Functional Nanomaterials on 2D Surfaces and in 3D Nanocomposite Hydrogels for Biomedical Applications

An emerging approach to improve the physicobiochemical properties and the multifunctionality of biomaterials is to incorporate functional nanomaterials (NMs) onto 2D surfaces and into 3D hydrogel networks. This approach is starting to generate promising advanced functional materials such as self‐assembled monolayers (SAMs) and nanocomposite (NC) hydrogels of NMs with remarkable properties and tailored functionalities that are beneficial for a variety of biomedical applications, including tissue engineering, drug delivery, and developing biosensors. A wide range of NMs, such as carbon‐, metal‐, and silica‐based NMs, can be integrated into 2D and 3D biomaterial formulations due to their unique characteristics, such as magnetic properties, electrical properties, stimuli responsiveness, hydrophobicity/hydrophilicity, and chemical composition. The highly ordered nano‐ or microscale assemblies of NMs on surfaces alter the original properties of the NMs and add enhanced and/or synergetic and novel features to the final SAMs of the NM constructs. Furthermore, the incorporation of NMs into polymeric hydrogel networks reinforces the (soft) polymer matrix such that the formed NC hydrogels show extraordinary mechanical properties with superior biological properties.     

Organogels versus Hydrogels: Advantages,Challenges, and Applications

Organogels are an important class of gels, and are comparable to hydrogels owing to their properties as liquid-infused soft materials. Despite the extensive choice of liquid media and compatible networks that can provide a broader range of properties, relatively few studies are reported in this area. This review presents the applicability of organogels concerning their choice of components, unique properties, and applications. Their distinctive features compared to other gels are discussed, including multi-stimuli responses, affinity to a broad range of substances, thermal and environmental stability, electronic and ionic conductivity, and actuation. The active role of solvents is highlighted in the versatility of organogel properties. To differentiate between organogels and other gels, these are classified as gels filled with different organic liquids, including highly polar organic solvents and binary solvent systems. Most promising applications of organogels as sophisticated multifunctional materials are discussed in light of their unique features.     

4D Printing of Multi-Stimuli Responsive Protein-Based Hydrogels for Autonomous Shape Transformations

Stimuli responsive hydrogels that can change shape in response to applied external stimuli are appealing for soft robotics, biomedical devices, drug delivery, and actuators. However, existing 3D printed shape morphing materials are non-biodegradable, which limits their use in biomedical applications. Here, 3D printed protein-based hydrogels are developed and applied for programmable structural changes under the action of temperature, pH, or an enzyme. Key to the success of this strategy is the use of methacrylated bovine serum albumin (MA–BSA) as a biodegradable building block to Pickering emulsion gels in the presence of N-isopropylacrylamide or 2-dimethylaminoethyl methacrylate. These shear-thinning gels are ideal for direct ink write (DIW) 3D printing of multi-layered stimuli-responsive hydrogels. While poly(N-isopropylacrylamide) and poly(dimethylaminoethyl methacrylate) introduce temperature and pH-responsive properties into the printed objects, a unique feature of this strategy is an enzyme-triggered shape transformation based on the degradation of the bovine serum albumin network. To highlight this technique, protein-based hydrogels that reversibly change shape based on environmental temperature and pH are fabricated, and irreversibly altered by enzymatic degradation, which demonstrates the complexity that can be introduced into 4D printed systems.     

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.     

Bioinspired Reversibly Cross‐linked Hydrogels Comprising Polypeptide Micelles Exhibit Enhanced Mechanical Properties

Noncovalently cross‐linked networks are attractive hydrogel platforms because of their facile fabrication, dynamic behavior, and biocompatibility. The majority of noncovalently cross‐linked hydrogels, however, exhibits poor mechanical properties, which significantly limit their utility in load bearing applications. To address this limitation, hydrogels are presented composed of micelles created from genetically engineered, amphiphilic, elastin‐like polypeptides that contain a relatively large hydrophobic block and a hydrophilic terminus that can be cross‐linked through metal ion coordination. To create the hydrogels, heat is firstly used to trigger the self‐assembly of the polypeptides into monodisperse micelles that display transition metal coordination motifs on their coronae, and subsequently cross‐link the micelles by adding zinc ions. These hydrogels exhibit hierarchical structure, are stable over a large temperature range, and exhibit tunable stiffness, self‐healing, and fatigue resistance. Gels with polypeptide concentration of 10%, w/v, and higher show storage moduli of ≈1 MPa from frequency sweep tests and exhibit self‐healing within minutes. These reversibly cross‐linked, hierarchical hydrogels with enhanced mechanical properties have potential utility in a variety of biomedical applications.     

