Integration of Self‐Assembled Microvascular Networks with Microfabricated PEG‐Based Hydrogels

Despite tremendous efforts, tissue engineered constructs are restricted to thin, simple tissues sustained only by diffusion. The most significant barrier in tissue engineering is insufficient vascularization to deliver nutrients and metabolites during development in vitro and to facilitate rapid vascular integration in vivo. Tissue engineered constructs can be greatly improved by developing perfusable microvascular networks in vitro in order to provide transport that mimics native vascular organization and function. Here a microfluidic hydrogel is integrated with a self‐assembling pro‐vasculogenic co‐culture in a strategy to perfuse microvascular networks in vitro. This approach allows for control over microvascular network self‐assembly and employs an anastomotic interface for integration of self‐assembled microvascular networks with fabricated microchannels. As a result, transport within the system shifts from simple diffusion to vessel supported convective transport and extra‐vessel diffusion, thus improving overall mass transport properties. This work impacts the development of perfusable prevascularized tissues in vitro and ultimately tissue engineering applications in vivo.     

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.     

Mussel‐Inspired Hydrogels for Self‐Adhesive Bioelectronics

Wearable and implantable bioelectronics are receiving a great deal of attention because they offer huge promise in personalized healthcare. Currently available bioelectronics generally rely on external aids to form an attachment to the human body, which leads to unstable performance in practical applications. Self‐adhesive bioelectronics are highly desirable for ameliorating these concerns by offering reliable and conformal contact with tissue, and stability and fidelity in the signal detection. However, achieving adequate and long‐term self‐adhesion to soft and wet biological tissues has been a daunting challenge. Recently, mussel‐inspired hydrogels have emerged as promising candidates for the design of self‐adhesive bioelectronics. In addition to self‐adhesiveness, the mussel‐inspired chemistry offers a unique pathway for integrating multiple functional properties to all‐in‐one bioelectronic devices, which have great implications for healthcare applications. In this report, the recent progress in the area of mussel‐inspired self‐adhesive bioelectronics is highlighted by specifically discussing: 1) adhesion mechanism of mussels, 2) mussel‐inspired hydrogels with long‐term and repeatable adhesion, 3) the recent advance in development of hydrogel bioelectronics by reconciling self‐adhesiveness and additional properties including conductivity, toughness, transparency, self‐healing, antibacterial properties, and tolerance to extreme environment, and 4) the challenges and prospects for the future design of the mussel‐inspired self‐adhesive bioelectronics.     

Self‐Assembled Injectable Nanocomposite Hydrogels Stabilized by Bisphosphonate‐Magnesium (Mg2+) Coordination Regulates the Differentiation of Encapsulated Stem Cells via Dual Crosslinking

Nanocomposite hydrogels consist of a polymer matrix embedded with nanoparticles (NPs), which provide the hydrogels with unique bioactivities and mechanical properties. Incorporation of NPs via in situ precipitation in the polymer matrix further enhances these desirable hydrogel properties. However, the noncytocompatible pH, osmolality, and lengthy duration typically required for such in situ precipitation strategies preclude cell encapsulation in the resultant hydrogels. Bisphosphonate (BP) exhibits a variety of specific bioactivities and excellent binding affinity to multivalent cations such as magnesium ions (Mg²⁺). Here, the preparation of nanocomposite hydrogels via self‐assembly driven by bisphosphonate‐Mg²⁺ coordination is described. Upon mixing solutions of polymer bearing BPs, BP monomer (Ac‐BP), and Mg²⁺, this effective and dynamic coordination leads to the rapid self‐assembly of Ac‐BP‐Mg NPs which function as multivalent crosslinkers stabilize the resultant hydrogel structure at physiological pH. The obtained nanocomposite hydrogels are self‐healing and exhibit improved mechanical properties compared to hydrogels prepared by blending prefabricated NPs. Importantly, the hydrogels in this study allow the encapsulation of cells and subsequent injection without compromising the viability of seeded cells. Furthermore, the acrylate groups on the surface of Ac‐BP‐Mg NPs enable facile temporal control over the stiffness and crosslinking density of hydrogels via UV‐induced secondary crosslinking, and it is found that the delayed introduction of this secondary crosslinking enhances cell spreading and osteogenesis.     

