Encapsulation systems are urgently needed both as micrometer and sub-micrometer capsules for active chemicals' delivery, to encapsulate biological objects and capsules immobilized on surfaces for a wide variety of advanced applications. Methods for encapsulation, prolonged storage and controllable release are discussed in this review. Formation of stimuli responsive systems via layer-by-layer (LbL) assembly, as well as via mobile chemical bonding (hydrogen bonds, chemisorptions) and formation of special dynamic stoppers are presented. The most essential advances of the systems presented are multifunctionality and responsiveness to a multitude of stimuli – the possibility of formation of multi-modal systems. Specific examples of advanced applications – drug delivery, diagnostics, tissue engineering, lab-on-chip and organ-on-chip, bio-sensors, membranes, templates for synthesis, optical systems, and antifouling, self-healing materials and coatings – are provided. Finally, we try to outline emerging developments.
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Interfaces are most important on one hand to understand and control colloidal systems with their large fraction of specific surface, on the other hand most processes start at an interface, and therefore they determine many physical and chemical properties. From a basic science point of view they exhibit peculiarities as low-dimensional systems and are anisotropic systems where molecules can be oriented. Macromolecules like proteins and peptides may change their secondary and tertiary structure and thus their function at interfaces. Within the strategy of building and understanding hierarchical structures they are positioned at the lowest length scale which one may also consider the base. Accordingly the main aim is to understand and to control molecular interfaces as regards structure, dynamics and properties. As an offspring of this the knowledge could be used to prepare complex films, coated colloids and capsules.
As a general trend in interface research an increase in complexity for advanced functional systems develops. Planar and non-planar interfaces mostly contain several substances of proteins, polypeptides or nanoparticles, polyelectrolytes that are responsive to external stimuli or convert internal chemical and biochemical signals into optical, electrical, thermal and mechanical signals. Small molecules at the interface with their dynamics are relevant for drug delivery systems, self-healing materials, coating, tissue engineering, etc. This concerns reorganization of molecules, their diffusion as well as collective motion like flow under a surface pressure gradient.
Encapsulation of responsive active species is developing in two directions (Section 'Encapsulation and Release'): 1) capsules with different sizes from micrometer to nanometer ranges or encapsulation of biological objects; and 2) surface capsule formation for special surface nanoarchitecture connected with their applications. The complex encapsulation system could contain inorganic (silica or titania, Si, carbon or titanium nanotubes, halloysites, CaCO3, etc.) and organic parts (low molecular weight species, natural (protein, peptides) or synthetic (polyelectrolytes, micelles) polymer substances together with some life objects (neurons cells, stem cells, yeasts, spores, bacteria, etc.)) (Section 'Prospects of Stimuli Response').
Stimuli responsive systems are based on the sensitivity of their building blocks (Section 'Multi-Modal Systems'). Most common stimuli are determined by the soft organic part of the system. Stimuli responsive macromolecules are capable of conformational and chemical changes on receiving an external signal (T, pH, ionic strength, electromagnetic irradiation or magnetic field, electric potential, chemical composition or applied mechanical force). The discussed systems are planar films, coatings, non-planar capsules and micelles; as well as combinations of two non-planar in planar systems (surface capsules + coating) (Figure1). Different architectures and fundamental approaches in the area provide specific advanced applications which are also highlighted in this review. Responsive planar polymer surfaces can be grafted polymer thin films or self-organized monolayers, thin films of polymer networks and self-assembled multilayered thin films. Different architecture provides control of dynamics (system response) and amplitude of changes of the interfacial properties, reversibility of the changes and the intensity of the external signal that could trigger the changes. The inorganic part of encapsulation systems, for example mesoporous particles themselves or being a core of polyelectrolyte 3D capsules, could be bonded with an encapsulated chemical with relatively weak bonds or chemisorbed. The release from such systems is responsive to external or internal stimuli. This review discusses trends and challenges in designing next generation carriers for a broad range of applications both in vivo and in vitro.
One specific task in designing intelligent systems is to provide systems with multi trigger stimuli response – multi-modal systems – to mimic of natural systems. A multi-responsive system can be achieved (i) with combining in one system the sub-organization of blocks responsive to different stimuli; (ii) with spatially and temporally resolved release from multi-chemical delivery systems. Moreover mimicking both encapsulation and release processes would be of high priority. There are some background ideas presented in Section 'Specific Examples of Advanced Applications'.
Responsive encapsulation systems are finding an increasingly large number of applications in biomedicine and drug delivery, optical materials, bio-sensors and bio-membranes, templates for synthesis, surface coatings, photonics, self-healing and antifouling surfaces. Some specific examples of advanced applications are presented in Section 'Conclusions', which focuses on recent developments including highlights in use of multi-modal systems for specific applications.
