Polymersomes Containing a Hydrogel Network for High Stability and Controlled Release

Capillary microfluidic devices are used to prepare monodisperse polymersomes consisting of a hydrogel core and a bilayer membrane of amphiphilic diblock‐copolymers. To make polymersomes, water‐in‐oil‐in‐water double‐emulsion drops are prepared as templates through single‐step emulsification in a capillary microfluidic device. The amphiphile‐laden middle oil phase of the double‐emulsion drop dewets from the surface of the innermost water drop, which contains hydrogel prepolymers; this dewetting leads to the formation of a bilayer membrane. Subsequently, the oil phase completely separates from the innermost water drop, leaving a polymersome. Upon UV illumination of the polymersome, the prepolymers encapsulated within the interior are crosslinked, forming a hydrogel core. The hydrogel network within the polymersomes facilitates sustained release of the encapsulated materials and increases the stability of the polymersomes through the formation of a scaffold to support the bilayer. In addition, this approach provides a facile method to make monodisperse hydrogel particles directly dispersed in water.     

Multi‐Reservoir Bioadhesive Microdevices for Independent Rate‐Controlled Delivery of Multiple Drugs

A variety of oral administrative systems such as enterically coated tablets, capsules, particles, and liposomes have been developed to improve oral bioavailability of drugs. However, they suffer from poor intestinal localization and therapeutic efficacy due to the various physiological conditions and high shear fluid flow. Fabrication of novel microdevices combined with the introduction of controlled release, improved adhesion, selective targeting, and tissue permeation may overcome these issues and potentially diminish the toxicity and high frequency of conventional oral administration. Herein, thin, asymmetric, poly(methyl methacrylate) (PMMA) microdevices are fabricated with multiple reservoirs using photolithography and reactive ion etching. They are loaded with different individual model drug in each reservoir. Enhanced bioadhesion of the microdevices is observed in the presence of a conjugated of targeting protein (tomato lectin) to the PMMA surface. As compared to drug encompassing hydrogels, an increase in drug permeation across the caco‐2 monolayer is noticed in the presence of a microdevice loaded with the same drug–hydrogel system. Also, the release of multiple drugs from their respective reservoirs is found to be independent from each other. The use of different hydrogel systems in each reservoir shows differences in the controlled release of the respective drugs over the same release period. These results suggest that, in the future, microfabricated unidirectional multi‐drug releasing devices will have an impact on the oral administration of a broad range of therapeutics.     

Vacancy‐Driven Gelation Using Defect‐Rich Nanoassemblies of 2D Transition Metal Dichalcogenides and Polymeric Binder for Biomedical Applications

A new approach of vacancy‐driven gelation to obtain chemically crosslinked hydrogels from defect‐rich 2D molybdenum disulfide (MoS₂) nanoassemblies and polymeric binder is reported. This approach utilizes the planar and edge atomic defects available on the surface of the 2D MoS₂ nanoassemblies to form mechanically resilient and elastomeric nanocomposite hydrogels. The atomic defects present on the lattice plane of 2D MoS₂ nanoassemblies are due to atomic vacancies and can act as an active center for vacancy‐driven gelation with a thiol‐activated terminal such as four‐arm poly(ethylene glycol)–thiol (PEG‐SH) via chemisorption. By modulating the number of vacancies on the 2D MoS₂ nanoassemblies, the physical and chemical properties of the hydrogel network can be controlled. This vacancy‐driven gelation process does not require external stimuli such as UV exposure, chemical initiator, or thermal agitation for crosslinking and thus provides a nontoxic and facile approach to encapsulate cells and proteins. 2D MoS₂ nanoassemblies are cytocompatible, and encapsulated cells in the nanocomposite hydrogels show high viability. Overall, the nanoengineered hydrogel obtained from vacancy‐driven gelation is mechanically resilient and can be used for a range of biomedical applications including tissue engineering, regenerative medicine, and cell and therapeutic delivery.     