3D Electrophoresis‐Assisted Lithography (3DEAL): 3D Molecular Printing to Create Functional Patterns and Anisotropic Hydrogels

The ability to easily generate anisotropic hydrogel environments made from functional molecules with microscale resolution is an exciting possibility for the biomaterials community. This study reports a novel 3D electrophoresis‐assisted lithography (3DEAL) platform that combines elements from proteomics, biotechnology, and microfabrication to print well‐defined 3D molecular patterns within hydrogels. The potential of the 3DEAL platform is assessed by patterning immunoglobulin G, fibronectin, and elastin within nine widely used hydrogels and characterizing pattern depth, resolution, and aspect ratio. Furthermore, the technique's versatility is demonstrated by fabricating complex patterns including parallel and perpendicular columns, curved lines, gradients of molecular composition, and patterns of multiple proteins ranging from tens of micrometers to centimeters in size and depth. The functionality of the printed molecules is assessed by culturing NIH‐3T3 cells on a fibronectin‐patterned polyacrylamide‐collagen hydrogel and selectively supporting cell growth. 3DEAL is a simple, accessible, and versatile hydrogel‐patterning platform based on controlled molecular printing that may enable the development of tunable, chemically anisotropic, and hierarchical 3D environments.     

Protein‐Release Behavior of Self‐Assembled PEG–β‐Cyclodextrin/PEG–Cholesterol Hydrogels

This paper reports on the degradation and protein release behavior of a self‐assembled hydrogel system composed of β‐cyclodextrin‐ (βCD) and cholesterol‐derivatized 8‐arm star‐shaped poly(ethylene glycol) (PEG₈). By mixing βCD‐ and cholesterol‐derivatized PEG₈ (molecular weights 10, 20 and 40 kDa) in aqueous solution, hydrogels with different rheological properties are formed. It is shown that hydrogel degradation is mainly the result of surface erosion, which depends on the network swelling stresses and initial crosslink density of the gels. This degradation mechanism, which is hardly observed for other water‐absorbing polymer networks, leads to a quantitative and nearly zero‐order release of entrapped proteins. This system therefore offers great potential for protein delivery.     

3D Printing of Multifunctional Hydrogels

3D printing technology has been widely explored for the rapid design and fabrication of hydrogels, as required by complicated soft structures and devices. Here, a new 3D printing method is presented based on the rheology modifier of Carbomer for direct ink writing of various functional hydrogels. Carbomer is shown to be highly efficient in providing ideal rheological behaviors for multifunctional hydrogel inks, including double network hydrogels, magnetic hydrogels, temperature‐sensitive hydrogels, and biogels, with a low dosage (at least 0.5% w/v) recorded. Besides the excellent printing performance, mechanical behaviors, and biocompatibility, the 3D printed multifunctional hydrogels enable various soft devices, including loadable webs, soft robots, 4D printed leaves, and hydrogel Petri dishes. Moreover, with its unprecedented capability, the Carbomer‐based 3D printing method opens new avenues for bioprinting manufacturing and integrated hydrogel devices.     

Complex 3D‐Printed Microchannels within Cell‐Degradable Hydrogels

3D‐printing is emerging as a technology to introduce microchannels into hydrogels, for the perfusion of engineered constructs. Although numerous techniques have been developed, new techniques are still needed to obtain the complex geometries of blood vessels and with materials that permit desired cellular responses. Here, a printing process where a shear‐thinning and self‐healing hydrogel “ink” is injected directly into a “support” hydrogel with similar properties is reported. The support hydrogel is further engineered to undergo stabilization through a thiol‐ene reaction, permitting (i) the washing of the ink to produce microchannels and (ii) tunable properties depending on the crosslinker design. When adhesive peptides are included in the support hydrogel, endothelial cells form confluent monolayers within the channels, across a range of printed configurations (e.g., straight, stenosis, spiral). When protease‐degradable crosslinkers are used for the support hydrogel and gradients of angiogenic factors are introduced, endothelial cells sprout into the support hydrogel in the direction of the gradient. This printing approach is used to investigate the influence of channel curvature on angiogenic sprouting and increased sprouting is observed at curved locations. Ultimately, this technique can be used for a range of biomedical applications, from engineering vascularized tissue constructs to modeling in vitro cultures.     