2 Principles of Encapsulation Systems
Use of encapsulation systems has been started before people did understand the principle of their intelligent design and nano-organization. Thus dairies on use of perfumes which smell differently during a day, drug pills with prolonged action, go back to many centuries. Nowadays encapsulation is an imperative technology in pharmacy, food industry and medicine. Recent progress in science provides understanding of design principles and fundamental scientific background of encapsulation systems for wider areas of advanced applications including further progress in drug delivery, diagnostics, tissue engineering, lab-on-chip and organ-on-chip, membranes, templates for synthesis, optical systems, bio-sensors, antifouling, self-healing materials and coatings. The encapsulation systems have been developed mainly in two directions to be used as “free” systems (Figure 1I) or being immobilized on surfaces (Figure 1II). Most recently it was suggested that if specific applications are connected with use of planar surfaces – self-healing, antifouling surfaces, material for tissue engineering, implants – it would be more reasonable to provide systems where surface capsules are not immobilized, but formed in surface vis-à-vis surface nanostructuring with existing methodology (Figure 1III). Examples of possible methods for surface nanostructuring are highlighted in a recent review:[1a] electrochemical surface modification, plasma etching technologies, laser induced surface modification, chemical etching, sol-gel route and bio-inspired ultrasound assisted methodology. Direct formation of encapsulation systems in a surface provides an effective manner for submicron delivery vehicles for prolonged release of easily diffusing low molecular weight substances: corrosion inhibitors, biocide agents.[2a]
Typically encapsulation systems are from submicron to micrometer ranges. The size range is particularly important for in vivo applications because only nanometer-sized delivery vehicles can be used for circulation. Micrometer sized capsules are still very attractive objects because of the simplicity, of superior loading capacity, and large surface area for modification. In addition capsules of several hundred of micrometers may provide the development of the manner of release and reveal the feasibility of direction-specific release.
Mesoporous carriers are often used as core of encapsulation systems (Figure2a,b). The core material is variable and depends on the desired potential application. It could be, for example, highly luminescent biocompatible silicon, highly porous silica particles (MCM-41, MCM-48, etc.) or photosensitive mesoporous titania, biocompatible and biodegradable calcium carbonate, metal sponges for anticorrosion, antifouling, lab-on-chip and tissue engineering materials, CdCO3 and MnCO3, etc. 1D nanotubes (Figure 2c,d) with defined kinetics of diffusion from oriented channels and being excellent templates for synthesis are also very prospective to be the core of encapsulation systems: natural tubule halloysites, surface anodized aluminum or titanium layers, carbon nanotubes. Some specific features of inorganic carriers can be mentioned. i) In some cases stabilization of “free” inorganic carriers (Figure 1I) is needed to avoid aggregation, and ii) during immobilization of them in coating (Figure 1II) they can have low compatibility with organic coating and decrease coating adhesion and long term stability. Simultaneously they can be effectively used in sol-gel coatings. Inorganic carriers are shape constant and thermostable at high temperatures, in comparison with most polymer systems.
Polymers are traditional and ubiquitous components in designing drug delivery carriers (Figure 2e,f). The main properties of polymers depend on such parameters as their molecular weight, the persistence length and grafting ratio/charge density of functional groups. These parameters determine the melting temperature of polymers, their thermal properties, hydrodynamic radius, and configuration. Complexation of polymers due to opposite charges is used in assembling polyelectrolyte multilayers, while their alternative deposition leads to layer-by-layer (LbL) films which can be constructed either on planar substrates or on non-planar (spherical,[9, 17] cubes, etc.) templates. Assembling LbL layers on non-planar templates followed by dissolution of the templates resulted in the production of 3D polymer capsules with semipermeability. The capsule permeability depends on nature of polymers used for LbL and number of layers. Combination of inorganic carriers and organic LbL for formation of capsules allow to decrease number of LbL without negative effect to diffusion from such capsules. Moreover an advantage of an inorganic carrier, e.g., constant shape, is achievable for the hybrid system, in comparison with pure polymer capsules which can deform dramatically during their immobilization inside coating.
Polymer capsules with strong barrier properties in acidic media could be prepared by conductive polymers through their chemical or electrochemical synthesis, e.g., polypyrrole capsules were successfully prepared on stainless steel electrodes,[18a] by in situ polymerization of pyrrole in polymer matrix[18b] or by LbL deposition of polyelectrolytes and polypyrrole.[18c] The size of the capsule and the thickness of the polypyrrole shell (up to their complete filling with grown polypyrrole) can be varied by changing both the scan speed of the electrode potential and potential range.
Capsules made of cross-linked polymers and liquid core are also attracting great attention. Thus three types of polymers with high cross-link density – polyurethane, polyurea, and polyamide – can be examples of systems enabling storage of low molecular weight substances. The structure of the resulting capsules depends on the type of polymer. Polyurethane and polyurea formed “compact” microcapsules, while in the case of polyamide nanoscale core@shell structures were formed. “Compact” morphologies form due to the high affinity of the liquid capsule component to the polymer; core@shell morphology is formed when the affinity is low. Application of the Hansen solubility parameters approach allows prediction and control of the morphology of capsules made of cross-linked polymers.
Thermal conversion in polymers, e.g., conversion of the polyamide layers into polyimide coatings, provides an effective manner for encapsulation. The thickness of the polyamide/polyimide shells can be size variable.
Emulsion carriers can be used as core of encapsulation systems. Various shells around emulsion droplets can be mentioned: polyelectrolytes, nanoparticles, proteins, enzymes, etc. The layer growth is governed by their electrostatic, hydrogen bonding, hydrophobic, etc. forces and allows the formation of nanostructured shells.
The combination of two acoustic phenomena (emulsification and cavitation) provides versatile ultrasonic assisted ways for microcapsule formation. The yield of microspheres strongly depends on the temperature/time profile of the solution during irradiation. In the preparation of protein microspheres by ultrasound, the sizes of microspheres are affected by the sonication variables, such as energy input and sonication time. It was found that the mean sizes of the ultrasonically prepared emulsions decrease with the increase of sonication time and sonication amplitude. The dispersion of emulsion size during ultrasonic fabrication is caused by the uneven distribution of acoustic energy in the ultrasonic vessel and the region with intensive energy is restricted to areas close to the sound emitting surface of the ultrasonic probe producing the emulsion particles with the minimal size. Far from this area the acoustic energy decreases sharply, which results in the formation of big microspheres.