Conductive Polymer Hydrogel Microfibers from Multiflow Microfluidics

Conductive hydrogels are receiving increasing attention for their utility in electronic area applications requiring flexible conductors. Here, it is presented novel conductive hydrogel microfibers with alginate shells and poly (3, 4‐ethylenedioxythiophene): poly (4‐styrenesulfonate) (PEDOT: PSS) cores fabricated using a multiflow capillary microfluidic spinning approach. Based on multiflow microfluidics, alginate shells are formed immediately from the fast gelation reaction between sodium alginate (Na‐Alg) and sheath laminar calcium chloride flows, while PEDOT: PSS cores are solidified slowly in the hollow alginate hydrogel shell microreactors after their precursor solutions are injected in situ as the center fluids. The resultant PEDOT: PSS‐containing microfibers are with features of designed morphology and highly controllable package, because material compositions or the sizes of their shell hydrogels can be tailored by using different concentrations or flow rates of pregel solutions. Moreover, the practical values of these microfibers in stretch sensitivity and bending stability are explored based on various electrical characterizations of the compound materials. Thus, it is believed that these microfluidic spinning PEDOT: PSS conductive microfibers will find important utility in electronic applications requiring flexible electronic systems.     

Temperature‐Sensitive Hydrogel‐Particle Films from Evaporating Drops

A simple method to prepare temperature‐sensitive films composed of micrometer‐sized colloidal hydrogel particles using evaporating drops of colloidal suspensions is demonstrated. The films range in thickness from a monolayer to approximately fifty particle diameters depending on initial particle volume fraction. Sessile droplets of hydrogel‐particle suspensions are evaporated on silicon wafers. The film is formed from particles spread densely over the air–water interface which then cross‐link and are deposited on the surface during the evaporation process. The resultant thin films exhibit a temperature‐responsiveness characteristic of the individual particles permitting modulation of size, shape, porosity, and optical transmission.     

Skin‐Inspired Multifunctional Autonomic‐Intrinsic Conductive Self‐Healing Hydrogels with Pressure Sensitivity,Stretchability, and 3D Printability

The advent of conductive self‐healing (CSH) hydrogels, a class of novel materials mimicking human skin, may change the trajectory of the industrial process because of their potential applications in soft robots, biomimetic prostheses, and health‐monitoring systems. Here, the development of a mechanically and electrically self‐healing hydrogel based on physically and chemically cross‐linked networks is reported. The autonomous intrinsic self‐healing of the hydrogel is attained through dynamic ionic interactions between carboxylic groups of poly(acrylic acid) and ferric ions. A covalent cross‐linking is used to support the mechanical structure of the hydrogel. Establishing a fair balance between the chemical and physical cross‐linking networks together with the conductive nanostructure of polypyrrole networks leads to a double network hydrogel with bulk conductivity, mechanical and electrical self‐healing properties (100% mechanical recovery in 2 min), ultrastretchability (1500%), and pressure sensitivity. The practical potential of CSH hydrogels is further revealed by their application in human motion detection and their 3D‐printing performance.     

Therapeutic‐Gas‐Responsive Hydrogel

Nitric oxide (NO) is a crucial signaling molecule with various functions in physiological systems. Due to its potent biological effect, the preparation of responsive biomaterials upon NO having temporally transient properties is a challenging task. This study represents the first therapeutic‐gas (i.e., NO)‐responsive hydrogel by incorporating a NO‐cleavable crosslinker. The hydrogel is rapidly swollen in response to NO, and not to other gases. Furthermore, the NO‐responsive gel is converted to enzyme‐responsive gels by cascade reactions from an enzyme to NO production for which the NO precursor is a substrate of the enzyme. The application of the hydrogel as a NO‐responsive drug‐delivery system is proved here by revealing effective protein drug release by NO infusion, and the hydrogel is also shown to be swollen by the NO secreted from the cultured cells. The NO‐responsive hydrogel may prove useful in many applications, for example drug‐delivery vehicles, inflammation modulators, and as a tissue scaffold.     

