Stimuli-Responsive Nanocomposite Hydrogels for Biomedical Applications

The complex tissue-specific physiology that is orchestrated from the nano- to the macroscale, in conjugation with the dynamic biophysical/biochemical stimuli underlying biological processes, has inspired the design of sophisticated hydrogels and nanoparticle systems exhibiting stimuli-responsive features. Recently, hydrogels and nanoparticles have been combined in advanced nanocomposite hybrid platforms expanding their range of biomedical applications. The ease and flexibility of attaining modular nanocomposite hydrogel constructs by selecting different classes of nanomaterials/hydrogels, or tuning nanoparticle-hydrogel physicochemical interactions widely expands the range of attainable properties to levels beyond those of traditional platforms. This review showcases the intrinsic ability of hybrid constructs to react to external or internal/physiological stimuli in the scope of developing sophisticated and intelligent systems with application-oriented features. Moreover, nanoparticle-hydrogel platforms are overviewed in the context of encoding stimuli-responsive cascades that recapitulate signaling interplays present in native biosystems. Collectively, recent breakthroughs in the design of stimuli-responsive nanocomposite hydrogels improve their potential for operating as advanced systems in different biomedical applications that benefit from tailored single or multi-responsiveness.     

Synthesis of a Novel,Biodegradable Electrically Conducting Polymer for Biomedical Applications

We report the synthesis and characterization of a novel biomaterial that possesses the unique properties of being both electrically conducting and biodegradable; and thus capable of electronic interfacing with tissue. This polymer was synthesized from conducting oligomers of pyrrole and thiophene that are connected together via degradable ester linkages. We demonstrate that this polymer is conductive, degradable, and biocompatible.     

Polydopamine Encapsulation of Fluorescent Nanodiamonds for Biomedical Applications

Fluorescent nanodiamonds (FNDs) are promising bioimaging probes compared with other fluorescent nanomaterials such as quantum dots, dye‐doped nanoparticles, and metallic nanoclusters, due to their remarkable optical properties and excellent biocompatibility. Nevertheless, they are prone to aggregation in physiological salt solutions, and modifying their surface to conjugate biologically active agents remains challenging. Here, inspired by the adhesive protein of marine mussels, encapsulation of FNDs within a polydopamine (PDA) shell is demonstrated. These PDA surfaces are readily modified via Michael addition or Schiff base reactions with molecules presenting thiol or nitrogen derivatives. Modification of PDA shells by thiol terminated poly(ethylene glycol) (PEG‐SH) molecules to enhance colloidal stability and biocompatibility of FNDs is described. Their use as fluorescent probes for cell imaging is demonstrated; it is found that PEGylated FNDs are taken up by HeLa cells and mouse bone marrow‐derived dendritic cells and exhibit reduced nonspecific membrane adhesion. Furthermore, functionalization with biotin‐PEG‐SH is demonstrated and long‐term high‐resolution single‐molecule fluorescence based tracking measurements of FNDs tethered via streptavidin to individual biotinylated DNA molecules are performed. This robust polydopamine encapsulation and functionalization strategy presents a facile route to develop FNDs as multifunctional labels, drug delivery vehicles, and targeting agents for 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.     

Stimuli‐Responsive Thin Coatings Using Elastin‐Like Polymers for Biomedical Applications