Nowadays one can choose the right encapsulation system: i) for specific application, e.g., “free” capsule or planar system, capsule sizes; ii) taking into account conditions which will be applied to form final system, e.g., high temperature, bent fracture during formation of anticorrosion coatings; (iii) biocompatibility and kinetics of (bio)degradation; (iv) achieved encapsulation efficiency, e.g., high free volume, pore sizes; (v) with low cost and (vi) high stability.
3 Encapsulation and Release
There are several possibilities for encapsulation of needed material. The chosen method for encapsulation depends on 1) nature of species to encapsulate, e.g., low molecular weight substance[7, 8] or macromolecule, biological object, hydrophilic/hydrophobic agent;  2) capsule material, e.g., possibility of hydrogen or chemical bonding,[2a] electrostatic interaction;[16, 17] 3) limitation of capsule sizes, e.g., in some cases nanocarriers can be toxic or, on contrary, needed for circulation; 4) time-dependent release, e.g., either just prolonged release is needed with slow release or stimuli responsive release; 5) spatially dependent release, e.g., localization of release profile, etc. Moreover encapsulation could happen i) after capsules are already formed (for example, mesoporous systems, trapping in LbL capsules using physico-chemical stimuli which influence the interaction of polymers and, correspondingly, the permeability of capsules; ii) together with capsules' formation (adsorption in porous CaCO3 core followed by LbL polyelectrolyte deposition and core dissolution, emulsions; iii) capsule shell or core could be an active material (molybdate based capsules for corrosion protection; and iv) combined approach (combination of mentioned i-iii, or several encapsulation systems in one, e.g., multicompartmental and anisotropic micro- and nanocapsules.
In the case of mesoporous carriers if they are placed to the solution containing active agent the pores suitable in size for encapsulation of dissolved agent are loaded with it due to a concentration gradient (Figure3). Surface phenomena and surface tension determine the process. The exact nature of the bonding depends on the species involved, but the adsorption process is generally classified as physisorption (e.g., weak van der Waals forces) or chemisorption[2a] (characteristic of covalent bonding), it may also occur due to electrostatic attraction. Oxygen-containing compounds (Si, silica and titania, metal sponges, etc.) are typically hydrophilic and polar. Carbon-based compounds are typically hydrophobic and non-polar, including materials such as activated carbon and graphite. Polymer-based compounds are polar or non-polar functional groups in a polymer matrix. Mesoporous carriers could be in the form of 3D capsules or surface immobilized. Due to complex pore shape the prolonged release is possible even without formation of any protective shell. There is an attractive possibility to prevent release by relatively dynamic chemical bonding between mesoporous carrier and encapsulated agent without any other shell.[2a]
Thus silicon, metal sponges, SiO2 and TiO2 mesoporous carriers could chemisorb species through oxygen bridges.[2a,,] Moreover there is an attractive possibility to chemically graft organic species by direct oxygen free surface-carbon bonding, for example Si–C bonding by thermal hydrosilylation. The process is the “alkanethiols on gold” analogue reaction of the silicon system, allowing the chemist to place a wide variety of organic functional groups on a silicon or porous silicon surface. The main requirement of the reaction is that the surface provides hydrogen bonding, e.g., in the case of mesoporous silicon or metal sponges.
For 1D carriers, e.g., halloysites, carbon nanotubes or surface titanium nanotubes, in the case of unprotected systems there is a limitation of the proposed delivery systems. In particular the quantity of chemisorbed material is too low compared to the mesoporous systems. A direct diffusion of physically encapsulated molecules is relatively fast. The release kinetics depends on the structure dimensions and geometry. There are suggestions that at a size scale of 100 nm and larger, diffusion of drug molecules is largely insensitive to tube diameter and the total drug release is dependent only on the tube length. Nevertheless this high burst release can be beneficial for some applications (e.g., preventing bone infection in the cases of implant with drug loaded titanium nanotubes) in the case if it does not exceed optimal therapeutic dosage.
A versatile universal approach to prevent physisorbed encapsulation agent diffusion from the mentioned mesoporous carriers and 1D tubular structures is formation of a protective LbL assembly shell (Figure 3III). 3D polyelectrolyte capsules were initially suggested to be prepared by LbL adsorption of oppositely charges polyelectrolyte molecules around micron or submicron inorganic template cores with following core dissolution. Although LbL coating of uncharged colloids was reported, the charge still remains one of the main prerequisites in assembling polyelectrolyte multilayers. Later on it was suggested that the core could be left and be advanced for certain applications: self-healing,[1, 44] multi-component loading and time resolved drug delivery, antifouling and anticorrosion surfaces,[1, 2, 46] etc. Moreover the number of layers which was enough to protect release of the encapsulated material could be decreased: two bilaers were enough to prevent release from mesoporous silica and titania capsules. Although for LbL assembly and shell components synthetic polyelectrolytes, were initially suggested, nowadays the approach is expanded to biocompatible polyions, proteins, deoxyribonucleic acid, lipids, multivalent ions, small dye molecules, charged nanoparticles, dendrimers, micelles. The diversity of possible building-blocks is most promising for functionalization. Recently by Zhang et al. it was shown interesting approach to use LbL assembly of azulene-based supra-amphiphiles for reversible encapsulation of organic molecules in water by charge-transfer interaction: the loading capacity can be regulated by change of the layer pairs, selective pyrene uptake is capable by recognizing the hydrophobic template molecule in water, the reloading process increases with increasing of temperature.