Tetra‐PEG Based Hydrogel Sealants for In Vivo Visceral Hemostasis

Medical sealant devices for in vivo hemostasis are far from satisfactory in the aged society. A major challenge is effective integration of quick hemorrhage control of the increased anticoagulated patients, high safety, and facile accessibility. Here, a well‐defined ammonolysis‐based Tetra‐PEG hydrogel sealant is developed with rapid gelation speed, strong tissue adhesion, and high mechanical strength. Introduction of cyclized succinyl ester groups into a hydrogel matrix endows the sealant with fast degradable and controllably dissolvable properties. The hydrogel possesses outstanding hemostatic capabilities even under the anticoagulated conditions while displaying excellent biocompatibility and feasibility. These results reveal that the optimized hydrogel may be a facile, effective, and safe sealant for hemorrhage control in vivo.     

Self‐Assembly of Enzyme‐Like Nanofibrous G‐Molecular Hydrogel for Printed Flexible Electrochemical Sensors

Conducting hydrogels provide great potential for creating designer shape‐morphing architectures for biomedical applications owing to their unique solid–liquid interface and ease of processability. Here, a novel nanofibrous hydrogel with significant enzyme‐like activity that can be used as “ink” to print flexible electrochemical devices is developed. The nanofibrous hydrogel is self‐assembled from guanosine (G) and KB(OH)₄ with simultaneous incorporation of hemin into the G‐quartet scaffold, giving rise to significant enzyme‐like activity. The rapid switching between the sol and gel states responsive to shear stress enables free‐form fabrication of different patterns. Furthermore, the replication of the G‐quartet wires into a conductive matrix by in situ catalytic deposition of polyaniline on nanofibers is demonstrated, which can be directly printed into a flexible electrochemical electrode. By loading glucose oxidase into this novel hydrogel, a flexible glucose biosensor is developed. This study sheds new light on developing artificial enzymes with new functionalities and on fabrication of flexible bioelectronics.     

Cold‐Responsive Nanocapsules Enable the Sole‐Cryoprotectant‐Trehalose Cryopreservation of β Cell–Laden Hydrogels for Diabetes Treatment

Islet transplantation has been one promising strategy in diabetes treatment, which can maintain patient's insulin level long‐term and avoid periodical insulin injections. However, donor shortage and temporal mismatch between donors and recipients has limited its widespread use. Therefore, searching for islet substitutes and developing efficient cryopreservation technology (providing potential islet bank for transplantation on demand) is in great need. Herein, a novel cryopreservation method is developed for islet β cells by combining microfluidic encapsulation and cold‐responsive nanocapsules (CR‐NCs). The cryopreserved cell‐laden hydrogels (calcium alginate hydrogel, CAH) can be transplanted for diabetes treatment. During the freezing process, trehalose is released inside β cells through the CR‐NCs and serves as the sole cryoprotectant (CPA). Additionally, CAH helps cells to survive the freeze–thaw process and provide cells with a natural immune barrier in vivo. Different from traditional cryopreservation methods, this method combining the CR‐NCs and hydrogel encapsulation replaces the toxic CPAs with natural trehalose. Great preservation results are obtained and transplantation experiments of diabetic rats further prove the excellent glucose regulation ability of such β cell–laden hydrogels post cryopreservation. This novel cryopreservation method helps to establish a reliable and ready‐to‐use bank of biological samples for transplantation therapy and other biomedical applications.     

Adhesive Hemostatic Conducting Injectable Composite Hydrogels with Sustained Drug Release and Photothermal Antibacterial Activity to Promote Full‐Thickness Skin Regeneration During Wound Healing