Smart thin coatings using a recombinant elastin‐like polymer (ELP) containing the cell attachment sequence arginine–glycine–(aspartic acid) (RGD) are fabricated for the first time through simple deposition of the ELP dissolved in aqueous‐based solutions. The biopolymer is produced and characterized using electrophoresis and mass spectroscopy. The temperature and pH responsiveness are assessed by aggregate size measurements and differential scanning calorimetry. The deposition of the studied ELP onto chitosan is followed in situ with a quartz‐crystal microbalance with dissipation monitoring (QCM‐D). Contact angle measurements are performed at room temperature and at 50 °C, showing reversible changes from a moderate hydrophobic behavior to an extremely wettable surface. AFM analysis performed at room temperature reveals a smooth surface and no organized structure. At 50 °C, the surface presents spherical nanometer‐sized structures of collapsed biopolymer chains. Such results suggest that the ELP chains, when collapsed, aggregate into micelle‐like structures at the surface of the substrate, increasing its water affinity. Cell adhesion tests on the developed coatings are conducted using a SaOS‐2 cell line. Enhanced cell adhesion could be observed in the H‐RGD6‐coated surfaces, as compared with the original chitosan monolayer. An intermediate behavior is found in chitosan coated with the corresponding ELP without the RGD sequence. Therefore, the developed films have great potential as biomimetic coatings of biomaterials for different biomedical applications, including tissue engineering and controlled delivery of bioactive agents. Their thermo‐responsive behavior can also be exploited for tunable cell adhesion and controlled protein adsorption.     

Squaraine Dyes for Photovoltaic and Biomedical Applications

Squaraine dyes (SQs) are an important class of polymethine dyes with a unique reasonable-stabilized zwitterionic structure, in which electrons are highly delocalized over the conjugated bridge. These dyes can not only be easily synthesized via a condensation, but also exhibit intense absorption and emission in the visible and near-infrared region with excellent photochemical stability, making them attractive material candidates for many photoelectric and biomedical applications. Thus, in this review, after an introduction of SQs, the recent advances of SQs in the photovoltaic field are comprehensively summarized including dye-sensitized solar cells, organic solar cells, and perovskite solar cells. Then, the important advances in the use of SQs as the biosensors, biological imaging, and photodynamic/photothermal therapy reagents in the biomedical field are also discussed. Finally, a summary and outlook will be provided with some new perspectives for the future design of SQs.     

Tunable 3D Nanoresonators for Gas‐Sensing Applications

The detection of gas species with high sensitivity is a significant task for fundamental sciences as well as for industrial applications. Similarly, the ongoing trend for device miniaturization brings new challenges for advanced fabrication including on‐demand functionality tuning. Following this motivation, here the additive, direct‐write fabrication of freestanding 3D nanoarchitectures is introduced, which can be brought into mechanical resonance via electric AC fields. Specifically, this study focuses on the 3D nanostructure synthesis, the subsequent determination of Young's modulus, and demonstrates a postgrowth procedure, which can precisely tune the material modulus. As‐fabricated resonators reveal a Young's modulus of 9–13 GPa, which can be increased by a factor greater than 5. Next, the electric readout of the resonance behavior is demonstrated via electric current measurement as an essential element for the resonance sensor applications. Finally, the implications of gas‐physisorption and gas‐chemisorption on the resonance frequencies are studied, representing a proof‐of‐principle for sensing applications by the here presented approach.     

An Anti-Freezing,Ambient-Stable and Highly Stretchable Ionic Skin with Strong Surface Adhesion for Wearable Sensing and Soft Robotics

Natural living systems such as wood frogs develop tissues composed of active hydrogels with cryoprotectants to survive in cold environments. Recently, hydrogels have been intensively studied to develop stretchable electronics for wearables and soft robots. However, regular hydrogels are inevitably frozen at the subzero temperature and easily dehydrated, and have weak surface adhesion. Herein, a novel hydrogel-based ionic skin (iSkin) capable of strain sensing is demonstrated with high toughness, high stretchability, excellent ambient stability, superior anti-freezing capability, and strong surface adhesion. The iSkin consists of a piece of ionically and covalently cross-linked tough hydrogel with a thin bioadhesive layer. With the addition of biocompatible cryoprotectant and electrolyte, the iSkin shows good conductivity in wide ranges of relative humidity (15–90%) and temperature (−95–25 °C). In addition, the iSkin can adhere firmly to diverse material surfaces under different conditions, including cloth fabric, skin, and elastomers, in both dry and wet conditions, at subzero temperature, and/or with dynamic movement. The iSkin is demonstrated for applications including strain sensing on both human body and winter coat, human–machine interaction, motion/deformation sensing on a soft gripper and a soft robot at extremely cold conditions. This work provides a new paradigm for developing high-performance artificial skins for wearable sensing and soft robotics.     

