Tough Hydrogels with Programmable and Complex Shape Deformations by Ion Dip‐Dyeing and Transfer Printing

Stimuli‐responsive hydrogels with high mechanical strength, programmable deformation, and simple preparation are essential for their practical applications. Here the preparation of tough hydrogels with programmable and complex shape deformations is reported. Janus hydrogels with different compositions and hydrophilic natures on the two surfaces are first prepared, and they exhibit reversible bending/unbending upon swelling/deswelling processes. More impressively, the deformation rate and extent of the hydrogels can further be easily controlled through an extremely simple and versatile ion dip‐dyeing (IDD) and/or ion transfer printing (ITP) method. By selectively printing proper patterns on 1D gel strips, 2D gel sheets and 3D gel structures, the transformations from 1D to 2D, 2D to 3D, and 3D to more complicated 3D shapes can be achieved after swelling the ion‐patterned hydrogels in water. The swelling‐deformable Janus and ion‐patterned hydrogels with high mechanical strengths and programmable deformations can find many practical applications, such as soft machines.     

Soft Robotics Programmed with Double Crosslinking DNA Hydrogels

DNA nanotechnology is developed for decades to construct dynamic responsive systems in optics, quantum electronics, and therapeutics. While DNA nanotechnology is a powerful tool in nanomaterials, it is rare to see successful applications of DNA molecules in the macroscopic regime of material sciences. Here, a novel strategy to magnify the nanometer scale DNA self‐assembly into a macroscopic mechanical responsiveness is demonstrated. By incorporating molecularly engineered DNA sequences into a polymeric network, a new type of responsive hydrogel (D‐gel), whose overall morphology is dynamically controlled by DNA hybridization‐induced double crosslinking is able to be created. As a step toward manufacturing, the D‐gel in combination with a bottom‐up 3D printing technology is employed to rapidly create modular macroscopic structures that feature programmable reconfiguration and directional movement, which can even mimic the complex gestures of human hands. Mechanical operations such as catch and release are demonstrated by a proof‐of‐concept hydrogel palm, which possessed great promise for future engineering applications. Compared with previously developed DNA hydrogels, the D‐gel features an ease of synthesis, faster response, and a high degree of programmable control. Moreover, it is possible to scale up the production of D‐gel containing responsive devices through direct 3D printing.     

Conductive “Smart” Hybrid Hydrogels with PNIPAM and Nanostructured Conductive Polymers

Stimuli‐responsive hydrogels with decent electrical properties are a promising class of polymeric materials for a range of technological applications, such as electrical, electrochemical, and biomedical devices. In this paper, thermally responsive and conductive hybrid hydrogels are synthesized by in situ formation of continuous network of conductive polymer hydrogels crosslinked by phytic acid in poly(N‐isopropylacrylamide) matrix. The interpenetrating binary network structure provides the hybrid hydrogels with continuous transporting path for electrons, highly porous microstructure, strong interactions between two hydrogel networks, thus endowing the hybrid hydrogels with a unique combination of high electrical conductivity (up to 0.8 S m^?1), high thermoresponsive sensitivity (significant volume change within several seconds), and greatly enhanced mechanical properties. This work demonstrates that the architecture of the filling phase in the hydrogel matrix and design of hybrid hydrogel structure play an important role in determining the performance of the resulting hybrid material. The attractive performance of these hybrid hydrogels is further demonstrated by the developed switcher device which suggests potential applications in stimuli‐responsive electronic devices.     

Surface Patterning of Hydrogels for Programmable and Complex Shape Deformations by Ion Inkjet Printing

