Microgel‐Based Stimuli‐Responsive Capsules

In this paper, a preparation of stimuli‐responsive capsules based on aqueous microgels is described. Microgel particles act as stabilizers for oil‐in‐water emulsion and organize themselves on the surface of chloroform droplets containing the biodegradable polymer poly(4‐hydroxybutyrate‐co‐4‐hydroxyvalerate) (PHBV). After chloroform evaporation, composite capsules consisting of a thin PHBV wall with integrated microgels are obtained. Due to the presence of microgels acting as sensitive building blocks, the capsules respond to different stimuli (temperature, solvent concentration). Preliminary results indicate that the capsule dimensions and morphology can be tuned by microgel and PHBV concentration in water and chloroform, respectively.     

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.     

Harnessing the Power of Stimuli‐Responsive Polymers for Actuation

A common behavior found in nature is the ability of plants and animals to naturally respond to their surroundings through actuation. Stimuli‐responsive polymers exhibit the same ability to naturally respond to changes in their environment, although manipulating them in a manner that allows their responses to be harnessed to do work via actuation is far from trivial. In this Review, examples that use temperature, pH, light, and electric field (and other) stimulation for actuation are highlighted. The actuation can result in materials that can be used to grip, lift, and move objects as well as for their own movement. As tremendous progress is being made in this research area, it is hard to imagine a future without these materials impacting lives in some way.     

Stimuli‐Responsive DNA‐Gated Nanoscale Porous Carbon Derived from ZIF‐8

Stimuli‐responsive nanoscale porous carbon derived from ZIF‐8 (NCZIF) gated by DNA capping units is reported. The NCZIF is first obtained by calcination of nano‐ZIF‐8 crystals under an inert atmosphere. It is further conjugated with amine‐modified single‐stranded DNA after carboxylation (DNA/NCZIF). The guest molecules are sealed in the pore of NCZIF by the formation of a DNA duplex structure on the surface of NCZIF. As proof of principle, two systems that can be, respectively, used for controlled drug delivery and biosensing are introduced. In the first system, the drug model (rhodamine 6G, Rh6G) is locked in the NCZIF by the DNA capping units composed of rich‐G sequences and its complementary DNA strand. The in vitro cellular experiments reveal that DNA/NCZIF has good biocompatibility and can controllably release Rh6G upon the K⁺‐stimuli in cells. In the second system, the signal probe (methylene blue, MB) is locked in the NCZIF and then released after the unlocking of the pores triggered by the dissociation of the aptamer‐hybrid capping units. The MB‐loaded DNA/NCZIF can linearly respond to target molecules in the range from 1 × 10^?9 to 10 × 10^?6 m and has good specificity.     

Multi‐Stimuli‐Responsive Microcapsules for Adjustable Controlled‐Release

Novel multi‐stimuli‐responsive microcapsules with adjustable controlled‐release characteristics are prepared by a microfluidic technique. The proposed microcapsules are composed of crosslinked chitosan acting as pH‐responsive capsule membrane, embedded magnetic nanoparticles to realize “site‐specific targeting”, and embedded temperature‐responsive sub‐microspheres serving as “micro‐valves”. By applying an external magnetic field, the prepared smart microcapsules can achieve targeting aggregation at specific sites. Due to acid‐induced swelling of the capsule membranes, the microcapsules exhibit higher release rate at specific acidic sites compared to that at normal sites with physiological pH. More importantly, through controlling the hydrodynamic size of sub‐microsphere “micro‐valves” by regulating the environment temperature, the release rate of drug molecules from the microcapsules can be flexibly adjusted. This kind of multi‐stimuli‐responsive microcapsules with site‐specific targeting and adjustable controlled‐release characteristics provides a new mode for designing “intelligent” controlled‐release systems and is expected to realize more rational drug administration.     

