Hollow Microcapsules Research Articles

Multilayer Hydrogel Capsules of Interpenetrated Network for Encapsulation of Small Molecules.

We report on a facile capsule-based platform for efficient encapsulation of a broad spectrum of hydrophilic compounds with molecular weight less than 1000 g mol-1. The encapsulated compounds extend from low-molecular-weight anionic Alexa Fluor 532 dye and cationic anticancer drug doxorubicin (DOX) to fluorescein isothiocyanate-dextrans with Mw ranging from 4000 to 40 000 g mol-1. The pH-sensitive hydrogel capsules with an interpenetrated network shell are synthesized by layer-by-layer assembly of poly(methacrylic acid) (PMAA, Mw = 150 000 g mol-1) and poly( N-vinylpyrrolidone) (PVPON, Mw = 1 300 000 g mol-1) on 5 μm silica microparticles followed by chemical cross-linking of the PMAA multilayers. Following core dissolution, the result is a hollow microcapsule with PVPON interpenetrated in the PMAA network. The capsules exhibit a reversible change in the diameter with a swelling ratio of 1.5 upon pH variation from 7.5 to 5.5. Capsules cross-linked for 4 h display high permeability toward molecules with molecular weight under 1000 g mol-1 at pH = 7.5 but exclude dextran molecules with Mw ≥ 40 000 g mol-1. Encapsulation of small molecules was achieved at pH = 7.5 followed by sealing the capsule wall with 40 000 g mol-1 dextran at pH = 5.5. This approach results in negatively charged molecules such as Alexa Fluor being entrapped within the capsule cavity, whereas positively charged molecules such as DOX are encapsulated within the negatively charged capsule shell. Considering the simple postloading approach, the ability to entrap both anionic and cationic small molecules, and the pH-responsiveness of the interpenetrated network in the physiologically relevant range, these capsules offer a versatile method for controlled delivery of multiple hydrophilic compounds.

Ionic Strength and pH Responsive Permeability of Soy Glycinin Microcapsules.

Recently, hollow protein microcapsules have been made simply by heating the microphase separated soy glycinin microdomains. However, the properties (e.g., mechanical properties and permeability) that relate to the application of these microcapsules are unknown. In this study, the permeability of the soy glycinin microcapsules was investigated by confocal laser scanning microscopy (CLSM), as influenced by ionic strength and pH using fluorescein isothiocyanate-dextran (FITC-dextran).The glycinin microcapsules kept the integrity between pH 1 and 11.5, swelled when pH was below 3 or above pH 11, dissociated at pH above 11.5 and deswelled slightly at pH 1. When the pH increased above 11, the permeability of the microcapsule significantly increased. Remarkably, when the pH was below the isoelectric point of glycinin (≈pH 5), FITC-dextran spontaneously accumulated inside the microcapsule with a significantly higher concentration than that in bulk solution, as evidenced by the strong intensity increase of fluorescence. This unique feature significantly increased the loading amount of FITC-dextran. The permeability of microcapsules was also increased by adding salt but less significant than by adjusting pH. The surface of the microcapsules became coarser when the permeability increased, which was revealed by scanning electron microscopy. These results show that soy glycinin has a great potential to be used as a wall material to fabricate hollow microcapsules that could find applications in biomedicine and food industry.

Extraction of cage-like sporopollenin exine capsules from dandelion pollen grains

Pollen-based microcapsules such as hollow sporopollenin exine capsules (SECs) have emerged as excellent drug delivery and microencapsulation vehicles. To date, SECs have been extracted primarily from a wide range of natural pollen species possessing largely spherical geometries and uniform surface features. Nonetheless, exploring pollen species with more diverse architectural features could lead to new application possibilities. One promising class of candidates is dandelion pollen grains, which possess architecturally intricate, cage-like microstructures composed of robust sporopollenin biopolymers. Here, we report the successful extraction and macromolecular loading of dandelion SECs. Preservation of SEC morphology and successful removal of proteinaceous materials was evaluated using scanning electron microscopy (SEM), matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry, elemental CHN analysis, dynamic image particle analysis (DIPA) and confocal laser scanning microscopy (CLSM). Among the tested processing schemes, acidolysis using 85% (v/v) phosphoric acid refluxed at 70 °C for 5 hours yielded an optimal balance of intact particle yield, protein removal, and preservation of cage-like microstructure. For proof-of-concept loading, bovine serum albumin (BSA) was encapsulated within the dandelion SECs with high efficiency (32.23 ± 0.33%). Overall, our findings highlight how hollow microcapsules with diverse architectural features can be readily prepared and utilized from plant-based materials.