An example of such functionalization development is a new class of polyelectrolytes with modular biological functionality and tunable physicochemical properties which have been engineered to abrogate cytotoxicity. Highly permeable, hydrogen-bonded multilayers allowing gentle cell encapsulation using non-toxic, non-ionic and biocompatible components such as poly(N-vinylpyrrolidone) and tannic acid which were earlier exploited on abiotic surfaces but never assembled on cell surfaces were also presented recently.[30b] Encapsulation of Saccharomyces cerevisiae yeast cells with lightly cross-linked polymethacrylic acid was suggested.[30a] Neuron cellular uptake of biodegradable and synthetic polymeric microcapsules was demonstrated in situ.[30d] With the examples it is seen that nowadays encapsulation is not limited just for active molecules, but also expanded to biological objects with prospects of mimicking natural processes.
Porous thin layers of hydrogel films exhibit stimuli-dependent, e.g., pH-dependent, porosity and can be used as LbL for pore closure of encapsulation systems. Thus, increase of pH and subsequent swelling of porous gel films causes the growth of a pore size, and at decreased pH the polymers demonstrate the opposite behavior. More and more attention is directed to hydrogels based on natural polymers. Thus hydrogels designed with natural polymers as building blocks display multiple advantages over synthetic polymer networks with respect to their biocompatibility, biodegradability and good cell adhesion properties. The main classes of natural polymers studied in hydrogel formulations are polysaccharides (e.g., alginate, dextran, hyaluronan, chitosan), proteins/polypeptides (e.g., collagen, fibrin and gelatin.
Release control is also achievable with complex stoppers (Figure 3IV). Thus controllable release of benzotriazole from halloysite nanotubes could be achieved by the formation of metal-benzotriazole complex caps (stopper) at halloysite tube endings by the interaction of leaking benzotriazole and metal ions from the bulk solution.[67a,b] The suggested method requires only a short rinsing of benzotriazole-loaded halloysite nanotubes with an aqueous solution containing metal ions. Formation of stoppers at halloysite tubes is suggested through using Cu(II) ions. The release rate depends on a number of parameters, such as the chemistry and morphology of halloysite samples, the concentration and type of metal ion, and the concentration of benzotriazole available.
There are impressive developments in the area of supramolecular chemistry, i.e., host–guest complexes,[67c] and mechanostereochemical phenomena (e.g., cucurbits[67d-f] and bistable rotaxanes) to use them for pore closure of mesoporous materials (Figure 3IV), e.g., MCM-41, etc. The feature in focus is stimuli response of the host-guest complexes, stimulated by changes in pH, light and redox potentials, magnetic field, in addition to enzymatic catalysis. Complexes of low molecular weight substances with polyelectrolytes can be also used for pore closure of a mesoporous system, e.g., benzotriazole or 8-hydrohyquinoline with sodium polystyrene sulfonate.[2a,]
Additional functionalization in some cases needs double-, multi- encapsulation systems. Thus, for example, it was suggested to use micellar drug carriers to encapsulate hydrophobic drugs into titanium nanotubes. An electrostatically mediated liposome-fused mesoporous system was suggested. The negatively charged drugs are absorbed into the pores of silica. To increase cargo retention, the positively charged silica is fused with an anionic liposome, 1,2-dioleoyl-sn-glycero-3[phospho-L-serine], followed by further lipid exchange with a cationic liposome, 1,2-dioleoyl-3-trimethylammoniumpropane.
4 Prospects of Stimuli Response
To gain fundamental knowledge on “smart” stimuli responsive systems with regulated release and/or interface behavior, e.g., cell/surface interaction, prompt feedback effects are important aims. In particular, specific applications, e.g., interaction with life systems need dedicated adaptive stimuli of nanoengineered systems.
System design is such a way to provide regulated release materials following a change in stimuli (Figure4) (pH, temperature, ionic strength and solvent, electromagnetic and magnetic field, ultrasound, mechanical action, biological species, e.g., enzymes and cell receptors, etc). Stimuli to choose depend on system applications. Moreover multi-trigger systems are of high priority. Simultaneously one should avoid systems are too complicated to understand fundamental aspects of their stimuli response. Since parts of the system would affect at each other.
Chemically encapsulated species can be detached through chemical stimuli, pH, ionic strength, solvent; or biological stimuli, enzymes, cell receptors. Physical stimuli, e.g., electromagnetic irradiation could be also applied resulting in following chemical changes. Under electromagnetic irradiation with suitable wavelength on titania (Figure 4b)[8, 70] or on Au nanoparticles production of reactive oxygen species takes place which could influence the stability of chemisorbed bonds and encapsulated species can be released on demand by irradiation. Moreover production of reactive species affects the system responsive behavior. It is known that self-healing ability of the titania surface could be optimized through immobilization of noble nanoparticles. In particular, the nanostructured photocatalysts TiO2, TiO2:In2O3, TiO2/Ag, and TiO2/Ag/Ni prepared as thin film on ceramic substrates by spraying oxide sols with subsequent silver photodeposition and electroless nickel deposition were screened for their antibacterial efficiency against P. fluorescens and L. lactis. The photocatalysts show higher activity against P. fluorescens than L. lactis that can be explained in terms of different morphologies of gram positive and gram negative cell envelopes. Gram positive bacteria were more sensitive to O2•−. Probably, active species initiate different deactivation mechanisms of OH• due to cell wall degradation/mineralisation, and O2•− affects the cell nucleus. In some cases over exposure can be a problem and provide system degradation. When TiO2 is used as capsule carrier in introduced in anticorrosion coating during over irradiation the anticorrosion coating can be slowly degraded due to photocatalytic activity of titania.