Multifunctional and Stimuli‐Responsive Polydopamine Nanoparticle‐Based Platform for Targeted Antimicrobial Applications

The rising threat of antimicrobial resistance is a crisis of a global scale. If not addressed, it can lead to health care system problems worldwide. This warrants alternative therapeutic approaches whose mechanism of action starkly differs from conventional antibiotic‐based therapies. Here, a multifunctional and stimuli‐responsive (NIR laser‐activated) antimicrobial platform is engineered by combining the intrinsic photothermal capability and excellent biocompatibility of polydopamine nanoparticles (PdNPs), with the membrane targeting and lytic activities of an antimicrobial peptide (AMP). The resulting PdNP‐AMP nanosystem can specifically target and destabilize the mechanical integrity of the outer membrane of Escherichia coli, as measured using the atomic force microscope. Furthermore, the laser‐induced nano‐localized heating of PdNP—in close proximity to the already compromised bacterial envelope—induces further membrane damage. This results in a more efficient, laser‐activated, bacterial killing action of PdNP‐AMP. The antimicrobial platform developed in this work is shown to be effective against a drug‐resistant E. coli. Overall, this work highlights the advantage and strength of combining multiple and coordinated biocidal mechanisms, into one nanomaterial‐based system and its promise in treating drug‐resistant pathogens.     

Stimuli‐Responsive Materials for Controlled Release of Theranostic Agents

Stimuli‐responsive materials are so named because they can alter their physicochemical properties and/or structural conformations in response to specific stimuli. The stimuli can be internal, such as physiological or pathological variations in the target cells/tissues, or external, such as optical and ultrasound radiations. In recent years, these materials have gained increasing interest in biomedical applications due to their potential for spatially and temporally controlled release of theranostic agents in response to the specific stimuli. This article highlights several recent advances in the development of such materials, with a focus on their molecular designs and formulations. The future of stimuli‐responsive materials will also be explored, including combination with molecular imaging probes and targeting moieties, which could enable simultaneous diagnosis and treatment of a specific disease, as well as multi‐functionality and responsiveness to multiple stimuli, all important in overcoming intrinsic biological barriers and increasing clinical viability.     

Stimuli‐Responsive Materials Based on Interpenetrating Polymer Liquid Crystal Hydrogels

Stimuli‐responsive materials based on interpenetrating liquid crystal‐hydrogel polymer networks are fabricated. These materials consist of a cholesteric liquid crystalline network that reflects color and an interwoven poly(acrylic acid) network that provides a humidity and pH response. The volume change in the cross‐linked hydrogel polymer results in a dimensional alteration in the cholesteric network as well, which, in turn, leads to a color change yielding a dual‐responsive photonic material. Furthermore a patterned coating having responsive and static interpenetrating polymer network areas is produced that changes both its surface topography and color.     

Templated Assembly of pH‐Labile Polymer‐Drug Particles for Intracellular Drug Delivery

The preparation of pH‐labile polymer‐drug particles via mesoporous silica‐templated assembly for anticancer drug delivery into cancer cells is reported. The polymer‐drug conjugate is synthesized via thiol‐maleimide click chemistry using thiolated poly(methacrylic acid) (PMA_SH) and a pH‐labile doxorubicin (Dox) derivative. Drug‐loaded polymer particles that are stable under physiological conditions are obtained through infiltration of the conjugates into mesoporous silica particles, followed by cross‐linking the PMA_SH chains, and subsequent removal of the porous silica templates. The encapsulated Dox is released from the particles through cleavage of the hydrazone bonds between Dox and PMA_SH at endosomal/lysosomal pH. Cell viability assays show that the assembled PMA_SH particles have negligible cytotoxicity to LIM1899 human colorectal cancer cells. In comparison, Dox‐loaded PMA_SH particles cause significant cell death following internalization. The reported particles represent a novel and versatile class of stimuli‐responsive carriers for controlled drug delivery.     

Dual Stimuli‐Responsive Supramolecular Polypeptide‐Based Hydrogel and Reverse Micellar Hydrogel Mediated by Host–Guest Chemistry

Versatile strategies are currently being discovered for the fabrication of synthetic polypeptide‐based hybrid hydrogels, which have potential applications in polymer therapeutics and regenerative medicine. Herein, a new concept—the reverse micellar hydrogel—is introduced, and a versatile strategy is provided for fabricating supramolecular polypeptide‐based normal micellar hydrogel and reverse micellar hydrogels from the same polypeptide‐based copolymer via the cooperation of host–guest chemistry and hydrogen‐bonding interactions. The supramolecular hydrogels are thoroughly characterized, and a mechanism for their self‐assembly is proposed. These hydrogels can respond to dual stimuli—temperature and pH—and their mechanical and controlled drug‐release properties can be tuned by the copolymer topology and the polypeptide composition. The reverse micellar hydrogel can load 10% of the anticancer drug doxorubicin hydrochloride (DOX) and sustain DOX release for 45 days, indicating that it could be useful as an injectable drug delivery system.     