Hydrogel−Solid Hybrid Materials for Biomedical Applications Enabled by Surface‐Embedded Radicals

Combinations of hydrogels and solids provide high level functionality for devices such as tissue engineering scaffolds and soft machines. However, the weak bonding between hydrogels and solids hampers functionality. Here, a versatile strategy to develop mechanically robust solid?hydrogel hybrid materials using surface embedded radicals generated through plasma immersion ion implantation (PIII) of polymeric surfaces is reported. Evidence is provided that the reactive radicals play a dual role: inducing surface‐initiated, spontaneous polymerization of hydrogels; and binding the hydrogels to the surfaces. Acrylamide and silk hydrogels are formed and covalently attached through spontaneous reactions with the radicals on PIII activated polymer surfaces without cross‐linking agents or initiators. The hydrogel amount increases with incubation time, monomer concentration, and temperature. Stability tests indicate that 95% of the hydrogel is retained even after 4 months in PBS solution. T‐peel tests show that failure occurs at the tape?hydrogel interface and the hydrogel‐PIII‐treated PTFE interfacial adhesion strength is over 300 N m^?1. Cell assays show no adhesion to the as‐synthesized hydrogels; however, hydrogels synthesized with fibronectin enable cell adhesion and spreading. These results show that polymers functionalized with surface‐embedded radicals provide excellent solid platforms for the generation of robust solid?hydrogel hybrid structures for biomedical applications.     

Hydrophobized Hydrogels: Construction Strategies,Properties, and Biomedical Applications

Hydrogels, as 3D networks containing huge amount of water, display similarity to soft tissues, and thus they are of wide interest in tissue engineering. Hydrogels, due to biocompatibility and porous structure, are valuable therapeutic platforms for hydrophilic drugs. Over the last decade, there has been a strong emphasis on the development of hydrogel platforms with the ability to increase the solubility of hydrophobic drugs. However, the pronounced discrepancy between the hydrophilic character of hydrogels and the hydrophobic nature of numerous pharmacologically active compounds is problematic. In recent years, different strategies are applied using special polymer constructs or composite materials exploiting the advanced scientific knowledge in the area of polymer and lipid-based nano- and microcarriers hydrophobization of the hydrogel turns out to be not only valuable in terms of achieving the ability to dissolve poorly soluble drugs in water, but also proves to be crucial in obtaining bioadhesion in wet conditions, but also, unexpected abnormal water swelling behavior, as well as in mechanical properties such as the dissipation mechanism and self-healable hydrogel properties. This review is mainly focused on recent advances in the usage of hydrophobized hydrogels in biomedical applications.     

Double-Interlinked Colloidal Gels for Programable Fabrication of Supraparticle Architectures

Engineering colloidal gel inks with suitable features for fabricating robust supraparticle architectures through 3D printing may overcome the challenges of precisely controlling nanoparticles spatial distribution across multiple scales. Herein, oppositely charged proteinaceous-polymeric nanoparticles are combined to generate multi-component colloidal gel (COGEL) inks for fabricating supraparticle volumetric architectures. Leveraging on different nano-functional units, double-interlinked supraparticle assemblies are established via electrostatic interactions and on-demand covalent photocrosslinking. The COGEL inks are readily processable through in-air extrusion 3D printing, forming stable colloidal filaments. 3D printing yielded architecturally defined and robust supraparticle constructs that supported human stem cells attachment and cytoskeletal spreading. Owing to double interparticle interlinks the fabricated supraparticle constructs remained stable under physiological conditions and high/low shear stress, improving over the lower mechanical stability of single-interlinked platforms. Double-interlinked COGELs are processable via suspension 3D printing, unlocking the freeform volumetric writing of nanoparticle inks in protein-based hydrogels volume. The dual-interlinked COGEL technology opens new possibilities for generating user-defined supraparticle architectures with precise volumetric distribution of nanoparticles, both in-air and in-hydrogel platforms. The freedom to select modular multi-particle combinations, as well as the rapid 3D programming of COGEL inks, broadens the range of modular colloidal materials that can be fabricated for a variety of biomedical applications.     