Layer-by-layer hollow photosensitizer microcapsule design via a manganese carbonate hard template for photodynamic therapy in cells

Microcapsules fabricated using layer-by-layer self-assembly have unique properties, making them attractive for drug delivery applications. The technique has been improved, allowing the deposition of multiple layers of oppositely charged polyelectrolytes on spherical, colloidal templates. These templates can be decomposed by coating multiple layers, resulting in hollow shells. In this paper, we describe a novel drug delivery system for loading photosensitizer drugs into hollow multilayered microcapsules for photoprocess applications. Manganese carbonate particles were prepared by mixing NH4HCO3 and MnSO4 and performing consecutive polyelectrolyte adsorption processes onto these templates using poly-(sodium 4-styrene sulfonate) and poly-(allylamine hydrocholoride). A photosensitizer was also incorporated into the layers. Hollow spheres were fabricated by removing the cores in the acidic solution. The hollow, multilayered microcapsules were studied by scanning electron microscopy, steady-state, and time-resolved techniques. Their biological activity was evaluated in vitro with cancer cells using a conventional MTT assay. The synthesized CaCO3 microparticles were uniform, non-aggregated, and highly porous spheres. The phthalocyanine derivatives loaded in the microcapsules maintained their photophysical behaviour after encapsulation. The spectroscopic results presented here showed excellent photophysical behaviour of the studied drug. We observed a desirable increase in singlet oxygen production, which is favourable for the PDT protocol. Cell viability after treatment was determined and the proposed microcapsules caused 80% cell death compared to the control. The results demonstrate that photosensitizer adsorption into the CaCO3 microparticle voids together with the layer-by-layer assembly of biopolymers provide a method for the fabrication of biocompatible microcapsules for use as biomaterials.

Patterned Arrays of Supramolecular Microcapsules

AbstractMicropatterning of hydrogel has brought innovative outcomes in fundamental and applied material sciences. Previous approaches have mainly been dedicated to fabricate arrays of bulk hydrogel beads, which have inherent challenges including loading ability, scalability, specificity, and versatility. Here, a methodology is presented to create hollow microcapsule arrays from sessile microdroplets. The difference in wettability between hydrophilic and hydrophobic surfaces enables self‐partitioning of liquid into microdroplet arrays, serving as microreservoirs to load complementarily functionalized host–guest polymers, cucurbit[8]uril‐threaded highly branched polyrotaxanes (HBP‐CB[8]) and naphthyl‐functionalized hydroxyethyl cellulose (HEC‐Np). The interfacial dynamic complexation between positively charged HBP‐CB[8] and HEC‐Np occurs in the presence of negatively charged surfactants, resulting in condensed supramolecular hydrogel skins. The hydrogel microcapsules are uniform in size and are developed to encapsulate target cargos in a robust and well‐defined manner. Moreover, the microcapsule substrates are further used for surface enhanced Raman spectroscopy sensing upon loading of gold nanoparticles. This facile assembly of microcapsule arrays has potential applications in controlled cargo delivery, bio‐sensing, high‐throughput analysis, and sorting.

Preparation of Well-Dispersed Chitosan/Alginate Hollow Multilayered Microcapsules for Enhanced Cellular Internalization.

Hollow multilayered capsules have shown massive potential for being used in the biomedical and biotechnology fields, in applications such as cellular internalization, intracellular trafficking, drug delivery, or tissue engineering. In particular, hollow microcapsules, developed by resorting to porous calcium carbonate sacrificial templates, natural-origin building blocks and the prominent Layer-by-Layer (LbL) technology, have attracted increasing attention owing to their key features. However, these microcapsules revealed a great tendency to aggregate, which represents a major hurdle when aiming for cellular internalization and intracellular therapeutics delivery. Herein, we report the preparation of well-dispersed polysaccharide-based hollow multilayered microcapsules by combining the LbL technique with an optimized purification process. Cationic chitosan (CHT) and anionic alginate (ALG) were chosen as the marine origin polysaccharides due to their biocompatibility and structural similarity to the extracellular matrices of living tissues. Moreover, the inexpensive and highly versatile LbL technology was used to fabricate core-shell microparticles and hollow multilayered microcapsules, with precise control over their composition and physicochemical properties, by repeating the alternate deposition of both materials. The microcapsules’ synthesis procedure was optimized to extensively reduce their natural aggregation tendency, as shown by the morphological analysis monitored by advanced microscopy techniques. The well-dispersed microcapsules showed an enhanced uptake by fibroblasts, opening new perspectives for cellular internalization.