Stimuli‐Responsive Donor–Acceptor and DNA‐Crosslinked Hydrogels: Application as Shape‐Memory and Self‐Healing Materials

Carboxymethyl cellulose (CMC) chains are functionalized with self‐complementary nucleic acid tethers and electron donor or electron acceptor functionalities. The polymer chains crosslinked by the self‐complementary duplex nucleic acids and the donor–acceptor complexes as bridging units, yield a stiff stimuli‐responsive hydrogel. Upon the oxidation of the electron donor units, the donor–acceptor bridging units are separated, leading to a hydrogel of lower stiffness. By the cyclic oxidation and reduction of the donor units, the hydrogel is reversibly transformed across low and high stiffness states. The controlled stiffness properties of the hydrogel are used to develop shape‐memory hydrogels. In addition, CMC hydrogels crosslinked by donor–acceptor complexes and K⁺‐stabilized G‐quadruplexes reveal stimuli‐responsive properties that exhibit dually triggered stiffness functions. While the hydrogel bridged by the two crosslinking motifs reveals high stiffness, the redox‐stimulated separation of the donor–acceptor complexes or the crown‐ether‐stimulated separation of the G‐quadruplex bridges yields two alternative hydrogels exhibiting low stiffness states. The control over the stiffness properties of the dually triggered hydrogel is used to develop shape‐memory hydrogels, where the donor–acceptor units or G‐quadruplex bridges act as “memories”, and to develop triggered self‐healing process of the hydrogel.     

Chitosan Hydrogel‐Capped Porous SiO2 as a pH Responsive Nano‐Valve for Triggered Release of Insulin

A pH responsive, chitosan‐based hydrogel film is used to cap the pores of a porous SiO₂ layer. The porous SiO₂ layer is prepared by thermal oxidation of an electrochemically etched Si wafer, and the hydrogel film is prepared by reaction of chitosan with glycidoxypropyltrimethoxysilane (GPTMS). Optical reflectivity spectroscopy and scanning electron microscopy (SEM) confirm that the bio‐polymer only partially infiltrates the porous SiO₂ film, generating a double layer structure. The optical reflectivity spectrum displays Fabry–Pérot interference fringes characteristic of a double layer, which is characterized using reflective interferometric Fourier transform spectroscopy (RIFTS). Monitoring the position of the RIFTS peak corresponding to the hydrogel layer allows direct, real‐time observation of the reversible volume phase transition of the hydrogel upon cycling of pH in the range 6.0–7.4. The swelling ratio and response time are controlled by the relative amount of GPTMS in the hydrogel. The pH‐dependent volume phase transition can be used to release insulin trapped in the porous SiO₂ layer underneath the hydrogel film. At pH 7.4, the gel in the top layer effectively blocks insulin release, while at pH 6.0 insulin penetrates the swollen hydrogel layer, resulting in a steady release into solution.     

Stimuli‐Directing Self‐Organized 3D Liquid‐Crystalline Nanostructures: From Materials Design to Photonic Applications

3D photonic nanostructures with desirable functionalities in the visible light region and beyond have been recently given vast and increasing attentions because of the ability to control or confine electromagnetic waves in all three dimensions. Although substantial progress has been made in fabricating 3D nanostructures by means of lithography and nanotechnology, various bottlenecks still need to be overcome, and developing soft 3D stimuli‐directed nanostructures with tailored properties remains a challenging but exciting work. In this context, soft nanotechnology—i.e., exploiting self‐organized soft materials in nanotechnology—is emerging as a vibrant and burgeoning field of research in the bottom‐up nanofabrication of intelligent stimuli‐driven 3D photonic materials and devices. Liquid‐crystalline materials undoubtedly represent such a marvelous dynamic system that combines the liquid‐like fluidity and crystal‐like ordering from molecular to macroscopic material levels. Importantly, being “soft” makes the materials responsive to various stimuli such as temperature, light, mechanical force, and electric and magnetic fields as well as chemical and electrochemical reactions, resulting in a fascinating tunability of dynamic photonic bandgaps in the 3D nanostructure that provides numerous opportunities in all‐optical integrated circuits and next‐generation communication systems. Here, the development of 3D photonic nanostructures is reviewed, culminating with perspectives for the future scope and challenges of these emerging soft 3D photonic nanostructures towards device applications.     