One more attractive possibility of laser-induced cell detachment on gold nanoparticle functionalized surfaces was demonstrated recently. It is interesting that the selective cell detachment from nanoengineered gold nanoparticle surfaces, triggered by laser irradiation, occurs in a nonthermal manner. It was shown that detachment is attributed to a photochemical mechanism due to production of reactive oxygen species under illumination of gold nanoparticles by green laser light. It was also demonstrated that cells migrate from unirradiated areas leading to their reattachment and surface recovery which is important for controlled spatial organization of cells in wound healing and tissue engineering.
Stimuli responsive release systems based on LbL encapsulation were developed extensively in recent decades and highlighted several times in competent reviews.[,,4a,,,,] Uncontrollable release can be regulated with all types of stimuli – chemical, biological, and physical – by proper LbL design. Thus centers of adsorption of electromagnetic irradiation centers between LbL, e.g., Au nanoparticles, or titania, provide LbL sensitivity to electromagnetic irradiation. It is very important that LbL system can resealed after stimuli stop which allows step-wise release for LbL based capsules. The material response to external stimuli is reversible and several transitions forwards and backwards are possible. Polyelectrolytes are a class of polymers which carry charged functional groups; these groups avail a variety of control of physical–chemical properties as biodegradability, pKa or the glass transition temperature of the polymer complex. Thus LbL themselves can be sensitive to pH. LbL films prepared from the aqueous polyelectrolyte solutions can increase their thickness by adding salt to these solutions. The reason for such changes in thickness of the film is a different conformation of the polyelectrolyte chains. They are flat and parallel to the substrate without salt, meanwhile in the solutions with higher salt concentration the chains form loops and then are adsorbed at the interface. Therefore, the polyelectrolyte density of the films prepared from solutions without salt is considered to be lower than the polyelectrolyte density of films made with a salt additive.
Polymer protection prepared from polypyrrole shells of the microcontainers exhibits very strong barrier properties in acidic media at 2<pH<7 and a high permeability at pH>7, providing effective encapsulation of low molecular weight species at low pH values.
As advanced surface encapsulation systems which are capsules formed in surfaces metal sponges are suggested (Figure 2b). The encapsulation possibilities inside the surface carrier were already mentioned together with regulation of release properties, especially from surface capsules, e.g., mesoporous metal sponges. Real-time control and reversibility of biomolecule/surface interactions at interfaces are an increasingly important goal for a range of scientific fields and applications. A further step in advanced intelligent systems is surface functionalization with various nonspecific or specific functional groups for engineering surface response. In general, hydrophilic surfaces that are nonreactive to proteins or cells are alternated by adding functional molecules that can undergo conformational changes or phase transitions in such a way that they expose demanded molecular fragments or even phases at the interface upon external signal. In many cases, hydrophobic fragments, electrically charged groups, polypeptide chains, micelles[2d] or hydrogels were used for the stimuli-triggered exposure at interfaces. In this way, nonspecific hydrophobic and electrostatic interactions or specific antibody-antigen interactions were switched on to bind proteins and cells by external signals. This interaction could be irreversible or reversible, if a proper balance between attractive interactions and steric repulsion was achieved in the latter case. By using new design techniques, response times from surfaces can now be tuned smoothly from seconds to hours.
A specific example of stimuli-responsive thin films protective for surface drug carriers involves macromolecules that are grafted chemically to a surface at sufficiently high grafting densities, so that the polymer chains experience excluded volume repulsions and adopt a stretched conformation. There is a disadvantage of the grafting of stimuli responsive polymers to the surface: limitation of the surface material. Use of special building blocks, e.g., stimuli responsive micelles,[2d] adsorbed at different surfaces together with LbL methodology provide universal control and help solving the problem.
The field of stimuli-responsive, smart or switchable systems has generated much research interest due to its potential to attain unprecedented levels of control over bioobjects (biomolecules, bacteria, cells) adsorption processes and interactions at engineered interfaces, including the control over reversibility of adsorption. Advances in this field are particularly relevant to applications in the areas of biosensing, chromatography, drug delivery, lab-on-chip, organ-on-chip, regenerative medicine. The control over bioadsorption and desorption processes at interfaces is often used to control subsequent events such as cell–surface interactions. Considerable research interest has been directed at systems that can be reversibly switched between interacting and non-interacting states and used thus for switching, on and off, bio-interfacial interactions such as protein adsorption. Such switchable coatings often incorporate features such as temporal resolution, spatial resolution and reversibility. Switchable interfaces employ stimuli such as light, temperature, electric potential, pH and ionic strength to control protein adsorption/desorption and cell attachment/detachment.
Thermal variations of the material environment have been used to induce the reconstruction of the polymer brushes and their properties. For example, poly(N-isopropylacrylamide) (PNIPAM) brushes possess a lower critical solution temperature (LCST), above which the material is insoluble, at about 35 °C in water. The polymer expands in water at room temperature and its surface becomes hydrophilic. Above the LCST, the polymer collapses and its surface gets less hydrophilic. This responsive characteristic can be used in the regulation of protein adsorption at the substrate surface. Thus, at room temperature protein adsorption on the PNIPAM film is negligible, while above the LCST the film surface becomes more hydrophobic and interacts more strongly with the proteins. Some zwitterionic polymer brushes possessing an upper critical solution temperature (UCST), above which the polymer is miscible, tend to change their wetting characteristics oppositely with temperature.
