“Smart” Surface Capsules for Delivery Devices

This review describes emerging trends, basic principles, applications, and future challenges for designing next generation responsive “smart” surface capsules. Advances and importance of “surface” capsules which are not deposited onto the surface but are built into the surface are highlighted for selective applications with specific examples of surface sponge structures formed by high intensity ultrasonic surface treatment (HIUS). Surface capsules can be adapted for biomedical applications, membrane materials, lab‐on‐chip, organ‐on‐chip, and for template synthesis. They provide attractive self‐healing anticorrosion and antifouling prospects. Nowadays delivery systems are built from inorganic, organic, hybrid, biological materials to deliver various drugs from low molecular weight substances to large protein molecules and even live cells. It is important that capsules are designed to have time prolonged release features. Available stimuli to control capsule opening are physical, chemical and biological ones. Understanding the underlying mechanisms of capsule opening by different stimuli is essential for developing new methods of encapsulation, release, and targeting. Development of “smart” surface capsules is preferable to respond to multiple stimuli. More and more often a new generation of “smart” capsules is designed by a bio‐inspired approach.     

Drug delivery: Layer‐By‐Layer‐Assembled Capsules and Films for Therapeutic Delivery (Small 17/2010)

Polymeric materials formed via layer‐by‐layer (LbL) assembly have promise for use as drug delivery vehicles. These multilayered materials, both as capsules and thin films, can encapsulate a high payload of toxic or sensitive drugs, and can be readily engineered and functionalized with specific properties. This review highlights important and recent studies that advance the use of LbL‐assembled materials as therapeutic devices. It also seeks to identify areas that require additional investigation for future development of the field. A variety of drug‐loading methods and delivery routes are discussed. The biological barriers to successful delivery are identified, and possible solutions to these problems are discussed. Finally, state‐of‐the‐art degradation and cargo release mechanisms are also presented.     

Subcompartmentalized Polymer Hydrogel Capsules with Selectively Degradable Carriers and Subunits

Subcompartmentalized hydrogel capsules (SHCs) with selectively degradable carriers and subunits are designed for potential applications in drug delivery and microencapsulated biocatalysis. Thiolated poly(methacrylic acid) and poly(N‐vinyl pyrrolidone) are used to assemble 3‐µm‐diameter carrier capsules and 300‐nm‐diameter subunits, independently stabilized by a diverse range of covalent linkages. This paper presents examples of SHCs with tens of subcompartments and their successful drug loading, as well as selective degradation of the SHC carrier and/or subunits in response to multiple chemical stimuli.     

Electronic Activation of a DNA Nanodevice Using a Multilayer Nanofilm

A method to control activation of a DNA nanodevice by supplying a complementary DNA (cDNA) strand from an electro‐responsive nanoplatform is reported. To develop functional nanoplatform, hexalayer nanofilm is precisely designed by layer‐by‐layer assembly technique based on electrostatic interaction with four kinds of materials: Hydrolyzed poly(β‐amino ester) can help cDNA release from the film. A cDNA is used as a key building block to activate DNA nanodevice. Reduced graphene oxides (rGOs) and the conductive polymer provide conductivity. In particular, rGOs efficiently incorporate a cDNA in the film via several interactions and act as a barrier. Depending on the types of applied electronic stimuli (reductive and oxidative potentials), a cDNA released from the electrode can quantitatively control the activation of DNA nanodevice. From this report, a new system is successfully demonstrated to precisely control DNA release on demand. By applying more advanced form of DNA‐based nanodevices into multilayer system, the electro‐responsive nanoplatform will expand the availability of DNA nanotechnology allowing its improved application in areas such as diagnosis, biosensing, bioimaging, and drug delivery.     

Advanced Subcompartmentalized Microreactors: Polymer Hydrogel Carriers Encapsulating Polymer Capsules and Liposomes

The design of compartmentalized carriers for advanced drug delivery systems or artificial cells and organelles is of interest for biomedical applications. Herein, a polymer carrier microreactor that contains two different classes of subcompartments, multilayered polymer capsules and liposomes, is presented. 50 nm‐diameter liposomes and 300 nm‐diameter polymer capsules are encapsulated into a larger polymer carrier capsule, demonstrating control over the spatial positioning of the subcompartments, which are either ‘membrane‐associated’ or 'free‐floating’ in the aqueous interior. Selective and spatially dependent degradation of the 300 nm‐diameter subcompartments (without destroying the structural integrity of the enzyme‐loaded liposomes) is also shown, by performing an encapsulated enzymatic reaction using the liposomal subcompartments. These findings cover several important aspects toward the development of engineered compartmentalized carrier vessels for the creation of artificial cell mimics or advanced therapeutic delivery systems.     