Multifunctional Graphene Oxide‐based Triple Stimuli‐Responsive Nanotheranostics

Construction of multifunctional stimuli‐responsive nanosystems intelligently responsive to inner physiological and/or external irradiations based on nanobiotechnology can enable the on‐demand drug release and improved diagnostic imaging to mitigate the side‐effects of anticancer drugs and enhance the diagnostic/therapeutic outcome simultaneously. Here, a triple‐functional stimuli‐responsive nanosystem based on the co‐integration of superparamagnetic Fe₃O₄ and paramagnetic MnO_x nanoparticles (NPs) onto exfoliated graphene oxide (GO) nanosheets by a novel and efficient double redox strategy (DRS) is reported. Aromatic anticancer drug molecules can interact with GO nanosheets through supramolecular π stacking to achieve high drug loading capacity and pH‐responsive drug releasing performance. The integrated MnO_x NPs can disintegrate in mild acidic and reduction environment to realize the highly efficient pH‐responsive and reduction‐triggered T₁‐weighted magnetic resonance imaging (MRI). Superparamagnetic Fe₃O₄ NPs can not only function as the T₂‐weighted contrast agents for MRI, but also response to the external magnetic field for magnetic hyperthermia against cancer. Importantly, the constructed biocompatible GO‐based nanoplatform can inhibit the metastasis of cancer cells by downregulating the expression of metastasis‐related proteins, and anticancer drug‐loaded carrier can significantly reverse the multidrug resistance (MDR) of cancer cells.     

Stimuli‐Responsive Nucleic Acid‐Based Polyacrylamide Hydrogel‐Coated Metal–Organic Framework Nanoparticles for Controlled Drug Release

The synthesis of doxorubicin‐loaded metal–organic framework nanoparticles (NMOFs) coated with a stimuli‐responsive nucleic acid‐based polyacrylamide hydrogel is described. The formation of the hydrogel is stimulated by the crosslinking of two polyacrylamide chains, P_A and P_B, that are functionalized with two nucleic acid hairpins ( 4 ) and ( 5 ) using the strand‐induced hybridization chain reaction. The resulting duplex‐bridged polyacrylamide hydrogel includes the anti‐ATP (adenosine triphosphate) aptamer sequence in a caged configuration. The drug encapsulated in the NMOFs is locked by the hydrogel coating. In the presence of ATP that is overexpressed in cancer cells, the hydrogel coating is degraded via the formation of the ATP–aptamer complex, resulting in the release of doxorubicin drug. In addition to the introduction of a general means to synthesize drug‐loaded stimuli‐responsive nucleic acid‐based polyacrylamide hydrogel‐coated NMOFs hybrids, the functionalized NMOFs resolve significant limitations associated with the recently reported nucleic acid‐gated drug‐loaded NMOFs. The study reveals substantially higher loading of the drug in the hydrogel‐coated NMOFs as compared to the nucleic acid‐gated NMOFs and overcomes the nonspecific leakage of the drug observed with the nucleic‐acid‐protected NMOFs. The doxorubicin‐loaded, ATP‐responsive, hydrogel‐coated NMOFs reveal selective and effective cytotoxicity toward MDA‐MB‐231 breast cancer cells, as compared to normal MCF‐10A epithelial breast cells.     

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.     

In‐Film Bioprocessing and Immunoanalysis with Electroaddressable Stimuli‐Responsive Polysaccharides

Advances in thin‐film fabrication are integral to enhancing the power of microelectronics while fabrication methods that allow the integration of biological molecules are enabling advances in bioelectronics. A thin‐film‐fabrication method that further extends the integration of biology with microelectronics by allowing living biological systems to be assembled, cultured, and analyzed on‐chip with the aid of localized electrical signals is described. Specifically, the blending of two stimuli‐responsive film‐forming polysaccharides for electroaddressing is reported. The first, alginate, can electrodeposit by undergoing a localized sol–gel transition in response to electrode‐imposed anodic signals. The second, agarose, can be co‐deposited with alginate and forms a gel upon a temperature reduction. Electrodeposition of this dual polysaccharide network is observed to be a simple, rapid, and spatially selective means for assembly. The bioprocessing capabilities are examined by co‐depositing a yeast clone engineered to display a variable lymphocyte receptor protein on the cell surface. Results demonstrate the in‐film expansion and induction of this cell population. Analysis of the cells' surface proteins is achieved by the electrophoretic delivery of immunoreagents into the film. These results demonstrate a simple and benign means to electroaddress hydrogel films for in‐film bioprocessing and immunoanalysis.