Polymer nanoparticles which have a network structure and therefore possess properties of hydrogels are called nanogels. They also demonstrate heat responsive behavior. The PNIPAM–polysaccharide (grafted) copolymer nanogel dissolves in cold water and congregates into nanogels because of collapse of the PNIPAM chains at high temperature.
Thin hydrogel films (Figure 4c-d) together with the above LbL polyelectrolyte multilayer nanonetwork[46c] are examples of systems which exhibit sensitivity to pH changes. The rise of pH leads to ionization of the weakly acid segments of hydrogels as in polyelectrolytes the functional groups of the weak polymers. It causes the repulsion between uncompensated charges and in order to balance these charges the concentration of the counter ions inside the system increases. As a result, the osmotic pressure grows, causing water infiltration and swelling and therefore increasing their mobility. The decrease of pH leads to protonation, reduction of osmotic pressure, expulsion of water and shrinking of the polymer structures.
The change in electric potential across polyelectrolyte gels induces changes in their conformation. This property of polyelectrolyte gels was demonstrated on a polyacrylamide gel, across which an electrical field was applied. With an application of the electric field a force was produced on H+ as well as on the negatively charged acrylic acid groups, which caused the shift of the gel towards the positive electrode. This shift created a stress along the gel axis with its minimum at the negative electrode and the maximum at the positive one and, as a result, the gel was deformed. With the increase of the voltage above 2,15 V the gel completely collapsed, and one could obtain the original form when the electric field was removed.
Novel biocompatible hybrid-materials composed of iron-ion-cross-linked alginate with embedded protein molecules have been designed for signal-triggered drug release. Electrochemically controlled oxidation of Fe2+ ions in the presence of soluble natural alginate polymer and drug mimicking protein (bovine serum albumin) results in the formation of an alginate-based thin-film cross-linked by Fe3+ ions at the electrode interface with the entrapped protein.
Altering of surface composition and physical properties of the material can be achieved through the change of a surrounding medium. For example, mixed polymer brushes made of polystyrene and poly(2-vinylpyridine) macromolecules were found to alter the surface composition and wettability after changing the solvents. Further, mixed brushes prepared from polystyrene and poly(methylmethacrylate) change their surface topography in different solutions, and it stimulates the local motion of different objects adsorbed on the surface. Also, poly(ethyleneimine)–poly(dimethylsiloxane) mixed brushes, hydrophilic in water switch to hydrophobic state in air.
Ultrasound has the potential for control of the permeability of encapsulation systems. Polyelectrolyte microcapsules with zinc oxide nanoparticles in their shell proved to have potential as drug-delivery systems with the possibility of opening under the action of ultrasound. Moreover a way to localize capsules with magnetic particles under the ultrasonic horn and their stimuli opening were demonstrated.
Targeting by a magnetic field is one of the main functions of magnetic nanoparticles incorporated into capsules. Furthermore, the therapeutic performance of capsules can be enhanced if magnetic field triggered release is achieved.
It was mentioned above that laser can be stimuli to provide catalytic activity of gold to provide formation of reactive oxygen species. Simultaneously laser-induced remote release can be based on localized heating of the polymeric component in hybrids in the vicinity of metal nanoparticles absorbing laser light. Thus, the polyelectrolyte multilayer becomes mobile above the glass temperature of the polyelectrolyte complex. It should be noted that excessive heating is undesirable for living cells, but it is desirable for cancer treatment. Besides noble nanoparticles, to make surface light switchable special molecules can be suggested. For example, azobenzene molecules, which undergo transitions from cis- to trans-configuration upon exposure to light close the pores in a cooperative way thus entrapping molecules inside, e.g., a porous surface.
Recent studies also aimed to use processes in functional systems to provide stimuli release in a certain time period (Figure5). Thus the possibility to use the cell metabolism to initiate stimuli response is extremely interesting as an example of self-responsive system.[2d]Lactic bacteria in their life cycle produce lactic acid and decrease the pH without using external stimuli. If a special stimulus sensitive system is included in the design of the surface where bacteria are grown, bacteria affect the material resulting in system response. pH responsive micelles which could increase their corona size depending on pH, being part of a responsive system could “push off” the bacteria from the surface.
5 Multi-Modal Systems
It is likely that future developments will be based on multicomponent and multifunctional, hierarchically organized interfaces that combine properties of functional materials and devices together with multi trigger stimuli response of the system. Multifunctionality achieved by tailoring the composition, structural, physico-chemical and mechanical properties at the nanometer scale and combination of stimuli responsive building blocks provides advances for system intelligence and multifuctionalization. However the effect of system blocks to each other should be clear. One should avoid unpredictable complexity. Thus nature uses very complex systems where each blocks improve each other. The multi-modal system needs to be totally understood from fundamental point of view to be used in real functional systems.
Multi-modal systems which are available consist of building blocks sensitive to different stimuli or one block sensitive to several stimuli (Figure6). Thus a multi-modal system can be achieved: (i) with material responsive to several stimuli; (ii) with a hybrid system whose components are sensitive to different stimuli, or (iii) with special nano-organized assembly into encapsulation systems, e.g., micelles, nanotubes.