Convenient patterning and precisely programmable shape deformations are crucial for the practical applications of shape deformable hydrogels. Here, a facile and versatile computer‐assisted ion inkjet printing technique is described that enables the direct printing of batched, very complicated patterns, especially those with well‐defined, programmable variation in cross‐linking densities, on one or both surfaces of a large‐sized hydrogel sample. A mechanically strong hydrogel containing poly(sodium acrylate) is first prepared, and then digital patterns are printed onto the hydrogel surfaces by using a commercial inkjet printer and an aqueous ferric solution. The complexation between the polyelectrolyte and ferric ions increases the cross‐linking density of the printed regions, and hence the gel sample can undergo shape deformation upon swelling/deswelling. The deformation rates and degrees of the hydrogels can be conveniently adjusted by changing the printing times or the different/gradient grayscale distribution of designed patterns. By printing appropriate patterns on one or both surfaces of the hydrogel sheets, many complex 3D shapes are obtained from shape deformations upon swelling/deswelling, such as cylindrical shell and forsythia flower (patterns on one surface), ding (patterns on both surfaces), blooming flower (different/gradient grayscale distributive patterns on one surface), and non‐Euclidean plates (different/gradient grayscale distributive patterns on both surfaces).     

4D Printing of Hydrogels: A Review

3D printing permits the construction of objects by layer‐by‐layer deposition of material, resulting in precise control of the dimensions and properties of complex printed structures. Although 3D printing fabricates inanimate objects, the emerging technology of 4D printing allows for animated structures that change their shape, function, or properties over time when exposed to specific external stimuli after fabrication. Among the materials used in 4D printing, hydrogels have attracted growing interest due to the availability of various smart hydrogels. The reversible shape‐morphing in 4D printed hydrogel structures is driven by a stress mismatch arising from the different swelling degrees in the parts of the structure upon application of a stimulus. This review provides the state‐of‐the‐art of 4D printing of hydrogels from the materials perspective. First, the main 3D printing technologies employed are briefly depicted, and, for each one, the required physico‐chemical properties of the precursor material. Then, the hydrogels that have been printed are described, including stimuli‐responsive hydrogels, non‐responsive hydrogels that are sensitive to solvent absorption/desorption, and multimaterial structures that are totally hydrogel‐based. Finally, the current and future applications of this technology are presented, and the requisites and avenues of improvement in terms of material properties are discussed.     

Stomata‐Inspired Membrane Produced Through Photopolymerization Patterning

The programmed movements of responsive functional hydrogels have received much attention because of their abundant functions and wide range of engineering applications. In this study, an innovative stomata‐inspired membrane (SIM) is fabricated by using a temperature‐responsive hydrogel through a simple, cost‐effective, and high‐throughput patterned photopolymerization. Polymerization‐induced diffusion on the macroscale surface results in formation of a double‐parted polymer membrane with fine pores after single illumination. After heating the SIM, the less deformable thick frame supports the whole structure and the highly deformable thin base regulates pore shape. Among various SIM types, the slit pores of monocot SIM, which are lined up in parallel, exhibit the largest radius deformation. The morphological configuration of the SIM can be easily controlled by changing the photomask for a given application. As the developed SIM features the sensing‐to‐activation functions of stimuli‐responsive hydrogels and can be easily fabricated, this membrane can be potentially used for numerous practical applications, such as filter membranes with adjustable pores, membrane‐based sensors, membrane‐based actuators, and multifunctional membranes.     

Poly(N‐isopropylacrylamide)‐Clay Nanocomposite Hydrogels with Responsive Bending Property as Temperature‐Controlled Manipulators

Novel poly(N‐isopropylacrylamide)‐clay (PNIPAM‐clay) nanocomposite (NC) hydrogels with both excellent responsive bending and elastic properties are developed as temperature‐controlled manipulators. The PNIPAM‐clay NC structure provides the hydrogel with excellent mechanical property, and the thermoresponsive bending property of the PNIPAM‐clay NC hydrogel is achieved by designing an asymmetrical distribution of nanoclays across the hydrogel thickness. The hydrogel is simply fabricated by a two‐step photo polymerization. The thermoresponsive bending property of the PNIPAM‐clay NC hydrogel is resulted from the unequal forces generated by the thermoinduced asynchronous shrinkage of hydrogel layers with different clay contents. The thermoresponsive bending direction and degree of the PNIPAM‐clay NC hydrogel can be adjusted by controlling the thickness ratio of the hydrogel layers with different clay contents. The prepared PNIPAM‐clay NC hydrogels exhibit rapid, reversible, and repeatable thermoresponsive bending/unbending characteristics upon heating and cooling. The proposed PNIPAM‐clay NC hydrogels with excellent responsive bending property are demonstrated as temperature‐controlled manipulators for various applications including encapsulation, capture, and transportation of targeted objects. They are highly attractive material candidates for stimuli‐responsive “smart” soft robots in myriad fields such as manipulators, grippers, and cantilever sensors.     