Biomimetic Extracellular Environment Based on Natural Origin Polyelectrolyte Multilayers

Surface modification of biomaterials is a well‐known approach to enable an adequate biointerface between the implant and the surrounding tissue, dictating the initial acceptance or rejection of the implantable device. Since its discovery in early 1990s layer‐by‐layer (LbL) approaches have become a popular and attractive technique to functionalize the biomaterials surface and also engineering various types of objects such as capsules, hollow tubes, and freestanding membranes in a controllable and versatile manner. Such versatility enables the incorporation of different nanostructured building blocks, including natural biopolymers, which appear as promising biomimetic multilayered systems due to their similarity to human tissues. In this review, the potential of natural origin polymer‐based multilayers is highlighted in hopes of a better understanding of the mechanisms behind its use as building blocks of LbL assembly. A deep overview on the recent progresses achieved in the design, fabrication, and applications of natural origin multilayered films is provided. Such films may lead to novel biomimetic approaches for various biomedical applications, such as tissue engineering, regenerative medicine, implantable devices, cell‐based biosensors, diagnostic systems, and basic cell biology.     

Biomedical Applications of Layer‐by‐Layer Assembly: From Biomimetics to Tissue Engineering

The design of advanced, nanostructured materials at the molecular level is of tremendous interest for the scientific and engineering communities because of the broad application of these materials in the biomedical field. Among the available techniques, the layer‐by‐layer assembly method introduced by Decher and co‐workers in 1992 has attracted extensive attention because it possesses extraordinary advantages for biomedical applications: ease of preparation, versatility, capability of incorporating high loadings of different types of biomolecules in the films, fine control over the materials' structure, and robustness of the products under ambient and physiological conditions. In this context, a systematic review of current research on biomedical applications of layer‐by‐layer assembly is presented. The structure and bioactivity of biomolecules in thin films fabricated by layer‐by‐layer assembly are introduced. The applications of layer‐by‐layer assembly in biomimetics, biosensors, drug delivery, protein and cell adhesion, mediation of cellular functions, and implantable materials are addressed. Future developments in the field of biomedical applications of layer‐by‐layer assembly are also discussed.     

Stabilization of Polymer‐Hydrogel Capsules via Thiol–Disulfide Exchange

Polymer hydrogels are used in diverse biomedical applications including drug delivery and tissue engineering. Among different chemical linkages, the natural and reversible thiol–disulfide interconversion is extensively explored to stabilize hydrogels. The creation of macro‐, micro‐, and nanoscale disulfide‐stabilized hydrogels commonly relies on the use of oxidizing agents that may have a detrimental effect on encapsulated cargo. Herein an oxidization‐free approach to create disulfide‐stabilized polymer hydrogels via a thiol–disulfide exchange reaction is reported. In particular, thiolated poly(methacrylic acid) is used and the conditions of polymer crosslinking in solution and on colloidal porous and solid microparticles are established. In the latter case, removal of the core particles yields stable, hollow, disulfide‐crosslinked hydrogel capsules. Further, a procedure is developed to achieve efficient disulfide crosslinking of multilayered polymer films to obtain stable, liposome‐loaded polymer‐hydrogel capsules that contain functional enzymatic cargo within the liposomal subcompartments. This approach is envisaged to facilitate the development of biomedical applications of hydrogels, specifically those including fragile cargo.     

Micrometer‐Thick Graphene Oxide–Layered Double Hydroxide Nacre‐Inspired Coatings and Their Properties

Robust, functional, and flame retardant coatings are attractive in various fields such as building construction, food packaging, electronics encapsulation, and so on. Here, strong, colorful, and fire‐retardant micrometer‐thick hybrid coatings are reported, which can be constructed via an enhanced layer‐by‐layer assembly of graphene oxide (GO) nanosheets and layered double hydroxide (LDH) nanoplatelets. The fabricated GO–LDH hybrid coatings show uniform nacre‐like layered structures that endow them good mechanic properties with Young's modulus of ≈18 GPa and hardness of ≈0.68 GPa. In addition, the GO–LDH hybrid coatings exhibit nacre‐like iridescence and attractive flame retardancy as well due to their well‐defined 2D microstructures. This kind of nacre‐inspired GO–LDH hybrid thick coatings will be applied in various fields in future due to their high strength and multifunctionalities.     