In the case of polyelectrolyte multilayer films, pH sensitivity of the material can be combined with response to altering ionic strength in order to trigger conformational transitions. The earlier mentioned PNIPAM brushes alter their shape in response to changes in pH, temperature and ionic strength.[85b] One more example of a multi-trigger responsive layer is a redox-polymer-modified electrode. It was found that the variations of the layer properties are dependent on pH, solution ionic strength and applied electrode potential. Some nanogels can also reversibly respond to different triggers, for instance, temperature- and redox-sensitive nanoparticles.
One of the background ideas is to combine in one system the nanoblocks responsive to different stimuli. An example of a hybrid system can be surface organized magnesium-polypyrrole hybrids.[2e] An active chemical release of such a hybrid is achievable by pH-change or an electric field. Functionalization by magnetic and metal nanoparticles produces capsules which respond to multiple stimuli.
Double- or multi-responsive systems can be based just on the polymer architecture. Random copolymers are used to tailor the transition point depending on two independent parameters, for example, pH and temperature. In contrast block copolymers tend to self-assemble reversibly and form micelles depending on the environmental conditions. The micelles are then either stabilized through strong non-covalent interaction (e.g., ionic) or fixed through subsequent crosslinking. In both cases, one obtains a nano-object, which can be utilized as a micellar responsive drug delivery system, but it can also mimic biological entities like vesicles.
Moreover multifuctionality can be attributed to multicomponent system loading with different species and their time resolved release. Thus polymer micelles as drug carriers encapsulated with drugs were loaded at the bottom of titanium nanotube array structures, and their delayed release was obtained by loading blank micelles (without drug) on the top (Figure 6). Delayed and time-controlled drug release was successfully achieved by controlling the ratio of blank and drug-loaded micelles. The concept was demonstrated using four different polymer micelles (regular and inverted) loaded with water-insoluble (indomethacin) and water-soluble drugs (gentamicin).
An elegant approach on the multimodal release of different proteins from the same hydrogel was reported. An injectable PEGylated fibrin gel designed for the release of platelet-derived growth factor BB (PDGF-BB) and TGF-β1 gene with distinct kinetics. Growth factors were loaded into PEGylated fibrin gels via 3 mechanisms: entrapment, conjugation through a homobifunctional amine reactive PEG linker, and physical adsorption on the fibrin matrix. PDGF-BB was entrapped during thrombin-mediated crosslinking leading to its diffusion-controlled release over 2 days. TGF-β1 was both conjugated through the PEG linker and bound to the matrix via physical adsorption, increasing the release time of TGF-β1 up to 10 days. Further, the release rate was highly correlated to gel degradation rate, indicating that TGF-β1 release was degradation-controlled.
A new system with nanogate supported on silica is capable of simultaneously delivering both large and small molecules. The system can be expanded as a delivery system for a broad combination of cargo molecules and metal ions for biological application. In neutral conditions, the nanogate remains closed and cargo is stored, but the addition of acid opens the nanogate, releasing both metal ions and large cargo molecules. Controlled cargo release was also demonstrated by activation through competitive binding. By changing both the metal ion and/or the choice of nanogate, the pH responsiveness can be tuned to allow for biological pH activation.
Individually addressable patterned multilayer microchambers for site-specific release-on-demand was demonstrated. Patterned arrays of light-responsive microchambers were suggested as candidates for specific demand of chemicals. A composite film was made of poly(allylammonium)-poly(styrene sulfonate) multilayers and gold nanoparticles incorporated between subsequent stacks of polyelectrolytes. The film shaped as microchambers was loaded with colloid particles or oil-soluble molecules and chemical release with electromagnetic irradiation was demonstrated (Figure7).
6 Specific Examples of Advanced Applications
The mission of modern science is to concentrate on basic science with transfer technology and knowledge towards applications. Responsive systems can be introduced into many products at a relatively low cost. New design strategies for responsive materials establish an enabling technology for drug delivery, diagnostics, stem cell stimulation, lab-on-chip and organ-on-chip, bio-membranes and bio-sensors, template for synthesis, optical systems,[74, 110] antifouling,[2a] self-healing materials and coatings.[8, 32, 46, 111]
Providing added functionality can enhance the value of a product significantly – for example, materials that are capable of repairing themselves in less than an hour can be used in many coatings applications ranging from decoration, anticorrosion protection to biomedical industries. High-value materials in, for example, the automotive and aerospace industries require increasingly sophisticated eco-friendly coatings for improved performance, self-healing, and durability, and in this respect recent developments in stimuli responsive systems are most promising, making the coating “active” on macro and microlevels (Figure8I). Standard anticorrosion coatings developed so far passively prevent the interaction of corrosive species with the metal which require thicker coatings and does not solve the “cut-edge” problem. The next generation of stimuli responsive protective coatings should be much thinner and possess self-healing or self-curing effects in the scratched (damaged) areas. This requires development of components of the coatings reacting to external or internal impact (pH, humidity changes, or distortion of the coating integrity, etc.) and, if possible, able to combine the self-healing property with other functionality (e.g., detection, controlled reflection, self-cleaning).[8, 32, 46]
Antibiotic-releasing silk biomaterials for infection prevention and treatment was demonstrated recently. The release of penicillin and ampicillin from loaded silk films, silk microspheres suspended in silk hydrogels and bulk-loaded silk hydrogels was investigated and the in vivo efficacy was demonstrated in a murine infected-wound model. Special design of surface silk microneedles which contain an active chemical was also successfully used for controlled-release drug delivery (Figure 2f). The degradation rate of silk fibroin and the diffusion rate of the entrained molecules can be controlled simply by adjusting post-processing conditions. It was shown that room temperature and aqueous-based micromolding allows for the bulk loading of these microneedles with labile drugs. The drug release rate is decreased 5.6-fold by adjusting the post-processing conditions of the microneedles, mainly by controlling the silk protein secondary structure. Antibiotic loaded silk microneedles were manufactured and used to demonstrate a 10-fold reduction of bacterial density after their application.