Flexible,Conformal Organic Synaptic Transistors on Elastomer for Biomedical Applications

Bioelectronics in synaptic transistors for future biomedical applications, such as implanted treatments and human–machine interfaces, must be flexible with good mechanical compatibility with biological tissues. The rigid nature and high deposition temperature in conventional inorganic synaptic transistors restrict the development of flexible, conformal synaptic devices. Here, the dinaphtho[2,3‐b:2′,3′‐f]thieno[3,2‐b]‐thiophene organic synaptic transistor on elastic polydimethylsiloxane is demonstrated to avoid these limitations. The unique advantages of organic materials in low Young's modulus and low temperature process enable seamless adherence of organic synaptic transistors on arbitrary‐shaped objects. On 3D curved surfaces, the essential synaptic functions, such as potentiation/depression, short/long‐term synaptic plasticity, and spike voltage–dependent plasticity, are successfully realized. The time‐dependent surface potential characterization reveals the slow polarization of dipoles in the dielectric is responsible for hysteresis and synaptic behaviors. This work represents that organic materials offer a potential platform to realize the flexible, conformal synaptic transistors for the development of wearable and implantable artificial neuromorphic systems.     

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.     

Recent Progress of Conductive Hydrogel Fibers for Flexible Electronics: Fabrications,Applications, and Perspectives

Flexible conductive materials with intrinsic structural characteristics are currently in the spotlight of both fundamental science and advanced technological applications due to their functional preponderances such as the remarkable conductivity, excellent mechanical properties, and tunable physical and chemical properties, and so on. Typically, conductive hydrogel fibers (CHFs) are promising candidates owing to their unique characteristics including light weight, high length-to-diameter ratio, high deformability, and so on. Herein, a comprehensive overview of the cutting-edge advances the CHFs involving the architectural features, function characteristics, fabrication strategies, applications, and perspectives in flexible electronics are provided. The fundamental design principles and fabrication strategies are systematically introduced including the discontinuous fabrication (the capillary polymerization and the draw spinning) and the continuous fabrication (the wet spinning, the microfluidic spinning, 3D printing, and the electrospinning). In addition, their potential applications are crucially emphasized such as flexible energy harvesting devices, flexible energy storage devices, flexible smart sensors, and flexible biomedical electronics. This review concludes with a perspective on the challenges and opportunities of such attractive CHFs, allowing for better understanding of the fundamentals and the development of advanced conductive hydrogel materials.     

Mild Methodology for the Versatile Chemical Modification of Polylactide Surfaces: Original Combination of Anionic and Click Chemistry for Biomedical Applications

Biodegradable aliphatic polyesters such as polylactide (PLA) are widely used in medical applications. When employed as an implantable material, the control of the surface properties of PLA is of great interest because biochemical reactions occur on the surface or at interfaces. Thus, chemical modifications of the surface of degradable polyesters can be used to tailor the surface properties while preserving the bulk characteristics. This paper proposes a simple and versatile method of preventing polymer degradation and immobilizing simple molecules, macromolecules, and biomolecules on PLA surfaces. The method is based on a one‐pot, two‐step procedure: anionic activation under selected conditions followed by propargylation to form a “clickable” PLA surface. This surface is extensively characterized by SEC and fluorescence techniques using a fluorescent probe, confirming both the functionalization and the absence of PLA degradation. An example of the surface immobilization of a bioactive compound is then described: a well‐defined α‐azido‐functionalized poly(quaternary ammonium) synthesized via ATRP is covalently bound to the propargylated PLA surface using “click” chemistry. This covalent grafting is confirmed by SEC and XPS analyses. The increase in surface hydrophilicity is demonstrated by water contact‐angle measurements. Finally, a primary investigation is conducted to determine the antibacterial activity of modified PLA surfaces against E. coli and S. aureus.     