Encapsulation of Multiple Microalgal Cells via a Combination of Biomimetic Mineralization and LbL Coating.

The encapsulation of living cells is appealing for its various applications to cell-based sensors, bioreactors, biocatalysts, and bioenergy. In this work, we introduce the encapsulation of multiple microalgal cells in hollow polymer shells of rhombohedral shape by the following sequential processes: embedding of microalgae in CaCO3 crystals; layer-by-layer (LbL) coating of polyelectrolytes; and removal of sacrificial crystals. The microcapsule size was controlled by the alteration of CaCO3 crystal size, which is dependent on CaCl2/Na2CO3 concentration. The microalgal cells could be embedded in CaCO3 crystals by a two-step process: heterogeneous nucleation of crystal on the cell surface followed by cell embedment by the subsequent growth of crystal. The surfaces of the microalgal cells were highly favorable for the crystal growth of calcite; thus, micrometer-sized microalgae could be perfectly occluded in the calcite crystal without changing its rhombohedral shape. The surfaces of the microcapsules, moreover, could be decorated with gold nanoparticles, Fe3O4 magnetic nanoparticles, and carbon nanotubes (CNTs), by which we would expect the functionalities of a light-triggered release, magnetic separation, and enhanced mechanical and electrical strength, respectively. This approach, entailing the encapsulation of microalgae in semi-permeable and hollow polymer microcapsules, has the potential for application to microbial-cell immobilization for high-biomass-concentration cultivation as well as various other bioapplications.

Synthesizing Sodium Tungstate and Sodium Molybdate Microcapsules via Bacterial Mineral Excretion

We present a method, the bacterial mineral excretion (BME), for synthesizing two kinds of microcapsules, sodium tungstate and sodium molybdate, and the two metal oxides' corresponding nanoparticles—the former being as small as 22 nm and the latter 15 nm. We fed two strains of bacteria, Shewanella algae and Pandoraea sp., with various concentrations of tungstate or molybdate ions. The concentrations of tungstate and molybdate were adjusted to make microcapsules of different length-to-diameter ratios. We found that the higher the concentration the smaller the nanoparticles were. The nanoparticles came in with three length-to-diameter ratios: 10:1, 3:1 and 1:1, which were achieved by feeding the bacteria respectively with a low concentration, a medium concentration, and a high concentration. The images of the hollow microcapsules were taken via the scanning electron microsphere (SEM). Their crystal structures were verified by X-ray diffraction (XRD)—the crystal structure of molybdate microcapsules is Na2MoO4 and that of tungstate microcapsules is Na2WO4 with Na2W2O7. These syntheses all were accomplished under a near ambient condition.

Synthesizing Sodium Tungstate and Sodium Molybdate Microcapsules via Bacterial Mineral Excretion.

We present a method, the bacterial mineral excretion (BME), for synthesizing two kinds of microcapsules, sodium tungstate and sodium molybdate, and the two metal oxides' corresponding nanoparticles—the former being as small as 22 nm and the latter 15 nm. We fed two strains of bacteria, Shewanella algae and Pandoraea sp., with various concentrations of tungstate or molybdate ions. The concentrations of tungstate and molybdate were adjusted to make microcapsules of different length-to-diameter ratios. We found that the higher the concentration the smaller the nanoparticles were. The nanoparticles came in with three length-to-diameter ratios: 10:1, 3:1 and 1:1, which were achieved by feeding the bacteria respectively with a low concentration, a medium concentration, and a high concentration. The images of the hollow microcapsules were taken via the scanning electron microsphere (SEM). Their crystal structures were verified by X-ray diffraction (XRD)—the crystal structure of molybdate microcapsules is Na2MoO4 and that of tungstate microcapsules is Na2WO4 with Na2W2O7. These syntheses all were accomplished under a near ambient condition.