Highly Efficient Self‐Healable and Dual Responsive Cellulose‐Based Hydrogels for Controlled Release and 3D Cell Culture

To face the increasing demand of self‐healing hydrogels with biocompatibility and high performances, a new class of cellulose‐based self‐healing hydrogels are constructed through dynamic covalent acylhydrazone linkages. The carboxyethyl cellulose‐graft‐dithiodipropionate dihydrazide and dibenzaldehyde‐terminated poly(ethylene glycol) are synthesized, and then the hydrogels are formed from their mixed solutions under 4‐amino‐DL‐phenylalanine (4a‐Phe) catalysis. The chemical structure, as well as microscopic morphologies, gelation times, mechanical and self‐healing performances of the hydrogels are investigated with ¹H NMR, Fourier transform infrared spectroscopy, atomic force microscopy, rheological and compression measurements. Their gelation times can be controlled by varying the total polymer concentration or 4a‐Phe content. The resulted hydrogels exhibit excellent self‐healing ability with a high healing efficiency (≈96%) and good mechanical properties. Moreover, the hydrogels display pH/redox dual responsive sol‐gel transition behaviors, and are applied successfully to the controlled release of doxorubicin. Importantly, benefitting from the excellent biocompatibility and the reversibly cross‐linked networks, the hydrogels can function as suitable 3D culture scaffolds for L929 cells, leading to the encapsulated cells maintaining a high viability and proliferative capacity. Therefore, the cellulose‐based self‐healing hydrogels show potential applications in drug delivery and 3D cell culture for tissue engineering.     

Spatiotemporally Controlled Photoresponsive Hydrogels: Design and Predictive Modeling from Processing through Application

Photoresponsive hydrogels (PRHs) are soft materials whose mechanical and chemical properties can be tuned spatially and temporally with relative ease. Both photo‐crosslinkable and photodegradable hydrogels find utility in a range of biomedical applications that require tissue‐like properties or programmable responses. Progress in engineering with PRHs is facilitated by the development of theoretical tools that enable optimization of their photochemistry, polymer matrices, nanofillers, and architecture. This review brings together models and design principles that enable key applications of PRHs in tissue engineering, drug delivery, and soft robotics, and highlights ongoing challenges in both modeling and application.     

Combining 3D Printing with Electrospinning for Rapid Response and Enhanced Designability of Hydrogel Actuators

Porous structures have emerged as a breakthrough of shape‐morphing hydrogels to achieve a rapid response. However, these porous actuators generally suffer from a lack of complexity and diversity in obtained 3D shapes. Herein, a simple yet versatile strategy is developed to generate shape‐morphing hydrogels with both fast deformation and enhanced designability in 3D shapes by combining two promising technologies: electrospinning and 3D printing. Elaborate patterns are printed on mesostructured stimuli‐responsive electrospun membranes, modulating in‐plane and interlayer internal stresses induced by swelling/shrinkage mismatch, and thus guiding morphing behaviors of electrospun membranes to adapt to changes of the environment. With this strategy, a series of fast deformed hydrogel actuators are constructed with various distinctive responsive behaviors, including reversible/irreversible formations of 3D structures, folding of 3D tubes, and formations of 3D structures with multi low‐energy states. It is worth noting that although poly(N‐isopropyl acrylamide) is chosen as the model system in the present research, our strategy is applicable to other stimuli‐responsive hydrogels, which enriches designs of rapid deformed hydrogel actuators.     