A Self‐Healable,Highly Stretchable,and Solution Processable Conductive Polymer Composite for Ultrasensitive Strain and Pressure Sensing

Mimicking human skin's functions to develop electronic skins has inspired tremendous efforts in design and synthesis of novel soft materials with simplified fabrication methods. However, it still remains a great challenge to develop electronically conductive materials that are both stretchable and self‐healable. Here it is demonstrated that a ternary polymer composite comprised of polyaniline, polyacrylic acid, and phytic acid can exhibit high stretchability ( ≈ 500%) and excellent self‐healing properties. The polymer composite with optimized composition shows an electrical conductivity of 0.12 S cm^?1. On rupture, both electrical and mechanical properties can be restored with ≈ 99% efficiency in a 24 h period, which is enabled by the dynamic hydrogen bonding and electrostatic interactions. It is further shown that this composite is both strain and pressure sensitive, and therefore can be used for fabricating strain and pressure sensors to detect a variety of mechanical deformations with ultrahigh sensitivity. The sensitivity and sensing range are the highest among all of the reported self‐healable piezoresistive pressure sensors and even surpass most flexible mechanical sensors. Notably, this composite is prepared via a solution casting process, which potentially allows for large‐area, low‐cost fabrication electronic skins.     

Materials in Organic Electrochemical Transistors for Bioelectronic Applications: Past,Present, and Future

Organic electrochemical transistors are bioelectronic devices that exploit the coupled nature of ionic and electronic fluxes to achieve superior transducing abilities compared to conventional organic field effect transistors. In particular, the operation of organic electrochemical transistors relies on a channel material capable of conducting both ionic and electronic charge carriers to ensure bulk electrochemical doping. This review explores the various types of organic semiconductors that are employed as channel materials, with a particular focus on the past 5 years, during which the transducing abilities of organic electrochemical transistors have witnessed an almost tenfold increase. Specifically, the structure–property relationships of the various channel materials employed are investigated, highlighting how device performance can be related to functionality at the molecular level. Finally, an outlook on the field is provided, in particular toward the design guidelines of future materials and the challenges ahead in the field.     

A Review of Design and Fabrication Methods for Nanoparticle Network Hydrogels for Biomedical,Environmental, and Industrial Applications

Nanoparticle network hydrogels (NNHs) in which nanoparticles are used as a key building block to build the gel network have attracted significant interest given their potential to leverage the favorable properties of both hydrogels (e.g., hydrophilicity, tunable pore sizes, mechanics, etc.) and a variety of different nanoparticles (e.g., high surface area, chemical activity, independently tunable porosity, mechanics) to create new functional materials. Herein, recent progress in the design and use of NNHs is comprehensively reviewed, with an emphasis on defining the typical gel morphologies/architectures that can be achieved with NNHs, the typical crosslinking approaches used to fabricate NNHs, the fundamental properties and functional benefits of NNHs, and the reported applications of NNHs in electronics (flexible electronics, sensors), environmental (sorbents, separations), agriculture, self-cleaning-materials, and biomedical (drug delivery, tissue engineering) applications. In particular, the way in which the NNH structure is applied to improve the performance of the hydrogel in each application is emphasized, with the aim to develop a set of principles that can be used to rationally design NNHs for future uses.     