Preparation of Hollow Polystyrene Particles and Microcapsules by Radical Polymerization of Janus Droplets Consisting of Hydrocarbon and Fluorocarbon Oils.

In this article, we have demonstrated a method for producing hollow particles and microcapsules using oil droplets consisting of hydrocarbon oil (styrene) and fluorocarbon oil (perfluoro-n-octane, PFO) in aqueous surfactant (sodium dodecylsulfate, SDS) solutions. Since fluorocarbon oils are immiscible with hydrocarbon oils, the two oils are separated. Emulsions are prepared by stirring styrene/PFO/aqueous SDS solution mixtures at 80 °C. The type of emulsions and the morphology of droplets in the emulsions are observed by light microscope and scanning confocal fluorescence microscope. It is found that oil droplets with Janus-type morphologies consisting of mutually immiscible styrene and PFO are formed in aqueous SDS solutions. Polystyrene particles are fabricated by radical polymerization of the ternary mixtures of styrene/PFO/aqueous SDS solution at 80 °C. The morphologies of the polystyrene are confirmed by scanning electron microscopy and scanning transmission electron microscopy observations. These observations show the preparation of hollow polystyrene particles with a single hole on the surface. To our knowledge, this method is a novel strategy using the immiscibility of hydrocarbon and fluorocarbon oils. The hollow particles can also be applied to the preparation of microcapsules.

Preparation of Hollow Polystyrene Particles and Microcapsules by Radical Polymerization of Janus Droplets Consisting of Hydrocarbon and Fluorocarbon Oils

In this article, we have demonstrated a method for producing hollow particles and microcapsules using oil droplets consisting of hydrocarbon oil (styrene) and fluorocarbon oil (perfluoro-n-octane, PFO) in aqueous surfactant (sodium dodecylsulfate, SDS) solutions. Since fluorocarbon oils are immiscible with hydrocarbon oils, the two oils are separated. Emulsions are prepared by stirring styrene/PFO/aqueous SDS solution mixtures at 80 °C. The type of emulsions and the morphology of droplets in the emulsions are observed by light microscope and scanning confocal fluorescence microscope. It is found that oil droplets with Janus-type morphologies consisting of mutually immiscible styrene and PFO are formed in aqueous SDS solutions. Polystyrene particles are fabricated by radical polymerization of the ternary mixtures of styrene/PFO/aqueous SDS solution at 80 °C. The morphologies of the polystyrene are confirmed by scanning electron microscopy and scanning transmission electron microscopy observations. These observations show the preparation of hollow polystyrene particles with a single hole on the surface. To our knowledge, this method is a novel strategy using the immiscibility of hydrocarbon and fluorocarbon oils. The hollow particles can also be applied to the preparation of microcapsules.

Manganoporphyrin-Polyphenol Multilayer Capsules as Radical and Reactive Oxygen Species (ROS) Scavengers

Local modulation of oxidative stress is crucial for a variety of biochemical events including cellular differentiation, apoptosis, and defense against pathogens. Currently employed natural and synthetic antioxidants exhibit a lack of biocompatibility, bioavailability, and chemical stability, resulting in limited capability to scavenge reactive oxygen species (ROS). To mediate these drawbacks, we have developed a synergistic manganoporphyrin-polyphenol polymeric nanothin coating and hollow microcapsules with efficient antioxidant activity and controllable ROS modulation. These materials are produced by multilayer assembly of a natural polyphenolic antioxidant, tannic acid (TA), with a synthesized copolymer of polyvinylpyrrolidone containing a manganoporphyrin modality (MnP-PVPON) which mimics the enzymatic antioxidant superoxide dismutase. The redox activity of the copolymer is demonstrated to dramatically increase the antioxidant response of MnP-PVPON/TA capsules versus unmodified PVPON/TA capsules throug...

Bio-inspired microcapsule for targeted antithrombotic drug delivery.