Two-Photon Polymerization of Sugar Responsive 4D Microstructures

Stimuli-responsive hydrogels have attracted much attention owing to the versatility of their programmed response in offering intelligent solutions for biomimicry applications, such as soft robotics, tissue engineering, and drug delivery. To achieve the complexity of biomimetic structures, two photon polymerization (2PP) has provided a means of fabricating intricate 3D structures from stimuli-responsive hydrogels. Rapid swelling hydrogel microstructures are advantageous for osmotically driven stimuli-response, where actuation speed, that is reliant on the diffusion of analytes or bioanalytes, can be optimized. Herein, the flexibility of 2PP is exploited to showcase a novel sugar-responsive, phenylboronic acid-based photoresist. This offers a remarkable solution for achieving fast response hydrogel systems that have been often hindered by the volume-dependent diffusion times of analytes to receptor sites. A phenylboronic acid-based photoresist compatible with 2PP is presented to fabricate stimuli-responsive microstructures with accelerated response times. Moreover, microstructures with programmable actuation (i.e., bending and opening) are fabricated using the same photoresist within a one-step fabrication process. By combining the flexibility of 2PP with an easily adaptable photoresist, an accessible fabrication method is showcased for sophisticated and chemo-responsive 3D hydrogel actuators.     

Biomedical Applications of DNA‐Based Hydrogels

Nucleic acids are gaining significant attention as versatile building blocks for the next generation of soft materials. Due to significant advances in the chemical synthesis and biotechnological production, DNA becomes more widely available enabling its usage as bulk material in various applications. This has prompted researchers to actively explore the unique features offered by DNA‐containing materials like hydrogels. In this review article, recent developments in the field of hydrogels that feature DNA as a component either in the construction of the material or as functional unit within the construct and their biomedical applications are discussed in detail. First, different synthetic approaches for obtaining DNA hydrogels are summarized, which allows classification of DNA materials according to their structure. Then, new concepts, properties, and applications are highlighted such as DNA‐based biosensor devices, drug delivery platforms, and cell scaffolds. With the 2018 Nobel Prize in Physiology or Medicine being awarded to cancer immunotherapy underscoring the importance of this therapy, DNA hydrogel systems designed to modulate the immune system are introduced. This review aims to give the reader a timely overview of the most important and recent developments in this emerging class of therapeutically useful materials of DNA‐based hydrogels.     

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.     

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.     

Mechanically Strong and Multifunctional Hybrid Hydrogels with Ultrahigh Electrical Conductivity

Stretchable conductive hydrogels with simultaneous high mechanical strength/modulus, and ultrahigh, stable electrical conductivity are ideal for applications in soft robots, artificial skin, and bioelectronics, but to date, they are still very challenging to fabricate. Herein, sandwich-structured hybrid hydrogels based on layers of aramid nanofibers (ANFs) reinforced polyvinyl alcohol (PVA) hydrogels and a layer of silver nanowires (AgNWs)/PVA are fabricated by electrospinning combined with vacuum-assisted filtration. The hybrid ANF-PVA hydrogels exhibit excellent mechanical properties with the tensile modulus of 10.7–15.4 MPa, tensile strength of 3.3–5.5 MPa, and fracture energy up to 5.7 kJ m⁻², primarily attributed to the strong hydrogen bonding interactions between PVA and ANFs and in-plane alignment of the fibrous structure. Rational design of heterogeneous structure endows the hydrogels with ultrahigh apparent electrical conductivity of 1.66 × 10⁴ S m⁻¹, among the highest electrical conductivities ever reported so far for conductive hydrogels. More importantly, this ultrahigh conductivity remains constant upon a broad range of applied strains from 0–90% and over 500 stretching cycles. Furthermore, the hydrogels exhibit excellent Joule heating and electromagnetic interference shielding performances due to the ultrahigh electrical conductivity. These mechanically strong, hybrid hydrogels with ultrahigh and strain-invariant electrical conductivity represent great promises for many important applications such as flexible electronics.     

Ionic Liquid–Polymer Composites: A New Platform for Multifunctional Applications

Ionic liquids (ILs) have emerged as a novel class of chemical compounds for the development of advanced (multi)functional materials with outstanding potential in applications of several areas due to their unique properties and functionalities. The combination of ILs with polymers, in a composite, allows for developing smart materials, which synergistically combine the features of specific polymers and ILs. Moreover, ILs can be extensively modified by the incorporation of functional groups with specific properties into the cation, anion, or both. Thus, it is possible to tune the IL, the polymer, or both to obtain a broad spectrum of multifunctional composites and address the specific requirements of many applications. This work focusses on advanced materials and strategies concerning ILs and polymers for the development of smart IL/polymer‐based materials for applications including responsive and sensitive sensors, actuators, environment, batteries, fuel cells, and biomedical applications.     