Programmed Deformations of 3D‐Printed Tough Physical Hydrogels with High Response Speed and Large Output Force

Shape‐morphing hydrogels have emerging applications in biomedical devices, soft robotics, and so on. However, successful applications require a combination of excellent mechanical properties and fast responding speed, which are usually a trade‐off in hydrogel‐based devices. Here, a facile approach to fabricate 3D gel constructs by extrusion‐based printing of tough physical hydrogels, which show programmable deformations with high response speed and large output force, is described. Highly viscoelastic poly(acrylic acid‐co‐acrylamide) (P(AAc‐co‐AAm)) and poly(acrylic acid‐co‐N‐isopropyl acrylamide) (P(AAc‐co‐NIPAm)) solutions or their mixtures are printed into 3D constructs by using multiple nozzles, which are then transferred into FeCl₃ solution to gel the structures by forming robust carboxyl–Fe³⁺ coordination complexes. The printed gel fibers containing poly(N‐isopropyl acrylamide) segment exhibit considerable volume contraction in concentrated saline solution, whereas the P(AAc‐co‐AAm) ones do not contract. The mismatch in responsiveness of the gel fibers affords the integrated 3D gel constructs the shape‐morphing ability. Because of the small diameter of gel fibers, the printed gel structures deform and recover with a fast speed. A four‐armed gripper is designed to clamp plastic balls with considerable holding force, as large as 115 times the weight of the gripper. This strategy should be applicable to other tough hydrogels and broaden their applications.     

pH‐Responsive Round‐Way Motions of a Smart Device through Integrating Two Types of Chemical Actuators in One Smart System

Smart motions of objects from the submicrometer to millimeter scale through chemical control with stimulus‐responsive way are significant to achieve various applications. However, the intelligence of the current devices with chemical responding system remains to be improved; especially, achieving a round‐way motion is still a challenge. Therefore, two types of actuators are simultaneously integrated into single smart device at the opposite ends to achieve cooperated functions in an orderly manner. One actuator is the pH‐responsive power supply of hydrogen bubbles produced from the reaction between magnesium and HCl. The smart device undergoes on–off–on locomotion through control over the solution pH values by using the pH‐responsive actuator of magnesium–HCl system. The other actuator is the hydrogen peroxide‐responsive system of oxygen bubbles generated through the decomposition of hydrogen peroxide catalyzed by platinum aggregates. When introducing hydrogen peroxide solution into the system, the generated oxygen bubbles at the opposite end of the device to push the device backward for round‐way motions. For the first time, two different types of actuators are simultaneously integrated into single smart device without disturbing each other, which realize pH‐responsive round‐way motions of the smart device and improve the system intelligence for further applications.     

Design of Multistimuli Responsive Hydrogels Using Integrated Modeling and Genetically Engineered Silk–Elastin‐Like Proteins

Elastomeric, robust, and biocompatible hydrogels are rare, while the need for these types of biomaterials in biomedical‐related uses remains high. Here, a new family of genetically engineered silk–elastin‐like proteins (SELPs) with encoded enzymatic crosslinking sites is developed for a new generation of stimuli‐responsive yet robust hydrogels. Input into the designs is guided by simulation and realized via genetic engineering strategies. The avoidance of gamma irradiation or chemical crosslinking during gel fabrication, in lieu of an enzymatic process, expands the versatility of these new gels for the incorporation of labile proteins and cells. In the present study, the new SELP hydrogels offer sequence‐dependent, reversible stimuli‐responsive features. Their stiffness covers almost the full range of the elasticity of soft tissues. Further, physical modification of the silk domains provides a secondary control point to fine‐tune mechanical stiffness while preserving stimuli‐responsive features, with implications for a variety of biomedical material and device needs.     

High‐Strength and High‐Toughness Double‐Cross‐Linked Cellulose Hydrogels: A New Strategy Using Sequential Chemical and Physical Cross‐Linking

Polysaccharide‐based hydrogels have multiple advantages because of their inherent biocompatibility, biodegradability, and non‐toxicic properties. The feasibility of using polysaccharide‐based hydrogels could be improved if they could simultaneously fulfill the mechanical property and cell compatibility requirements for practical applications. Herein, the construction of double‐cross‐linked (DC) cellulose hydrogels is described using sequential chemical and physical cross‐linking, resulting in DC cellulose hydrogels that are mechanically superior to single‐cross‐linked cellulose hydrogels. The formation and spatial distribution of chemically cross‐linked domains and physically cross‐linked domains within the DC cellulose hydrogels are demonstrated. The molar ratio of epichlorohydrin to anhydroglucose units of cellulose and the concentration of the aqueous ethanol solution are two critical parameters for obtaining mechanically strong and tough DC cellulose hydrogels. The mechanical properties of the DC cellulose hydrogels under loading‐unloading cycles are described using compression and tension models. The possible toughening mechanism of double‐cross‐linking is discussed.     