Direct Microrolling Processing on a Silicon Wafer

Although, varieties of micro‐ to nanoscale fabrication technologies have been invented and refined for silicon (Si) processing because Si is the basic material of integrated circuits, the layouts are based on layer‐by‐layer approaches, making it difficult to realize three‐dimensional (3D) structures with complicated shapes normal to the planar surface (along the out‐of‐plane direction) of the wafers used. Here, a novel and direct Si‐processing technology that enables to bend thin layers of Si surfaces into various 3D curved structures at the micrometer scale is introduced. This bending is achieved by porosifying a Si wafer surface using anodic oxidation and then performing conventional photolithography patterning and wet etching. The porosity gradient in the depth direction gives rise to a stress‐internalized layer in which self‐rolling action is induced via subsequent patterning and wet etching. A subsequent oxidation process further enhances the curvature deformation, leading to the formation of tubes, for example. The rolling directions can be controlled by 2D patterning of the porous Si layer, which is explained well from a structural dynamics perspective. This technology has a wide range of capabilities for realizing 3D structures on Si substrates, enabling new design possibilities for Si‐based on‐chip devices.     

Polymer Nanosheet Containing Star‐Like Copolymers: A Novel Scalable Controlled Release System

Poly(ε‐caprolactone) (PCL)‐based nanomaterials, such as nanoparticles and liposomes, have exhibited great potential as controlled release systems, but the difficulties in large‐scale fabrication limit their practical applications. Among the various methods being developed to fabricate polymer nanosheets (PNSs) for different applications, such as Langmuir–Blodgett technique and layer‐by‐layer assembly, are very effort consuming, and only a few PNSs can be obtained. In this paper, poly(ε‐caprolactone)‐based PNSs with adjustable thickness are obtained in large quantity by simple water exposure of multilayer polymer films, which are fabricated via a layer multiplying coextrusion method. The PNS is also demonstrated as a novel controlled guest release system, in which release kinetics are adjustable by the nanosheet thickness, pH values of the media, and the presence of protecting layers. Theoretical simulations, including Korsmeyer–Peppas model and Finite‐element analysis, are also employed to discern the observed guest‐release mechanisms.     

Design of Magnetic‐Plasmonic Nanoparticle Assemblies via Interface Engineering of Plasmonic Shells for Targeted Cancer Cell Imaging and Separation

Magnetic‐plasmonic nanoparticles have received considerable attention for widespread applications. These nanoparticles (NPs) exhibiting surface‐enhanced Raman scattering (SERS) activities are developed due to their potential in bio‐sensing applicable in non‐destructive and sensitive analysis with target‐specific separation. However, it is challenging to synthesize these NPs that simultaneously exhibit low remanence, maximized magnetic content, plasmonic coverage with abundant hotspots, and structural uniformity. Here, a method that involves the conjugation of a magnetic template with gold seeds via chemical binding and seed‐mediated growth is proposed, with the objective of obtaining plasmonic nanostructures with abundant hotspots on a magnetic template. To obtain a clean surface for directly functionalizing ligands and enhancing the Raman intensity, an additional growth step of gold (Au) and/or silver (Ag) atoms is proposed after modifying the Raman molecules on the as‐prepared magnetic‐plasmonic nanoparticles. Importantly, one‐sided silver growth occurred in an environment where gold facets are blocked by Raman molecules; otherwise, the gold growth is layer‐by‐layer. Moreover, simultaneous reduction by gold and silver ions allowed for the formation of a uniform bimetallic layer. The enhancement factor of the nanoparticles with a bimetallic layer is approximately 10⁷. The SERS probes functionalized cyclic peptides are employed for targeted cancer‐cell imaging and separation.     