Thrombosis or embolism is the leading cause of death and long-term adult disability worldwide. To reduce the risk of thrombosis and hemorrhaging in patients, a facile and versatile method was developed to fabricate microcapsules for targeted antithrombotic drug delivery. The microcapsules were prepared via oxidative polymerization of dopamine on polystyrene microspheres, followed by immobilization of fibrinogen onto the surface of poly(dopamine) layers. Subsequently, microcapsules were obtained by removing the cores with THF. Nattokinase was loaded into the microcapsules via diffusion. The loading amount was approximately 0.05 mg g−1 at 37 °C, and the loading efficiency was nearly 75%, based on the initial concentration of nattokinase in PBS. The release of nattokinase was a gradual process at 37 °C, and the activity of the targeted activated platelets was highly efficient. The antithrombotic activity of the nattokinase microcapsules was evidenced by the sharp dissolution of fibrin clots and the blood clotting time indexes. A gradual release mechanism of platelet-inspired microcapsules used for targeted antithrombotic therapy was proposed. This strategy for targeted antithrombotic drug delivery, which lowers the demand dose and minimizes side effects while maximizing drug efficacy, provides a potential new way to treat life-threatening diseases caused by vascular disruption.

Preserving the inflated structure of lyophilized sporopollenin exine capsules with polyethylene glycol osmolyte

Extracted from natural pollen grains, sporopollenin exine capsules (SECs) are robust, chemically inert biopolymer shells that posess highly uniform size and shape characteristics and that can be utilized as hollow microcapsules for drug delivery applications. However, it is challenging to extract fully functional SECs from many pollen species because pollen grains often collapse, causing the loss of architectural features, loading volume, and bulk uniformity. Herein, we demonstrate that polyethylene glycol (PEG) osmolyte solutions can help preserve the native architectural features of extracted SECs, yielding inflated microcapsules of high uniformity that persist even after subsequent lyophilization. Optimal conditions were first identified to extract SECs from cattail (Typhae angustfolia) pollen via phosphoric acid processing after which successful protein removal was confirmed by elemental (CHN), mass spectrometry (MALDI-TOF), and confocal laser canning microscopy (CLSM) analyses. The shape of SECs was then assessed by scanning electron microscopy (SEM) and dynamic image particle analysis (DIPA). While acid-processed SECs experienced high degrees of structural collapse, incubation in 2.5% or higher PEG solutions significantly improved preservation of spherical SEC shape by inducing inflation within the microcapsules. A theoretical model of PEG-induced osmotic pressure effects was used to interpret the experimental data, and the results show excellent agreement with the known mechanical properties of pollen exine walls. Taken together, these findings demonstrate that PEG osmolyte is a useful additive for preserving particle shape in lyophilized SEC formulations, opening the door to broadly applicable strategies for stabilizing the structure of hollow microcapsules.

Layer‐by‐Layer Assembly of κ‐Casein Amyloid Fibrils for the Preparation of Hollow Microcapsules

AbstractAmyloids are known to self‐assemble into fibril forms derived from natural or artificial proteins exhibiting superior mechanical properties, stability, and biocompatibility. However, few studies have investigated the applications of amyloid fibrils. Herein, the layer‐by‐layer growth of zwitterionic κ‐casein amyloid fibrils (κCFs) to prepare stable hollow microcapsules is investigated, which is potentially applicable to drug delivery systems. The growth of κCFs increases linearly when electrostatic interactions between the constituent pair become more prominent, for instance, cationic κCFs paired with poly(sodium 4‐styrenesulfonate) (PSS), and anionic κCFs paired with poly(diallyldimethylammonium chloride). In contrast, the increase in film thickness shows the exponential‐to‐linear transition when hydrogen bonding is responsible for adsorption between cationic κCFs and poly(acrylic acid) (PAA). It is thus concluded that stable κCF/PSS hollow microcapsules are prepared by using the electrostatic interaction. However, the κCF/PAA hollow microcapsules are ruptured due to the breakage of hydrogen bonding upon removal of sacrificial templates.

Biotemplating synthesis and photocatalytic activities of N-doped CeO2 microcapsule tailored by hemerocallis pollen

As one of the most active rare earth, CeO2 has been receiving considerable attention due to its multifunctional properties. Herein, we present a facile and green route toward hierarchical N-doped CeO2 hollow microcapsule by using hemerocallis pollen as biotemplate. The resulting sample was characterized by X-ray diffraction spectroscopy, field emission scanning electron microscopy, transmission electron microscopy, nitrogen adsorption and desorption, UV–Vis diffuse reflectance spectra and X-ray photoelectron spectrogram. The obtained N-doped CeO2 microcapsule exhibits much more superior photocatalytic activity for the hydrogen generation by water splitting, which owing to the nitrogen doping and structural features. This facile method of research provides a rational approach to replicate desired biological structures for semiconductor nanoparticle catalysis in other potential areas.