Developing injectable nanocomposite conductive hydrogel dressings with multifunctions including adhesiveness, antibacterial, and radical scavenging ability and good mechanical property to enhance full‐thickness skin wound regeneration is highly desirable in clinical application. Herein, a series of adhesive hemostatic antioxidant conductive photothermal antibacterial hydrogels based on hyaluronic acid‐graft‐dopamine and reduced graphene oxide (rGO) using a H₂O₂/HPR (horseradish peroxidase) system are prepared for wound dressing. These hydrogels exhibit high swelling, degradability, tunable rheological property, and similar or superior mechanical properties to human skin. The polydopamine endowed antioxidant activity, tissue adhesiveness and hemostatic ability, self‐healing ability, conductivity, and NIR irradiation enhanced in vivo antibacterial behavior of the hydrogels are investigated. Moreover, drug release and zone of inhibition tests confirm sustained drug release capacity of the hydrogels. Furthermore, the hydrogel dressings significantly enhance vascularization by upregulating growth factor expression of CD31 and improve the granulation tissue thickness and collagen deposition, all of which promote wound closure and contribute to a better therapeutic effect than the commercial Tegaderm films group in a mouse full‐thickness wounds model. In summary, these adhesive hemostatic antioxidative conductive hydrogels with sustained drug release property to promote complete skin regeneration are an excellent wound dressing for full‐thickness skin repair.     

Diffusion–Freezing‐Induced Microphase Separation for Constructing Large‐Area Multiscale Structures on Hydrogel Surfaces

Hydrogels with multiscale structured surface have attracted significant attention for their valuable applications in diverse areas. However, current strategies for the design and fabrication of structured hydrogel surfaces, which suffer from complicated manufacturing processes and specific material modeling, are not efficient to produce structured hydrogel surfaces in large area, and therefore restrict their practical applications. To address this problem, a general and reliable method is reported, which relies on the interplay between polymer chain diffusion and the subsequent freezing‐induced gelation and microphase separation processes. The basic idea is systematically analyzed and further exploited to manufacture gel surfaces with gradient structures and patterns through the introduction of temperature gradient and shape control of the contact area. Moreover, the formed micro/nanostructured surfaces are exemplified to work as capillary systems and thus can uplift the liquid spontaneously indicating the potential application for anti‐dehydration. It is believed that the proposed facile and large‐area fabrication method can inspire the design of materials with various functionalized surfaces.     

Remotely Triggerable Drug Delivery Systems

Triggerable drug delivery systems enable on‐demand controlled release profiles that may enhance therapeutic effectiveness and reduce systemic toxicity. Recently, a number of new materials have been developed that exhibit sensitivity to visible light, near‐infrared (NIR) light, ultrasound, or magnetic fields. This responsiveness can be triggered remotely to provide flexible control of dose magnitude and timing. Here we review triggerable materials that range in scale from nano to macro, and are activated by a range of stimuli.     

Preparation of a Mitochondria‐targeted and NO‐Releasing Nanoplatform and its Enhanced Pro‐Apoptotic Effect on Cancer Cells

The therapeutic applications of exogenous nitric oxide are usually limited by its short half‐life and its vulnerability to many biological substances, thus straightforward and precise spatiotemporal control of NO delivery may be critical to its therapeutic effects. Herein, the mitochondria‐targeted and photoresponsive NO‐releasing nanosystem is demonstrated as a new approach for cancer treatment. The nanosystem is fabricated by covalently incorporating a NO photo‐donor and a mitochondria targeting ligand onto carbon‐dots; accordingly, multi‐functionalities (mitochondria‐targeting, light‐enhanced efficient NO‐releasing, and cell imaging) are achieved. The in vitro NO release profiles for the nanosystem show that the duration of NO release from the present C‐dot‐based nanosystem containing immobilized SNO can be extended up to 8 hours or more. Upon cellular internalization, the nanosystem can target mitochondria and release NO. The action of the nanosystem on three cancer cell lines is evaluated; it is found that the targeted NO‐releasing system can cause high cytotoxicity towards the cancer cells by specifically damaging their mitochondria. Additionally, light irradiation can amplify the cell apoptosis by enhancing NO release. These observations demonstrate that incorporating mitochondria‐targeting ligand onto a NO‐releasing system can enhance its pro‐apoptosis action, thereby providing new insights for exploiting NO in cancer therapy.     

