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Alternative means for drug delivery are needed to facilitate drug adherence and administration. Microneedles (MNs) have been previously investigated transdermally for drug delivery. To date, drug loading into MNs has been limited by drug solubility in the polymeric blend. We designed a highly drug-loaded MN patch to deliver macromolecules and applied it to the buccal area, which allows for faster delivery than the skin. We successfully delivered 1-mg payloads of human insulin and human growth hormone to the buccal cavity of swine within 30 s. In addition, we conducted a trial in 100 healthy volunteers to assess potential discomfort associated with MNs when applied in the oral cavity, identifying the hard palate as the preferred application site. We envisage that MN patches applied on buccal surfaces could increase medication adherence and facilitate the painless delivery of biologics and other drugs to many, especially for the pediatric and elderly populations.

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Submucosal elevation, the process of instilling material in the submucosal space for separation of the surface mucosa and deeper muscularis layer, is a significant aspect of the endoscopic mucosal resection of large lesions performed to facilitate lesion removal and maximize safety. Submucosal injection, when applied, has historically been performed with normal saline, though this is limited by its rapid dissipation; solutions ideally need to be easily injectable, biocompatible, and provide a long-lasting submucosal cushion with a desirable height. Here, reported is a new set of materials, endoscopically injectable shear-thinning hydrogels, meeting these requirements because of their biocompatible components and ability to form a solid hydrogel upon injection. These findings are supported by evaluation in a large animal model and ultimately demonstrate the potential of these shear-thinning hydrogels to serve as efficient submucosal injection fluids for cushion development. Given these unique characteristics, their broad application in mucosal resection techniques is anticipated.

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Long-term implantation of biomedical electronics into the human body enables advanced diagnostic and therapeutic functionalities. However, most long-term resident electronics devices require invasive procedures for implantation as well as a specialized receiver for communication. Here, a gastric resident electronic (GRE) system that leverages the anatomical space offered by the gastric environment to enable residence of an orally delivered platform of such devices within the human body is presented. The GRE is capable of directly interfacing with portable consumer personal electronics through Bluetooth, a widely adopted wireless protocol. In contrast to the passive day-long gastric residence achieved with prior ingestible electronics, advancement in multimaterial prototyping enables the GRE to reside in the hostile gastric environment for a maximum of 36 d and maintain ≈15 d of wireless electronics communications as evidenced by the studies in a porcine model. Indeed, the synergistic integration of reconfigurable gastric-residence structure, drug release modules, and wireless electronics could ultimately enable the next-generation remote diagnostic and automated therapeutic strategies.

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Gastric resident dosage forms have been used successfully in farm animals for the delivery of a variety of drugs helping address the challenge of extended dosing. Despite these advances, there remains a significant challenge across the range of species with large variation in body size. To address this, we investigate a scalable gastric resident platform capable of prolonged retention. We investigate prototypes in dimensions consistent with administration and retention in the stomachs of two species (rabbit and pig). We investigate sustained gastric retention of our scalable dosage form platform, and in pigs show the capacity to modulate drug release kinetics of a model drug in veterinary practice, meloxicam, with our dosage form. The ability to achieve gastric residence and thereby enable sustained drug levels across different species may have a significant impact in the welfare of animals in both research, agricultural, zoological, and clinical practice settings.

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Biomolecular monitoring in the gastrointestinal tract could offer rapid, precise disease detection and management but is impeded by access to the remote and complex environment. Here, we present an ingestible micro-bio-electronic device (IMBED) for in situ biomolecular detection based on environmentally resilient biosensor bacteria and miniaturized luminescence readout electronics that wirelessly communicate with an external device. As a proof of concept, we engineer heme-sensitive probiotic biosensors and demonstrate accurate diagnosis of gastrointestinal bleeding in swine. Additionally, we integrate alternative biosensors to demonstrate modularity and extensibility of the detection platform. IMBEDs enable new opportunities for gastrointestinal biomarker discovery and could transform the management and diagnosis of gastrointestinal disease.

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Improvements in ingestible electronics with the capacity to sense physiological and pathophysiological states have transformed the standard of care for patients. Yet, despite advances in device development, significant risks associated with solid, non-flexible gastrointestinal transiting systems remain. Here, we report the design and use of an ingestible, flexible piezoelectric device that senses mechanical deformation within the gastric cavity. We demonstrate the capabilities of the sensor in both in vitro and ex vivo simulated gastric models, quantify its key behaviours in the gastrointestinal tract using computational modelling and validate its functionality in awake and ambulating swine. Our proof-of-concept device may lead to the development of ingestible piezoelectric devices that might safely sense mechanical variations and harvest mechanical energy inside the gastrointestinal tract for the diagnosis and treatment of motility disorders, as well as for monitoring ingestion in bariatric applications.