Bio‐microfluidics: Biomaterials and Biomimetic Designs

Bio‐microfluidics applies biomaterials and biologically inspired structural designs (biomimetics) to microfluidic devices. Microfluidics, the techniques for constraining fluids on the micrometer and sub‐micrometer scale, offer applications ranging from lab‐on‐a‐chip to optofluidics. Despite this wealth of applications, the design of typical microfluidic devices imparts relatively simple, laminar behavior on fluids and is realized using materials and techniques from silicon planar fabrication. On the other hand, highly complex microfluidic behavior is commonplace in nature, where fluids with nonlinear rheology flow through chaotic vasculature composed from a range of biopolymers. In this Review, the current state of bio‐microfluidic materials, designs and applications are examined. Biopolymers enable bio‐microfluidic devices with versatile functionalization chemistries, flexibility in fabrication, and biocompatibility in vitro and in vivo. Polymeric materials such as alginate, collagen, chitosan, and silk are being explored as bulk and film materials for bio‐microfluidics. Hydrogels offer options for mechanically functional devices for microfluidic systems such as self‐regulating valves, microlens arrays and drug release systems, vital for integrated bio‐microfluidic devices. These devices including growth factor gradients to study cell responses, blood analysis, biomimetic capillary designs, and blood vessel tissue culture systems, as some recent examples of inroads in the field that should lead the way in a new generation of microfluidic devices for bio‐related needs and applications. Perhaps one of the most intriguing directions for the future will be fully implantable microfluidic devices that will also integrate with existing vasculature and slowly degrade to fully recapitulate native tissue structure and function, yet serve critical interim functions, such as tissue maintenance, drug release, mechanical support, and cell delivery.     

Layer‐by‐Layer Hydrogen‐Bonded Polymer Films: From Fundamentals to Applications

Recent years have seen increasing interest in the construction of nanoscopically layered materials involving aqueous‐based sequential assembly of polymers on solid substrates. In the booming research area of layer‐by‐layer (LbL) assembly of oppositely charged polymers, self‐assembly driven by hydrogen bond formation emerges as a powerful technique. Hydrogen‐bonded (HB) LbL materials open new opportunities for LbL films, which are more difficult to produce than their electrostatically assembled counterparts. Specifically, the new properties associated with HB assembly include: 1) the ease of producing films responsive to environmental pH at mild pH values, 2) numerous possibilities for converting HB films into single‐ or two‐component ultrathin hydrogel materials, and 3) the inclusion of polymers with low glass transition temperatures (e.g., poly(ethylene oxide)) within ultrathin films. These properties can lead to new applications for HB LbL films, such as pH‐ and/or temperature‐responsive drug delivery systems, materials with tunable mechanical properties, release films dissolvable under physiological conditions, and proton‐exchange membranes for fuel cells. In this report, we discuss the recent developments in the synthesis of LbL materials based on HB assembly, the study of their structure–property relationships, and the prospective applications of HB LbL constructs in biotechnology and biomedicine.     

Graphene‐Based Smart Platforms for Combined Cancer Therapy

The extensive research of graphene and its derivatives in biomedical applications during the past few years has witnessed its significance in the field of nanomedicine. Starting from simple drug delivery systems, the application of graphene and its derivatives has been extended to a versatile platform of multiple therapeutic modalities, including photothermal therapy, photodynamic therapy, magnetic hyperthermia therapy, and sonodynamic therapy. In addition to monotherapy, graphene‐based materials are widely applied in combined therapies for enhanced anticancer activity and reduced side effects. In particular, graphene‐based materials are often designed and fabricated as “smart” platforms for stimuli‐responsive nanocarriers, whose therapeutic effects can be activated by the tumor microenvironment, such as acidic pH and elevated glutathione (termed as “endogenous stimuli”), or light, magnetic, or ultrasonic stimuli (termed as “exogenous stimuli”). Herein, the recent advances of smart graphene platforms for combined therapy applications are presented, starting with the principle for the design of graphene‐based smart platforms in combined therapy applications. Next, recent advances of combined therapies contributed by graphene‐based materials, including chemotherapy‐based, photothermal‐therapy‐based, and ultrasound‐therapy‐based synergistic therapy, are outlined. In addition, current challenges and future prospects regarding this promising field are discussed.     