Induction of Four-Dimensional Spatiotemporal Geometric Transformations in High Cell Density Tissues via Shape-Changing Hydrogels

Developing and healing tissues begin as cellular condensations. Spatiotemporal changes in tissue geometry, transformations in the spatial distribution of the cells, and extracellular matrix are essential for its evolution into a functional tissue. 4D materials, 3D materials capable of geometric changes, may have the potential to recreate the aforementioned biological phenomenon. However, most reported 4D materials are non-degradable and/or not biocompatible, limiting their application in regenerative medicine, and to date, there are no systems controlling the geometry of high density cellular condensations and differentiation. Here, 4D high cell density tissues based on shape-changing hydrogels are described. By sequential photocrosslinking of oxidized and methacrylated alginate (OMA) and methacrylated gelatin (GelMA), bilayered hydrogels presenting controllable geometric changes without any external stimuli are fabricated. Fibroblasts and human adipose-derived stem cells (ASCs) are encapsulated at concentrations up to 1.0 × 10⁸ cells mL^–1 in the 4D constructs, and controllable shape changes are achieved in concert with ASCs differentiated down chondrogenic and osteogenic lineages. Bioprinting of the high density cell-laden OMA and GelMA permits the formation of more complex constructs with defined 4D geometric changes, which may further expand the promise of this approach in regenerative medicine applications.     

Ascidian‐Inspired Fast‐Forming Hydrogel System for Versatile Biomedical Applications: Pyrogallol Chemistry for Dual Modes of Crosslinking Mechanism

Exploitation of unique biochemical and biophysical properties of marine organisms has led to the development of functional biomaterials for various biomedical applications. Recently, ascidians have received great attention, owing to their extraordinary properties such as strong underwater adhesion and rapid self‐regeneration. Specific polypeptides containing 3,4,5‐trihydroxyphenylalanine (TOPA) in the blood cells of ascidians are associated with such intrinsic properties generated through complex oxidative processes. In this study, a bioinspired hydrogel platform is developed, demonstrating versatile applicability for tissue engineering and drug delivery, by conjugating pyrogallol (PG) moiety resembling ascidian TOPA to hyaluronic acid (HA). The HA–PG conjugate can be rapidly crosslinked by dual modes of oxidative mechanisms using an oxidant or pH control, resulting in hydrogels with different mechanical and physical characteristics. The versatile utility of HA–PG hydrogels formed via different crosslinking mechanisms is tested for different biomedical platforms, including microparticles for sustained drug delivery and tissue adhesive for noninvasive cell transplantation. With extraordinarily fast and different routes of PG oxidation, ascidian‐inspired HA–PG hydrogel system may provide a promising biomaterial platform for a wide range of biomedical applications.     

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.     

Environmentally Adaptive Polymer Hydrogels: Maintaining Wet-Soft Features in Extreme Conditions

Hydrogels have been widely explored to adapt to different application circumstances. As typical wet-soft materials, the high-water content of hydrogels is beneficial to their wide biomedical applications. Moreover, hydrogels have been displaying considerable application potential in some high-tech areas, like brain-computer interface, intelligent actuator, flexible sensor, etc. However, traditional hydrogel is susceptive to freezing below zero, dehydration, performance swelling-induced deformation, and suffers from mechanical damage in extremely mechanical environments, which result in the loss of wet-soft peculiarities (e.g., flexibility, structure integrity, transparency), greatly limiting their applications. Therefore, reducing the freezing point, improving the dehydration/solution resistance, and designing mechanical adaptability are effective strategies to endow hydrogels with the extreme environmental adaptability, thus broadening their application fields. This review systematically summarizes research advances of environmentally adaptive hydrogels (EAHs), comprising anti-freezing, dehydration-resistant, acid/base/swelling deformation-resistant, and mechanical environment adaptive hydrogels (MEAHs). Firstly, fabrication methods are presented, including the deep eutectic solvent/ionic liquid substituent, the addition of salts, organogel, polymer network modification, and double network (DN) complex/nanocomposite strategy, etc. Meanwhile, the features of different approaches are overviewed. The mechanisms, properties, and applications (e.g., intelligent actuator, wound dressing, flexible sensor) of EAHs are demonstrated. Finally, the issues and future perspectives for EAHs’ researches are demonstrated.     

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.