Drug Delivery: Plant‐Based Hollow Microcapsules for Oral Delivery Applications: Toward Optimized Loading and Controlled Release (Adv. Funct. Mater. 31/2017)

Drug Delivery: Plant‐Based Hollow Microcapsules for Oral Delivery Applications: Toward Optimized Loading and Controlled Release (Adv. Funct. Mater. 31/2017)

Fabrication of hard-shell microcapsules containing inorganic materials

The fabrication method of silica hard shell microcapsules containing disodium hydrogen phosphate dodecahydrate (Na2HPO4⋅12H2O) has been developed. The effects of the mixing rates for the emulsification, of the volume ratios of solutions and of surfactant concentrations on the size of hollow microcapsules have been also studied. From the results, it was confirmed that silica hard shell microcapsules can contains Na2HPO4⋅12H2O with the present method using hollow microcapsules. The present micro-encapsulated Na2HPO4⋅12H2O was also found to cause the supercooling depression effect. As the fabricated microcapsules have no flammability, the present microcapsule was concluded to be a promising item not only for latent heat transportation media but also for the static thermal storage materials for architectural structures. From the studies on the fabrication parameters, it was concluded that the control of the surfactant concentration is effective for controlling the size of microcapsule.

One-Step Generation of Salt-Responsive Polyelectrolyte Microcapsules via Surfactant-Organized Nanoscale Interfacial Complexation in Emulsions (SO NICE).

Polyelectrolyte microcapsules are versatile compartments for encapsulation, protection, and controlled/triggered release of active agents. Conventional methods of polyelectrolyte microcapsule preparation require multiple steps or do not allow for efficient encapsulation of active agents in the lumen of the microcapsule. In this work, we present the fabrication of hollow polyelectrolyte microcapsules with a salt-responsive property based on surfactant organized nanoscale interfacial complexation in emulsions (SO NICE). In SO NICE, polyelectrolyte microcapsules are templated by water-in-oil-in-water (W/O/W) double emulsions. One polyelectrolyte is dissolved in the inner water droplet of the W/O/W double emulsions, whereas the second polyelectrolyte is dissolved in the organic phase by hydrophobic ion paring with an oppositely charged hydrophobic surfactant. Interfacial complexation of the two polyelectrolytes generates a few hundred-nanometer thick film at the inner water-oil interface of the W/O/W double emulsions. SO NICE microcapsules can be triggered to release their cargo by increasing the ionic strength of the solution, which is a hallmark of polyelectrolyte-based microcapsules. By enabling dissolution and interfacial complexation of polyelectrolytes in organic solvents, SO NICE widens the pallet of polymers that can be used to generate functional polyelectrolyte microcapsules with high encapsulation efficiency for applications in encapsulation and controlled/triggered release.

Plant‐Based Hollow Microcapsules for Oral Delivery Applications: Toward Optimized Loading and Controlled Release

Efficient oral administration of protein‐based therapeutics faces significant challenges due to degradation from the highly acidic conditions present in the stomach and proteases present in the digestive tract. Herein, investigations into spike‐covered sunflower sporopollenin exine capsules (SECs) for oral protein delivery using bovine serum albumin (BSA) as a model drug are reported and provide significant insights into the optimization of SEC extraction, SEC loading, and controlled release. The phosphoric‐acid‐based SEC extraction process is optimized. Compound loading is shown to be driven by the evacuation of air bubbles from SEC cavities through the porous SEC shell wall, and vacuum loading is shown to be the optimal loading method. Three initial BSA‐loading proportions are evaluated, leading to a practical loading efficiency of 22.3 ± 1.5 wt% and the determination that the theoretical maximum loading is 46.4 ± 2.5 wt%. Finally, an oral delivery formulation for targeted intestinal delivery is developed by tableting BSA‐loaded SECs and enteric coating. BSA release is inhibited for 2 h in simulated gastric conditions followed by 100% release within 8 h in simulated intestinal conditions. Collectively, these results indicate that sunflower SECs provide a versatile platform for the oral delivery of therapeutics.