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We report the incorporation of graphene-oxide quantum dots (GOQDs) into films, diluted solutions, and light-emitting diodes (LEDs) as part of a water-soluble derivative of poly(p-phenylene vinylene), or PDV.Li, to investigate their impact on the light-emission properties of this model conjugated polymer. Despite the well-known ability of graphene and graphene oxide to quench the photoluminescence of nearby emitters, we find that the addition of GOQDs to diluted solutions of PDV.Li does not significantly affect the photoluminescence (PL) dynamics of PDV.Li, bringing about only a modest quenching of the PL. However, loading the polymer with GOQDs led to a substantial decrease in the turn-on voltage of LEDs based on GOQD-PDV.Li composites. This effect can be attributed to either the improved morphology of the host polymer, resulting in an increase in the charge mobility, or the enhanced injection through GOQDs near the electrodes.

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Resonance Raman (RR) spectroscopy is used to investigate the effect of ß-cyclodextrin encapsulation on the structural and photophysical properties of poly(4,4'-diphenylenevinylene). We especially focus on the thermal stability of the polymer. We find that within the range of 10-55 °C the uninsulated polymer exhibits decreased Raman intensity in all the vibrational bands with temperature, along with changes in the relative intensity of the C-C inter-ring stretch mode at 1270 cm(-1) with respect to the ring C-H in-plane symmetric bend at 1187 cm(-1), which provides evidence for conformational changes as a function of temperature. No changes are observed in the intensity of the in-phase CH out-of-plane wag of the vinylene group at 968 cm(-1). Therefore, the conformational changes involve mainly dihedral angle modification between the adjacent phenyl rings toward planarization, and little or no change in the planarity of the trans-vinylene group. The decrease of the optical absorption at 55 °C with respect to that at room temperature and the appearance of a new absorption band at lower energies explain the decrease in the RR intensities and the wavelength dependence of the relative intensities of the Raman band. We note that the conformational change into a more planar geometry, which affects a significant portion of the polymer population, is irreversible and consistent with thermally induced aggregation. Such a planarization is unexpected in view of the usually observed thermochromic behavior of conjugated polymers, which leads to an increase of the energy gap for increasing temperature, as the average dihedral angles are increased due to excitation of a larger number of vibrational modes. Interestingly, the higher threading ratio polymers are resistant to any conformational changes within this temperature range, as reflected by their unchanged RR spectra, due to the rotaxane's ability to suppress intermolecular interactions and aggregation. Interestingly, the conformation of the uninsulated polymer at room temperature appears to be the same as that in the threaded analogues, which suggests that the cyclodextrin cavity hosts the polymer without physically interacting with it.

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The tetraarylazadipyrromethene chromophore class has gained increasing attention in the past decade for a diverse set of scientific interests and applications. The most direct synthetic route available for their generation is heating of 4-nitro-1,3-diarylbutan-1-ones with an ammonium source in an alcohol solvent. Despite the practical simplicity, the reaction pathway(s) for these conversions are lengthy and unclear. To gain insight into the steps involved, (15)N labeling experiments with MS and NMR analysis were utilized for conversion of 4-nitro-1,3-diphenylbutan-1-one 1 into tetraphenylazadipyrromethene 2 with (15)NH(4)OAc. To permit examination of later stages of the reaction sequence to 2, the (15)N-labeled potential intermediate 3,5-diphenyl-1H-pyrrol-2-amine 10 was synthesized. A study of the dimerization pathway utilizing (15)N-labeled 10 revealed an unprecedented nitrogen rearrangement in the final stages of the pathway involving a ring-opening/closing of a pyrrole ring. Utilizing (15)N labeling experiments we have shown that 2,4-diphenylpyrrole 8 can also react under the reaction conditions with 3,5-diphenyl-2H-pyrrol-2-imine 7 (from oxidation of 10) to produce 2. Overall in the conversion of 1 into 2, two related pathways are ongoing concurrently; the first involves a dimerization of 3,5-diphenyl-2H-pyrrol-2-imine 7, and the other a reaction of 7 with 2,4-diphenylpyrrole 8.

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Strategic incorporation of sulfonic acid, carboxylic acid or ammonium salt motifs generate water soluble BF(2)-chelated tetraarylazadipyrromethenes which exhibit strong near infra-red (NIR) emissions above 720 nm and can be readily imaged in both eukaryotic and prokaryotic cells.

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Complementary synthetic routes to a new class of near-IR fluorophores are described. These allow facile access (four synthetic steps) to the core fluorophore and substituted derivatives with emissions between 740 and 780 nm in good quantum yields.