Directed Emission from Self‐Assembled Microhelices

Bottom‐up assembly can organize simple building blocks into complex architectures for light manipulation. The optical properties of self‐assembled polycrystalline barium carbonate/silica double helices are studied using fluorescent Fourier and Mueller matrix microscopy. Helices doped with fluorescein direct light emission along the long axis of the structure. Furthermore, light transmission measured normal and parallel to the long axis exhibits twist sense‐specific circular retardance and waveguiding, respectively, although the measurements suffer from depolarization. The helices thus integrate highly directional emission with enantiomorph‐specific polarization. This optical response emerges from the arrangement of nanoscopic mineral crystallites in the microscopic helix, and demonstrates how bottom‐up assembly can achieve ordering across multiple length scales to form complex functional materials.     

Engineering of Self‐Assembled Domain Architectures with Ultra‐high Piezoelectric Response in Epitaxial Ferroelectric Films

Substrate clamping and inter‐domain pinning limit movement of non‐180° domain walls in ferroelectric epitaxial films thereby reducing the resulting piezoelectric response of ferroelectric layers. Our theoretical calculations and experimental studies of the epitaxial PbZr_xTi_1–xO₃ films grown on single crystal SrTiO₃ demonstrate that for film compositions near the morphotropic phase boundary it is possible to obtain mobile two‐domain architectures by selecting the appropriate substrate orientation. Transmission electron microscopy, X‐ray diffraction analysis, and piezoelectric force microscopy revealed that the PbZr_0.52Ti_0.48O₃ films grown on (101) SrTiO₃ substrates feature self‐assembled two‐domain structures, consisting of two tetragonal domain variants. For these films, the low‐field piezoelectric coefficient measured in the direction normal to the film surface (d₃₃) is 200 pm V^–1, which agrees well with the theoretical predictions. Under external AC electric fields of about 30 kV cm^–1, the (101) films exhibit reversible longitudinal strains as high as 0.35 %, which correspond to the effective piezoelectric coefficients in the order of 1000 pm V^–1 and can be explained by elastic softening of the PbZr_xTi_1–xO₃ ferroelectrics near the morphotropic phase boundary.     

3D Printing of Strong and Tough Double Network Granular Hydrogels

Many soft natural tissues display a fascinating set of mechanical properties that remains unmatched by manmade counterparts. These unprecedented mechanical properties are achieved through an intricate interplay between the structure and locally varying the composition of these natural tissues. This level of control cannot be achieved in soft synthetic materials. To address this shortcoming, a novel 3D printing approach to fabricate strong and tough soft materials is introduced, namely double network granular hydrogels (DNGHs) made from compartmentalized reagents. This is achieved with an ink composed of microgels that are swollen in a monomer-containing solution; after the ink is additive manufactured, these monomers are converted into a percolating network, resulting in a DNGH. These DNGHs are sufficiently stiff to repetitively support tensile loads up to 1.3 MPa. Moreover, they are more than an order of magnitude tougher than each of the pure polymeric networks they are made from. It is demonstrated that this ink enables printing macroscopic, strong, and tough objects, which can optionally be rendered responsive, with high shape fidelity. The modular and robust fabrication of DNGHs opens up new possibilities to design adaptive, strong, and tough hydrogels that have the potential to advance, for example, soft robotic applications.     

Highly Ordered Self‐Assembled Architectures of Modified Terpyridines on Highly Ordered Pyrolitic Graphite Imaged by Scanning Tunneling Microscopy

Scanning tunneling microscopy has been used to study the adsorbed phases of functionalized terpyridines at the solid–liquid interface of highly ordered pyrolitic graphite (HOPG). Terpyridines are well‐known for their complexing behavior to transition metal ions, making them widely used ligands in organometallic and supramolecular chemistry. We found that solutions of 2,2′:6′,2″‐terpyridine‐4′‐oxydodecane (tpy‐O‐C12) and 2,2′:6′,2″‐4′‐oxyoctadecane (tpy‐O‐C18) form highly ordered two‐ dimensional (2D) arrays on HOPG in phenyloctane. For both compounds, large, well‐defined lamellar domains have been observed with domain sizes larger than 500 nm. Sequential scans of an area with two grain boundaries indicate that desorption–resorption is taking place along the domain edges. High‐resolution images of the lamella have been obtained, and the 2D packing within the lamella was determined in detail. The terpyridines align in long uniform double rows with their alkyl chains packing in an alternating, zipper‐like fashion. The terpyridines pack with the polar head‐groups head to head, and the observed size and shape of the molecules fit exactly to their modeled geometries.     