Tuning and switching adhesion between stimuli-responsive materials, proteins and cells has been explored for the control of cell and protein adhesion, and used for tissue engineering and bioseparation. Thus muscle tissues in heart and skeletal muscle require orientational structures for expressing their functions effectively in vivo. Thermoresponsive polymer surfaces provide normal human dermal fibroblasts aligning on the physicochemically patterned surfaces simply by one-pot cell seeding. Furthermore, the aligned cells were harvested as a tissue-like cellular monolayer, called “cell sheet” only by reducing temperature. The cell sheet harvested from the micropatterned surface possessed a different shrinking rate between vertical and parallel sides of the cell alignment, maintaining the alignment of cells and related ECM proteins, promising to show the mechanical and biological aspects of cell sheets harvested from the functionalized thermoresponsive surfaces.
Different sensitivity of different microorganisms, e.g., bacteria and bacteriophages, provide effective instrumentation to manipulate their live cycles. In particular it was shown that the kinetic activity of the deactivation of bacteriophages dramatically exceeds that of bacterial deactivation. This allows to suggest a procedure of photocatalytic lysogenic bacteria detection (Figure 8IId).
Encapsulation of lubricant into porous surfaces was demonstrated yielding a robust synthetic surface that repels various liquids: self-repairing slippery surfaces with pressure-stable omniphobicity. The slippery surfaces are useful in fluid handling and transportation, optical sensing, medicine, and as self-cleaning and antifouling materials operating in extreme environments (Figure 8III).
Biocompatible stimuli-responsive hydrogel porous membranes via phase separation of a polyvinyl alcohol and Na-alginate intermolecular complex was demonstrated. Ion cross-linked porous alginate thin films were fabricated from mixtures of sodium alginate and polyvinyl alcohol in an aqueous solution. The porous membranes are a pH-sensitive material whose pore diameter can be tuned by changes in pH. The membranes are mechanically robust and can be transferred onto the surface of porous substrates.
Reversible swelling-shrinking transitions in polyelectrolyte brushes and hydrogel thin film plasmonic biosensors for monitor pH changes, the concentration of cholesterol, and the concentration of glucose using the enzymatic reaction of glucose oxidase were also demonstrated. In all extensive work is available on biopolymer-based hydrogels for cell and growth factor encapsulation in regenerative medicine.
Biomedical systems that can deliver multiple growth factors in a multimodal mode and provide desirable pore structure and porosity to potentially encapsulate cells, have considerable potential as future therapeutic tools in tissue engineering.[1a]
There are just few examples presented, however it goes without saying that the concepts presented in this review will be beneficial for many new applications in the future because they will allow for the introduction of new aspects and possibilities in the field of conventional materials. Many important applications may be developed on the basis of implementation of biomimetic concepts into responsive surfaces in the near future. We foresee development of smart surfaces that can, for example, recognize specific biological signals, selectively separate biological molecules, release functional groups or proteins, and change mechanical properties.
In this review we highlighted the roles of dynamic interfaces for responsive encapsulation systems. Interfaces adapted to self-control and self-regulation requires a complex hierarchical organization of stimuli responsive nanoorganized blocks. However to have background knowledge from a basic science point of view lower detentions or building blocks for “intelligent” systems deserve scientific attention. Thus prospective materials for encapsulation with suggestions concerning loading and release strategies to provide systems for advanced applications. In living systems nature broadly exploits the principles of hierarchical organization for self-control and stimuli responsive switching and self-regulation. However, synthetic intelligence is still a challenge. Even more challenging is in vivo design. The research concerns predominantly experiments between chemistry, physics and in some cases biology.
Switchable interfaces have been demonstrated for a variety of applications. Some examples are presented in the review. Advantages that are expected from such switchable interfaces include speed, ease, reversibility, temporal and spatial control over interfacial interactions and events. Whilst there has been much excitement generated in this area, in many cases the understanding of the underlying mechanisms is still limited and needs to be extended.
There are great opportunities and challenges for further developments, toward an eventual goal to enable understanding, design and fabrication of encapsulation systems. We believe that the area will be explored further in nearest future. A next step in dynamic interface construction can be self-adaptive systems for needed applications.
Ekaterina V. Skorb received her diploma degree in chemistry at Belarusian State University in 2005. She got her PhD from the same university in physical chemistry in the area of photochemistry in 2008. She came to the Max Planck Institute of Colloids and Interfaces as a Humboldt fellow in 2010. She is currently a senior lecturer at Belarusian State University and an independent researcher in the Max Planck Institute of Colloids and Interfaces. Her research interests include study of the processes on dynamic interfaces, fabrication and characterization of stimuli-responsive encapsulation systems, nanomaterials, drug delivery systems for “smart intelligent” nanoarchitecture.
Helmuth Möhwald received his diploma in physics (1971) and PhD (1974) from the University of Gottingen (Germany) for research in organic solids. In 1981 he became associate professor in biophysics at TU Munich and in1987 a chair in physical chemistry at the University of Mainz. He became founding director of the Max Planck Institute of Colloids and Interfaces in Potsdam in 1993. His main research interests include chemistry and physics in confined spaces, dynamics at interfaces, and supramolecular interactions.