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BACKGROUND: Smith-Lemli-Opitz syndrome (SLOS), a severe disorder of cholesterol synthesis, is classically diagnosed prenatally by GC-MS analysis of sterols in amniotic fluid. Considering the current trend toward tandem mass spectrometry (MS/MS) methodologies, we developed prototype LC-MS/MS methods for accurate diagnosis of the disorder. METHODS: 3beta-Hydroxysterols in amniotic fluid are oxidized with cholesterol oxidase to their corresponding 3-ketones, which are then derivatized with Girard P (GP) hydrazine in a "one-pot" reaction. The resulting GP-hydrazones give an improved response in electrospray (ES)-MS/MS owing to the presence of a charged quaternary nitrogen and are analyzed by reversed-phase LC-ES-MS/MS. Both capillary and conventional LC-MS/MS formats are suitable, and the method is also applicable to paper-absorbed blood spots. RESULTS: In a double-blind analysis of 18 amniotic fluid samples comprising 6 SLOS and 12 controls, the ratio of 7 + 8-dehydrocholesterol (7 + 8-DHC) to cholesterol was <0.02 [range 0.00-0.02, mean (SD) 0.01 (0.007)] in all control samples (intraassay variation 5.91%) and >0.20 [0.20-1.13, 0.79 (0.35)] in SLOS (intraassay variation 4.56%), corresponding to a difference in ratios between the 2 groups of at least a factor of 10. The limit of quantification was equivalent to that of 2 nL amniotic fluid injected on-column. CONCLUSIONS: We describe a proof-of-concept for the prenatal diagnosis of SLOS. Further developments will be necessary to automate sample handling and reduce chromatographic time for the methodology to be used in pre- and postnatal diagnosis.

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Effective nanoscale control of intermolecular interactions in conjugated polymers is needed for the optimal development and exploitation of the latter in low-cost, large-area consumer electronics items, such as light-emitting and photovoltaic diodes, or transistors. Here we report our investigations on insulated molecular wires constituted by conjugated polymers threaded into cyclodextrin rings. Until now, there has been no detailed quantitative understanding of the role of progressive cyclodextrin encapsulation (quantifiable by the so-called "threading ratio", TR, or number of cyclodextrins per repeat unit) in tailoring the photophysics of the conjugated polymeric wires. We combine spectroscopic, electrical and surface analysis techniques to elucidate how the TR of cyclodextrin-threaded molecular wires controls formation of interchain species and related physical properties (0 < TR < or = 2.3; the maximum theoretical TR for close-packed CDs is 2.8). Increasing TR enhances the solid-state photoluminescence (PL) and electroluminescence quantum efficiency. To unravel the effect of progressive encapsulation on the intrachain decay kinetics of the polymer backbone, we added an electron-accepting quenching agent, methyl viologen (MV), to the polymer solutions. MV predominantly quenches the aggregate PL, thus enabling measurement of the decay kinetics of the intrinsic exciton even for low-TR polyrotaxanes, for which the different contributions are otherwise difficult to disentangle.

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[reaction: see text] The synthesis and sensing characteristics of a new class of organic colorimetric and fluorometric chemosensor which operates in the 850-650 nm spectral region is outlined. Judicious placing of amine substituents on the BF2-chelated tetraarylazadipyrromethene chromophore generates a triple absorption and emission responsive sensor. Dramatic pH responsive absorption and fluorescence changes can be observed across a broad acidity range, from pH 5 to 6 M HCl, in conjunction with a visible colorimetric change from red to purple to blue.

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A new approach to achieving selectivity for photodynamic therapy based upon the reversible off/on switching of the key therapeutic property (singlet oxygen generation) of a supramolecular photonic therapeutic agent (SPTA) in response to an external stimulus in the surrounding microenvironment is described. A series of SPTA analogues with pH responsive receptors of varying pKa are presented, in which the generation of singlet oxygen is shown to be dependent upon a proton source. For example, systems have been constructed such that the excited state energy of the photosensitizer can be decayed by a rapid photoinduced electron transfer (PET) mechanism, resulting in virtually no singlet oxygen being generated, but when the amine receptor is protonated the PET mechanism does not operate and singlet oxygen is produced. In vitro efficacy demonstrated that the SPTA derivatives can be activated within cells and one analogue is measured to have an EC50 value of 5.8 nM when assayed in the MRC5 cell line.

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[reaction: see text] A stepwise route to unsymmetrical tetraarylazadipyrromethenes by a condensation of 2,4-diaryl-5-nitroso-pyrroles with 2,4-diarylpyrroles is described. This modular building-block approach allows for the introduction of up to four different aryl substituents on the azadipyrromethene and is tolerant of a varied substituent set. An efficient synthesis of the 2,4-diarylpyrroles building blocks from 1,3-diaryl-4-nitro-butan-1-ones by nitro hydrolysis to a keto-aldehyde and subsequent ammonia condensation reaction has been achieved. The facile conversion of 2,4-diarylpyrroles into their alpha-nitroso analogues by their reaction with sodium nitrite generated the second building block required for the synthesis.