Dynamic Electromechanical Hydrogel Matrices for Stem Cell Culture

Hydrogels have numerous biomedical applications including synthetic matrices for cell culture and tissue engineering. Here we report the development of hydrogel based multifunctional matrices that not only provide three‐dimensional structural support to the embedded cells but also can simultaneously provide potentially beneficial dynamic mechanical and electrical cues to the cells. A unique aspect of these matrices is that they undergo reversible, anisotropic bending dynamics in an electric field. The direction and magnitude of this bending can be tuned through the hydrogel crosslink density while maintaining the same electric potential gradient, allowing control over the mechanical strain imparted to the cells in a three‐dimensional environment. The conceptual design of these hydrogels was motivated through theoretical modeling of the osmotic pressure changes occurring at the gel‐solution interfaces in an electric field. These electro‐mechanical matrices support survival, proliferation, and differentiation of stem cells. Thus, these new three‐dimensional in vitro synthetic matrices, which mimic multiple aspects of the native cellular environment, take us one step closer to in vivo systems.     

Anisotropic Hybrid Hydrogels with Superior Mechanical Properties Reminiscent of Tendons or Ligaments

Mimicking the hierarchically anisotropic structure and excellent mechanical properties of natural tissues, such as tendons and ligaments, using biomaterials is challenging. Despite recent achievements with anisotropic hydrogels, limitations remain because of difficulties in achieving both structural and mechanical characteristics simultaneously. A simple approach for fabricating hybrid hydrogels with a hierarchically anisotropic structure and superior mechanical properties that are reminiscent of tendons or ligaments is proposed. Alginate–polyacrylamide double‐network (DN) hydrogels incorporated with high aspect ratio mesoporous silica microparticles are stretched and fixed via subsequent drying and ionic crosslinking to achieve multiscale structures composed of an anisotropically aligned polymer network embedded with aligned microparticles. The mechanical properties of hydrogels can be further controlled by the degree of stretching, quantities, and functional groups of inorganic microparticles, and types of crosslinking cations. The subsequent reswelling results in a high water content (>80%) similar to that of natural tendons while high strength, modulus, and toughness are maintained. The optimized anisotropic hybrid hydrogel exhibits a tensile modulus of 7.2 MPa, strength of 1.3 MPa, and toughness of 1.4 MJ m^?3 even in the swollen state, which is 451‐, 27‐, and 2.2 times higher than that observed in the non‐swollen tough DN hydrogel. This study suggests a new strategy for fabricating anisotropic hydrogels with superior mechanical properties to develop new biomaterials for artificial tendons or ligaments.     

Rationally Designed Dynamic Protein Hydrogels with Reversibly Tunable Mechanical Properties

Protein hydrogels have attracted considerable interest due to their potential applications in biomedical engineering. Creating protein hydrogels with dynamic mechanical properties is challenging. Here, the engineering of a novel, rationally designed protein‐hydrogel is reported that translates molecular level protein folding‐unfolding conformational changes into macroscopic reversibly tunable mechanical properties based on a redox controlled protein folding‐unfolding switch. This novel protein folding switch is constructed from a designed mutually exclusive protein. Via oxidation and reduction of an engineered disulfide bond, the protein folding switch can switch its conformation between folded and unfolded states, leading to a drastic change of protein's effective chain length and mechanical compliance. This redox‐responsive protein can be readily photochemically crosslinked into solid hydrogels, in which molecular level conformational changes (folding‐unfolding) can result in significant macroscopic changes in hydrogel's physical and mechanical properties due to the change of the effective chain length between two crosslinking points in the protein hydrogel network. It is found that when reduced, the hydrogel swells and is mechanically compliant; when oxidized, it swells to a less extent and becomes resilient and stiffer, exhibiting an up to fivefold increase in its Young's modulus. The changes of the mechanical and physical properties of this hydrogel are fully reversible and can be cycled using redox potential. This novel protein hydrogel with dynamic mechanical and physical properties could find numerous applications in material sciences and tissue engineering.     