25th Anniversary Article: What Can Be Done with the Langmuir‐Blodgett Method? Recent Developments and its Critical Role in Materials Science

The Langmuir‐Blodgett (LB) technique is known as an elegant method for fabrication of well‐defined layered structures with molecular level precision. Since its discovery the LB method has made an indispensable contribution to surface science, physical chemistry, materials chemistry and nanotechnology. However, recent trends in research might suggest the decline of the LB method as alternate methods for film fabrication such as layer‐by‐layer (LbL) assembly have emerged. Is LB film technology obsolete? This review is presented in order to challenge this preposterous question. In this review, we summarize recent research on LB and related methods including (i) advanced design for LB films, (ii) LB film as a medium for supramolecular chemistry, (iii) LB technique for nanofabrication and (iv) LB involving advanced nanomaterials. Finally, a comparison between LB and LbL techniques is made. The latter reveals the crucial role played by LB techniques in basic surface science, current advanced material sciences and nanotechnologies.     

Atomic Layer Deposition for Membranes,Metamaterials, and Mechanisms

Bending and folding techniques such as origami and kirigami enable the scale‐invariant design of 3D structures, metamaterials, and robots from 2D starting materials. These design principles are especially valuable for small systems because most micro‐ and nanofabrication involves lithographic patterning of planar materials. Ultrathin films of inorganic materials serve as an ideal substrate for the fabrication of flexible microsystems because they possess high intrinsic strength, are not susceptible to plasticity, and are easily integrated into microfabrication processes. Here, atomic layer deposition (ALD) is employed to synthesize films down to 2 nm thickness to create membranes, metamaterials, and machines with micrometer‐scale dimensions. Two materials are studied as model systems: ultrathin SiO₂ and Pt. In this thickness limit, ALD films of these materials behave elastically and can be fabricated with fJ‐scale bending stiffnesses. Further, ALD membranes are utilized to design micrometer‐scale mechanical metamaterials and magnetically actuated 3D devices. These results establish thin ALD films as a scalable basis for micrometer‐scale actuators and robotics.     

Advances in Hydrogels in Organoids and Organs‐on‐a‐Chip

Significant advances in materials, microscale technology, and stem cell biology have enabled the construction of 3D tissues and organs, which will ultimately lead to more effective diagnostics and therapy. Organoids and organs‐on‐a‐chip (OOC), evolved from developmental biology and bioengineering principles, have emerged as major technological breakthrough and distinct model systems to revolutionize biomedical research and drug discovery by recapitulating the key structural and functional complexity of human organs in vitro. There is growing interest in the development of functional biomaterials, especially hydrogels, for utilization in these promising systems to build more physiologically relevant 3D tissues with defined properties. The remarkable properties of defined hydrogels as proper extracellular matrix that can instruct cellular behaviors are presented. The recent trend where functional hydrogels are integrated into organoids and OOC systems for the construction of 3D tissue models is highlighted. Future opportunities and perspectives in the development of advanced hydrogels toward accelerating organoids and OOC research in biomedical applications are also discussed.     

Nucleic Acid–Based Functional Nanomaterials as Advanced Cancer Therapeutics

Nucleic acid–based functional nanomaterials (NAFN) have been widely used as emerging drug delivery nanocarriers for cancer therapeutics. Considerable works have demonstrated that NAFN can effectively load and protect therapeutic agents, and particularly enable targeting delivery to the tumor site and stimuli‐responsive release. These outstanding performances are due to NAFN's unique properties including inherent biological functions and sequence programmability as well as biocompatibility and biodegradability. In this Review, the recent progress on NAFN as advanced cancer therapeutics is highlighted. Three main cancer therapy approaches are categorized including chemo‐, immuno‐, and gene‐therapy. Examples are presented to show how NAFN are rationally and exquisitely designed to address problems in cancer therapy. The challenges and future development of NAFN are also discussed toward future more practical biomedical applications.     

Poly(Methacrylic Acid) Polymer Hydrogel Capsules: Drug Carriers,Sub‐compartmentalized Microreactors,Artificial Organelles

Multilayered polymer capsules attract significant research attention and are proposed as candidate materials for diverse biomedical applications, from targeted drug delivery to microencapsulated catalysis and sensors. Despite tremendous efforts, the studies which extend beyond proof of concept and report on the use of polymer capsules in drug delivery are few, as are the developments in encapsulated catalysis with the use of these carriers. In this Concept article, the recent successes of poly(methacrylic acid) hydrogel capsules as carrier vessels for delivery of therapeutic cargo, creation of microreactors, and assembly of sub‐compartmentalized cell mimics are discussed. The developed technologies are outlined, successful applications of these capsules are highlighted, capsules properties which contribute to their performance in diverse applications are discussed, and further directions and plausible developments in the field are suggested.