Covalent Organic Frameworks: Structures,Synthesis, and Applications

Covalent organic frameworks (COFs) are crystalline porous polymers formed by a bottom‐up approach from molecular building units having a predesigned geometry that are connected through covalent bonds. They offer positional control over their building blocks in two and three dimensions. This control enables the synthesis of rigid porous structures with a high regularity and the ability to fine‐tune the chemical and physical properties of the network. This Feature Article provides a comprehensive overview over the structures realized to date in the fast growing field of covalent organic framework development. Different synthesis strategies to meet diverse demands, such as high crystallinity, straightforward processability, or the formation of thin films are discussed. Furthermore, insights into the growing fields of COF applications, including gas storage and separations, sensing, electrochemical energy storage, and optoelectronics are provided.     

Cucurbiturils-Mediated Noble Metal Nanoparticles for Applications in Sensing,SERS, Theranostics,and Catalysis

Noble metal nanoparticles (NMNPs), which spring up like mushrooms, are gaining momentum owing to their unique physicochemical characteristics. Cucurbiturils, a class of synthetic macrocycles with intriguing and peculiar host–guest properties, have stimulated tremendous research interest in recent years. The marriage of NMNPs with cucurbiturils is expected to integrate and enhance the excellent characteristics of both components, e.g., precisely controlled particle size, stability, assembly, surface functionality, biocompatibility, tunable optical properties, and high catalytic activities. This review systematically outlines the recent progress on the fabricating strategies and important applications of cucurbiturils-mediated NMNPs in sensing, surface-enhanced Raman scattering, theranostics, and catalysis. A brief outlook on the future development of cucurbiturils-mediated NMNPs is also presented.     

Engineering Route for Stretchable, 3D Microarchitectures of Wide Bandgap Semiconductors for Biomedical Applications

Wide bandgap (WBG) semiconductors have attracted significant research interest for the development of a broad range of flexible electronic applications, including wearable sensors, soft logical circuits, and long-term implanted neuromodulators. Conventionally, these materials are grown on standard silicon substrates, and then transferred onto soft polymers using mechanical stamping processes. This technique can retain the excellent electrical properties of wide bandgap materials after transfer and enables flexibility; however, most devices are constrained by 2D configurations that exhibit limited mechanical stretchability and morphologies compared with 3D biological systems. Herein, a stamping-free micromachining process is presented to realize, for the first time, 3D flexible and stretchable wide bandgap electronics. The approach applies photolithography on both sides of free-standing nanomembranes, which enables the formation of flexible architectures directly on standard silicon wafers to tailor the optical transparency and mechanical properties of the material. Subsequent detachment of the flexible devices from the support substrate and controlled mechanical buckling transforms the 2D precursors of wide band gap semiconductors into complex 3D mesoscale structures. The ability to fabricate wide band gap materials with 3D architectures that offer device-level stretchability combined with their multi-modal sensing capability will greatly facilitate the establishment of advanced 3D bio-electronics interfaces.     

Surface-Triggered In Situ Gelation for Tunable Conformal Hydrogel Coating of Therapeutic Cells and Biomedical Devices

Hydrogel coatings have been proposed as a promising strategy to improve the biocompatibility of therapeutic cells and biomedical devices. However, developed coating methods are only applicable for simple geometries, typical sizes, and limited substrates. In addition, its applications in therapeutic cell encapsulation are hampered by inadequate construction of the hydrogel capsules such as off-center encapsulation, immense volume, and lack of control over the thickness of capsules. Here, a method called surface-triggered in situ gelation (STIG) for universal hydrogel coating of multiscale objects ranging from single cells to mini-organs to biomedical devices with arbitrary shapes and heterogeneous components is reported. By covering cells or devices with calcium carbonate particles, progressive propagation of alginate hydrogel from their surface under the stimulation of GDL is achieved. The thickness of the hydrogel layers can be easily controlled from several micrometers to hundreds of micrometers by adjusting the gelation time and the release rate of calcium ions. Importantly, STIG facilitates accurate, complete, and individual cell encapsulation, which potentially overcomes the pitfalls of conventional strategies. It is further proven that the low-cost and facile method can potentially lead to advances in different fields by rendering precisely controlled microscale alginate layers on a wide variety of biomedical substrates.