Liposome Crosslinked Polyacrylamide/DNA Hydrogel: a Smart Controlled‐Release System for Small Molecular Payloads

A novel stimuli‐responsive hydrogel system with liposomes serving as both noncovalent crosslinkers and functional small molecules carriers for controlled‐release is developed. Liposomes can crosslink polyacrylamide copolymers functionalized with cholesterol‐modified DNA motifs to yield a DNA hydrogel system, due to the hydrophobic interaction between cholesteryl groups and the lipid bilayer of liposomes. Functional information encoded DNA motifs on the polymer backbones endow the hydrogel with programmable smart responsive properties. In a model system, the hydrogel exhibits stimuli‐responsive gel‐to‐sol transformation triggered by the opening of DNA motifs upon the presence of a restriction endonuclease enzyme, EcoR I, or temperature change, realizing the controlled‐release of liposomes which are highly efficient carriers of active small molecules payloads. Two active molecules, 1,1‐dioctadecyl‐3,3,3,3‐tetramethylindodicarbocyanine perchlorate (DiIC18(5)) and calcein, are chosen as the hydrophobic and hydrophilic model payloads, respectively, to address the feasibility of the releasing strategy. Moreover, the hydrogel exhibits injectable property as well as self‐recovery behaviors.     

Efficient One‐Step Production of Microencapsulated Hepatocyte Spheroids with Enhanced Functions

Hepatocyte spheroids microencapsulated in hydrogels can contribute to liver research in various capacities. The conventional approach of microencapsulating spheroids produces a variable number of spheroids per microgel and requires an extra step of spheroid loading into the gel. Here, a microfluidics technology bypassing the step of spheroid loading and controlling the spheroid characteristics is reported. Double‐emulsion droplets are used to generate microencapsulated homotypic or heterotypic hepatocyte spheroids (all as single spheroids <200 μm in diameter) with enhanced functions in 4 h. The composition of the microgel is tunable as demonstrated by improved hepatocyte functions during 24 d culture (albumin secretion, urea secretion, and cytochrome P450 activity) when alginate‐collagen composite hydrogel is used instead of alginate. Hepatocyte spheroids in alginate‐collagen also perform better than hepatocytes cultured in collagen‐sandwich configuration. Moreover, hepatocyte functions are significantly enhanced when hepatocytes and endothelial progenitor cells (used as a novel supporting cell source) are co‐cultured to form composite spheroids at an optimal ratio of 5:1, which could be further boosted when encapsulated in alginate‐collagen. This microencapsulated‐spheroid formation technology with high yield, versatility, and uniformity is envisioned to be an enabling technology for liver tissue engineering as well as biomanufacturing.     

Simultaneous Measurements of Geometric and Viscoelastic Properties of Hydrogel Microbeads Using Continuous‐Flow Microfluidics with Embedded Electrodes

Geometric and mechanical characterizations of hydrogel materials at the microscale are attracting increasing attention due to their importance in tissue engineering, regenerative medicine, and drug delivery applications. Contemporary approaches for measuring the these properties of hydrogel microbeads suffer from low‐throughput, complex system configuration, and measurement inaccuracy. In this work, a continuous‐flow device is developed to measure geometric and viscoelastic properties of hydrogel microbeads by flowing the microbeads through a tapered microchannel with an array of interdigitated microelectrodes patterned underneath the channel. The viscoelastic properties are derived from the trajectories of microbeads using a quasi‐linear viscoelastic model. The measurement is independent of the applied volumetric flow rate. The results show that the geometric and viscoelastic properties of Ca‐alginate hydrogel microbeads can be determined independently and simultaneously. The bulky high‐speed optical systems are eliminated, simplifying the system configuration and making it a truly miniaturized device. A throughput of up to 394 microbeads min^?1 is achieved. This study may provide a powerful tool for mechanical profiling of hydrogel microbeads to support their wide applications.     