Complex Tuning of Physical Properties of Hyperbranched Polyglycerol‐Based Bioink for Microfabrication of Cell‐Laden Hydrogels

Microfabrication technology has emerged as a valuable tool for fabricating structures with high resolution and complex architecture for tissue engineering applications. For this purpose, it is imperative to develop “bioink” that can be readily converted to a solid structure by the modus operandi of a chosen apparatus, while optimally supporting the biological functions by tuning their physicochemical properties. Herein, a photocrosslinkable hyperbranched polyglycerol (acrylic hyperbranched glycerol (AHPG)) is developed as a crosslinker to fabricate cell‐laden hydrogels. Due to its hydrophilicity as well as numerous hydroxyl groups for the conjugation of reactive functional groups (e.g., acrylate), the mechanical properties of resulting hydrogels could be controlled in a wide range by tuning both molecular weight and degree of acrylate substitution of AHPG. The control of mechanical properties by AHPG is highly dependent on the type of monomer, due to the hydrophilic/hydrophobic balance of polyglycerol backbone and acrylate as well as the dynamic conformational flexibility based on the molecular weight of polyglycerol. The cell encapsulation studies demonstrate the biocompatibility of the AHPG‐linked hydrogels. Eventually, the AHPG‐based hydrogel precursor solution is employed as a bioink for a digital light processing based printing system to generate cell‐laden microgels with various shapes and sizes for tissue engineering applications.     

Inherent Photodegradability of Polymethacrylate Hydrogels: Straightforward Access to Biocompatible Soft Microstructures

Hydrogels are important functional materials useful for 3D cell culture, tissue engineering, 3D printing, drug delivery, sensors, or soft robotics. The ability to shape hydrogels into defined 3D structures, patterns, or particles is crucial for biomedical applications. Here, the rapid photodegradability of commonly used polymethacrylate hydrogels is demonstrated without the need to incorporate additional photolabile functionalities. Hydrogel degradation depths are quantified with respect to the irradiation time, light intensity, and chemical composition. It can be shown that these parameters can be utilized to control the photodegradation behavior of polymethacrylate hydrogels. The photodegradation kinetics, the change in mechanical properties of polymethacrylate hydrogels upon UV irradiation, as well as the photodegradation products are investigated. This approach is then exploited for microstructuring and patterning of hydrogels including hydrogel gradients as well as for the formation of hydrogel particles and hydrogel arrays of well‐defined shapes. Cell repellent but biocompatible hydrogel microwells are fabricated using this method and used to form arrays of cell spheroids. As this method is based on readily available and commonly used methacrylates and can be conducted using cheap UV light sources, it has vast potential to be applied by laboratories with various backgrounds and for diverse applications.     

Programmable Electrofabrication of Porous Janus Films with Tunable Janus Balance for Anisotropic Cell Guidance and Tissue Regeneration

Janus films with controlled pore structures can be particularly important in diverse applications. There remains a challenge for simple, rapid, and scalable fabrication methods to control Janus balance (JB) including the thickness of the individual face as well as porosity and pore size. Here the electrofabrication of a porous Janus film with controlled Janus balance from aminopolysaccharide chitosan under the salt effect is reported. Sequential deposition of chitosan under programmable salt environment and electrochemical conditions enables construction of Janus films with precisely controlled Janus balance. Bioactive partially soluble calcium phosphate (CaP) salts can also generate porous structure in Janus film. It is specifically reported that a chitosan/hydroxyl apatite (HAp) composite Janus film can serve as an effective scaffold for guided bone regeneration. The dense layer functions to provide mechanical support and serves as a barrier for fibrous connective tissue penetration. The porous composite layer functions to provide the microenvironment for osteogenesis. In vivo studies using a rat calvarial defect model confirm the beneficial features of this Janus composite for guided bone regeneration. These results suggest the potential of electrofabrication as a simple and scalable platform technology to tune the self‐organization of soft matter for a range of emerging applications.