Reversible Formation of g‐C3N4 3D Hydrogels through Ionic Liquid Activation: Gelation Behavior and Room‐Temperature Gas‐Sensing Properties

Many unique properties arise when the 3D stacking of layered materials is disrupted, originating nanostructures. Stabilization, and further reorganization of these individual layers into complex 3D structures, can be essential to allow these properties to persist in macroscopic systems. It is demonstrated that a simple hydrothermal process, assisted by ionic liquids (ILs), can convert bulk g‐C₃N₄ into a stable hydrogel. The gelation occurs through delamination of the layered structure, driven by particular interactions between the IL and the carbon nitride sheets, forming an amphiphilic foam‐like network. This study employs spectroscopic and computational tools to unravel the gelation mechanism, and provides a rational approach toward the stabilization of 2D materials in hydrogels. The solution‐processable hydrogels can also be used as building blocks of complex devices. Chemiresistive gas sensors employing g‐C₃N₄ 3D hydrogels exhibit superior response at room temperature, enabling effective gas sensing under low power conditions.     

3D2 Self‐Assembling Janus Peptide Dendrimers with Tailorable Supermultivalency

The self‐assembly of peptides enables the construction of self‐assembled peptide nanostructures (SPNs) with chemical composition similar to those of natural proteins; however, the structural complexity and functional properties of SPNs are far beneath those of natural proteins. One of the most fundamental challenges in fabricating more elaborate SPNs lies in developing building blocks that are simultaneously more complex and relatively easy to synthesize. Here, the development of self‐assembling Janus peptide dendrimers (JPDs) is reported, which have fully 3D structures similar to those of globular proteins. For the reliable and convenient synthesis of JPDs, a solid‐phase bifurcation synthesis method is devised. The self‐assembly behavior of JPDs is unique because only the dendrimer generation and not the weight fraction dictates the morphology of SPNs. The coassembly of two JPD building blocks provides an opportunity not only to enlarge the morphological repertoire in a predictable manner but also to discover SPNs with unusual and interesting morphologies. Because JPD assemblies have dual multivalency, i.e., supramolecular and unimolecular multivalency, the JPD system enables the statistical selection of materials with high avidity for the desired cell types and possibly any target receptors.     

Reinforcement of Shear Thinning Protein Hydrogels by Responsive Block Copolymer Self‐Assembly

Shear thinning hydrogels are promising materials that exhibit rapid self‐healing following the cessation of shear, making them attractive for applications including injectable biomaterials. Here, self‐assembly is demonstrated as a strategy to introduce a reinforcing network within shear thinning artificially engineered protein gels, enabling a responsive transition from an injectable state at low temperatures with a low yield stress to a stiffened state at physiological temperatures with resistance to shear thinning, higher toughness, and reduced erosion rates and creep compliance. Protein‐polymer triblock copolymers capable of the responsive self‐assembly of two orthogonal networks are synthesized. Midblock association forms a shear‐thinning network, while endblock aggregation at elevated temperatures introduces a second, independent physical network into the protein hydrogel. These reversible crosslinks introduce extremely long relaxation times and lead to a five‐fold increase in the elastic modulus, significantly larger than is expected from transient network theory. Thermoresponsive reinforcement reduces the high temperature creep compliance by over four orders of magnitude, decreases the erosion rate by at least a factor of five, and increases the yield stress by up to a factor of seven. Combined with the demonstrated potential of shear thinning artificial protein hydrogels for various uses, this reinforcement mechanism broadens the range of applications that can be addressed with shear‐thinning physical gels.     

