tissue engineering

UV photocross-linking might cause cell death for bioninks Use of nanoparticles caused less stable inks than that of the pure inks/decreased cell viability due to shear stress Low mechanical properties

-

Tissue engineering

High viscosity and UV light might cause cell death for using the hydrogel as a bionink

47

Autonomou s selfhealing and selfrecovery at RT

Tissue engineering

Control of rheology because the presence of dynamic covalent bonds/ control of solidification rate

59

Autonomou s selfhealing and selfrecovery at RT

Tissue engineering

Control of rheology because the presence of dynamic covalent bonds/ lack of instant self-healing

61

79

53

ACS Biomaterials Science & Engineering 1 2 3 polysacchar 4 ides 5 Poly(N,Ndimethylacr 6 ylamide-co7 coumarin 8 copolymer Poly(N9 acryloyl 10 glycinamide 11 )-co-(112 vinyl-1,2,4triazole) 13 Vinyl 14 terminated 15 polydimeth ylsiloxanes 16 and 17 (mercaptopr 18 opyl)methyl siloxane19 dimethylsilo 20 xane 21 copolymer 22 2-ureido4[1H]23 pyrimidinon 24 e/ 25 polycaprola ctone 26 Aliphatic 27 urethane 28 diacrylate/n 29 -butyl acrylate/pol 30 ycaprolacto 31 ne 32 κcarrageenan 33 and 34 polyacrylam 35 ide 36 Polypyrrole -g-double37 bond 38 decorated 39 chitosan/ poly 40 (acrylic 41 acid) 42 Graphene nanosheet43 reinforced 44 polyborosil 45 oxane 46 Poly(N47 acryloyl 48 glycinamide 49 -co-2acrylamide50 251 methylprop 52 anesulfonic) /(3,453 ethylenedio 54 xythiophene 55 )-poly 56 57 58 59 60

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Extrusio n

Photorespo nsive coumarin

Copolymer hydrogel

-

-

-

-

-

Tissue engineering

High viscosity caused cell death

48

Extrusio n

Hydrogen bonding

Copolymer hydrogel

∼90

0.75

-

-

Heating to 55 °C for 45 min

Biomedical applications

Need an external stimulus for self-healing

62

Stereolit hography

Thiol-ene chemistry

Copolymer elastomer

100

Instant

-

-

Sunlight induced photopolym erization

Antagonisti c muscle actuator


82

Stereolit hography

Hydrogen bonding

Double network

∼50

1

-

-

Heating to 80 °C for 1 h

Shape morphing/a ctuating devices


85

Extrusio n

diffusion/en tanglement of PCL chains and hydrogen bonding

Double network

Dynamic Hydrogels and Polymers as Inks for 3D Printing - ACS

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