Injectable and Radiopaque Liquid Metal/Calcium Alginate Hydrogels for Endovascular Embolization and Tumor Embolotherapy

Improved endovascular embolization can contribute to assistant treatment for patients. However, many traditional embolic materials, such as metal microcoils or liquid embolic agents, are associated with limitations of coil migration or recanalization. Herein, as the first trial, an injectable and radiopaque liquid metal/calcium alginate (LM/CA) hydrogel is introduced and fabricated as a candidate for endovascular embolization and tumor embolotherapy through developing LM droplets as radiopaque units into biocompatible calcium alginate cross‐linked network. The adoption of LM droplets makes hydrogels radiopaque under X‐ray and CT scan, which significantly facilitates the tracking of material location during surgical vascular operation. In addition, in vitro and in vivo experiments prove that such smart hydrogel could convert from liquid to solid rapidly via cross‐linking, showing pretty flexible and controllable functions. Benefiting from these properties, the hydrogel can be performed in blood vessels through injection via syringes and then served as an embolic material for endovascular embolization procedures. In vivo experiments demonstrate that such hydrogels can occlude arteries and block blood flow until they ultimately lead to ischemic necrosis of tumors and partial healthy tissues. Overall, the present LM/CA hydrogels are promising to be developed as new generation embolic materials for future tumor embolotherapy.     

Hierarchical Hydrogen Bonds Directed Multi‐Functional Carbon Nanotube‐Based Supramolecular Hydrogels

Supramolecular hydrogels (SMHs) are three‐dimensional networks filled with a large amount of water. The crosslinking force in the 3D network is always constructed by relatively weak and dynamic non‐covalent interactions, and thus SMHs usually possess extremely high susceptibility to external environment and can show extraordinary stimuli‐responsive, self‐healing or other attractive properties. However, the overall crosslinking force in hydrogel networks is difficult to flexibly modulate, and this leads to limited functions of the SMHs. In this regard, hierarchical hydrogen bonds, that is, the mixture of relatively strong and relatively weak hydrogen bonds, are used herein as crosslinking force for the hydrogel preparation. The ratio of strong and weak hydrogen bonds can be finely tuned to tailor the properties of resultant gels. Thus, by delicate manipulation of the overall crosslinking force in the system, a hydrogel with multiple (thermal, pH and NIR light) responsiveness, autonomous self‐healing property and interesting temperature dependent, reversible adhesion behavior is obtained. This kind of hierarchical hydrogen bond manipulation is proved to be a general method for multiple‐functionality hydrogel preparation, and the resultant material shows potential for a range of applications.     

Myocardial‐Infarction‐Responsive Smart Hydrogels Targeting Matrix Metalloproteinase for On‐Demand Growth Factor Delivery

Although in situ restoration of blood supply to the infarction region and attenuating pre‐existing extracellular matrix degradation remain potential therapeutic approaches for myocardial infarction (MI), local delivery of therapeutics has been limited by low accumulation (inefficacy) and unnecessary diffusion (toxicity). Here, a dual functional MI‐responsive hydrogel is fabricated for on‐demand drug delivery to promote angiogenesis and inhibit cardiac remodeling by targeting upregulated matrix metalloproteinase‐2/9 (MMP‐2/9) after MI. A glutathione (GSH)‐modified collagen hydrogel (collagen‐GSH) is prepared by conjugating collagen amine groups with GSH sulfhydryl groups and the recombinant protein GST‐TIMP‐bFGF (bFGF: basic fibroblast growth factor) by fusing bFGF with glutathione‐S‐transferase (GST) and MMP‐2/9 cleavable peptide PLGLAG (TIMP). Specific binding between GST and GSH significantly improves the amount of GST‐TIMP‐bFGF loaded in collagen‐GSH hydrogel. The TIMP peptide enclosed between GST and bFGF responds to MMPs for on‐demand release during MI. Additionally, the TIMP peptide is a competitive substrate of MMPs that inhibits the excessive degradation of cardiac matrix by MMPs after MI. GST‐TIMP‐bFGF/collagen‐GSH hydrogels promote the recovery of MI rats by enhancing vascularization and ameliorating myocardium remodeling. The results suggest that on‐demand growth factor delivery by synchronously controlling binding and responsive release to promote angiogenesis and attenuate cardiac remodeling might be promising for the treatment of ischemic heart disease.