Abstract
A method to assemble stimuli-responsive nucleic acid-based hydrogel-stabilized microcapsule-in-microcapsule systems is introduced. An inner aqueous compartment stabilized by a stimuli-responsive hydrogel-layer (∼150 nm) provides the inner microcapsule (diameter ∼2.5 μm). The inner microcapsule is separated from an outer aqueous compartment stabilized by an outer stimuli-responsive hydrogel layer (thickness of ∼150 nm) that yields the microcapsule-in-microcapsule system. Different loads, e.g., tetramethyl rhodamine-dextran (TMR-D) and CdSe/ZnS quantum dots (QDs), are loaded in the inner and outer aqueous compartments. The hydrogel layers exist in a higher stiffness state that prevents inter-reservoir or leakage of the loads from the respective aqueous compartments. Subjecting the inner hydrogel layer to Zn2+-ions and/or the outer hydrogel layer to acidic pH or crown ether leads to the triggered separation of the bridging units associated with the respective hydrogel layers. This results in the hydrogel layers of lower stiffness allowing either the mixing of the loads occupying the two aqueous compartments, the guided release of the load from the outer aqueous compartment, or the release of the loads from the two aqueous compartments. In addition, a pH-responsive microcapsule-in-microcapsule system is loaded with glucose oxidase (GOx) in the inner aqueous compartment and insulin in the outer aqueous compartment. Glucose permeates across the two hydrogel layers resulting in the GOx catalyzed aerobic oxidation of glucose to gluconic acid. The acidification of the microcapsule-in-microcapsule system leads to the triggered unlocking of the outer, pH-responsive hydrogel layer and to the release of insulin. The pH-stimulated release of insulin is controlled by the concentration of glucose. While at normal glucose levels, the release of insulin is practically prohibited, the dose-controlled release of insulin in the entire diabetic range is demonstrated. Also, switchable ON/OFF release of insulin is achieved highlighting an autonomous glucose-responsive microdevice operating as an “artificial pancreas” for the release of insulin.
Highlights
The synthesis of microcapsules and their applications have attracted growing interest in recent years.[1−3] Different methods to prepare microcapsules were reported. These include the chemical deposition of polymer or hydrogel coatings on substrate-loaded cores, followed by the etching of the core template.[4−6] For example, CaCO3 core templates were coated by a layer-by-layer deposition process of oppositely charged polyelectrolytes[7−11] or the use of interlayer biorecognition complexes,[12] e.g., lectin/saccharide complexes or the use of covalent bonds,[13,14] such as disulfides,[15] and the etching of the core templates, e.g., by EDTA, resulted in the substrate-loaded microcapsules
CaCO3 microparticles loaded with tetramethyl rhodamine-dextran (TMR-D) were coated with a poly(allylamine hydrochloride), PAH, layer followed by the electrostatic adsorption of DNA strand (1) on the coated particles
The strand (1) acts as a promoter strand for inducing the hybridization chain reaction (HCR) in the presence of two carboxymethyl cellulose (CMC) polymers, P1 and P2, functionalized with the anchoring tether (2) that acts as an anchoring site for the stimuli-responsive units and hairpins H1 and H2, respectively
Summary
The synthesis of microcapsules and their applications have attracted growing interest in recent years.[1−3] Different methods to prepare microcapsules were reported. Further enhancement of the complexities of stimuliresponsive microcapsules would involve the challenging assembly of microcapsule-in-microcapsule systems, where two aqueous compartments are separated and stabilized by two different stimuli-responsive layers Such systems could be applied for the programmed release of one of two drugs or the parallel release of two drugs (or prodrug and activator), and could act as an organized compartmentalized containment for chemical reactions. We apply a microcapsule-in-microcapsule system as a functional unit that operates as a closedloop device that senses glucose and releases insulin, acting as a model of an “artificial pancreas”
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