3D Printing of Hydrogels for Stretchable Ionotronic Devices

In the booming development of flexible electronics represented by electronic skins, soft robots, and human–machine interfaces, 3D printing of hydrogels, an approach used by the biofabrication community, is drawing attention from researchers working on hydrogel-based stretchable ionotronic devices. Such devices can greatly benefit from the excellent patterning capability of 3D printing in three dimensions, as well as the free design complexity and easy upscale potential. Compared to the advanced stage of 3D bioprinting, 3D printing of hydrogel ionotronic devices is in its infancy due to the difficulty in balancing printability, ionic conductivity, shape fidelity, stretchability, and other functionalities. In this review, a guideline is provided on how to utilize the power of 3D printing in building high-performance hydrogel-based stretchable ionotronic devices mainly from a materials’ point of view, highlighting the systematic approach to balancing the printability, printing quality, and performance of printed devices. Various 3D printing methods for hydrogels are introduced, and then the ink design principles, balancing printing quality, printed functions, such as elastic conductivity, self-healing ability, and device (e.g., flexible sensors, shape-morphing actuators, soft robots, electroluminescent devices, and electrochemical biosensors) performances are discussed. In conclusion, perspectives on the future directions of this exciting field are presented.     

2D/2D 1T‐MoS2/Ti3C2 MXene Heterostructure with Excellent Supercapacitor Performance

2D/2D heterostructures can combine the collective advantages of each 2D material and even show improved properties from synergistic effects. 2D Transition metal carbide Ti₃C₂ MXene and 2D 1T‐MoS₂ have emerged as attractive prototypes in electrochemistry due to their rich properties. Construction of these two 2D materials, as well as investigation about synergistic effects, is absent due to the instability of 1T‐MoS₂. Here, 3D interconnected networks of 1T‐MoS₂/Ti₃C₂ MXene heterostructure are constructed by magneto‐hydrothermal synthesis, and the electrochemical storage mechanisms are investigated. Improved extra capacitance is observed due to enlarged ion storage space from a synergistically interplayed effect in 3D interconnected networks. Outstanding rate performance is realized because of ultrafast electron transport originating from Ti₃C₂ MXene. This work provides an archetype to realize excellent electrochemical properties in 2D/2D heterostructures.     

3D Printing of Multifunctional Conductive Polymer Composite Hydrogels

Functional conductive hydrogels are widely used in various application scenarios, such as artificial skin, cell scaffolds, and implantable bioelectronics. However, their novel designs and technological innovations are severely hampered by traditional manufacturing approaches. Direct ink writing (DIW) is considered a viable industrial-production 3D-printing technology for the custom production of hydrogels according to the intended applications. Unfortunately, creating functional conductive hydrogels by DIW has long been plagued by complicated ink formulation and printing processes. In this study, a highly 3D printable poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS)-based ink made from fully commercially accessible raw materials is demonstrated. It is shown that complex structures can be directly printed with this ink and then precisely converted into high-performance hydrogels via a post-printing freeze–thawing treatment. The 3D-printed hydrogel exhibits high electrical conductivity of ≈2000 S m⁻¹, outstanding elasticity, high stability and durability in water, electromagnetic interference shielding, and sensing capabilities. Moreover, the hydrogel is biocompatible, showing great potential for implantable and tissue engineering applications. With significant advantages, the fabrication strategy is expected to open up a new route to create multifunctional hydrogels with custom features, and can bring new opportunities to broaden the applications of hydrogel materials.     

Responsive Macroscopic Materials From Self‐Assembled Cross‐Linked SiO2‐PNIPAAm Core/Shell Structures

A way to obtain macroscopic responsive materials from silicon‐oxide polymer core/shell microstructures is presented. The microparticles are composed of a 60 nm SiO₂‐core with a random copolymer corona of the temperature responsive poly‐N‐isopropylacrylamide (PNIPAAm) and the UV‐cross‐linkable 2‐(dimethyl maleinimido)‐N‐ethyl‐acrylamide. The particles shrink upon heating and form a stable gel in both water and tetrahydrofuran (THF) at 3–5 wt% particle content. Cross‐linking the aqueous gel results in shrinkage when the temperature is increased above the lower critical solution temperature and it regains its original size upon cooling. By freeze drying with subsequent UV irradiation, thin stable layers are prepared. Stable fibers are produced by extruding a THF gel into water and subsequent UV irradiation, harnessing the cononsolvency effect of PNIPAAm in water/THF mixtures. The temperature responsiveness translates to the macroscopic materials as both films and fibers show the same collapsing behavior as the microcore/shell particle. The collapse and re‐swelling of the materials is related to the expelling and re‐uptake of water, which is used to incorporate gold nanoparticles into the materials by a simple heating/cooling cycle. This allows for future applications, as various functional particles (antibacterial, fluorescence, catalysis, etc.) can easily be incorporated in these systems.