Microneedle Sensors for Point-of-Care Diagnostics.

Point-of-care (POC) has the capacity to support low-cost, accurate and real-time actionable diagnostic data. Microneedle sensors have received considerable attention as an emerging technique to evolve blood-based diagnostics owing to their direct and painless access to a rich source of biomarkers from interstitial fluid. This review systematically summarizes the recent innovations in microneedle sensors with a particular focus on their utility in POC diagnostics and personalized medicine. The integration of various sensing techniques, mostly electrochemical and optical sensing, has been established in diverse architectures of "lab-on-a-microneedle" platforms. Microneedle sensors with tailored geometries, mechanical flexibility, and biocompatibility are constructed with a variety of materials and fabrication methods. Microneedles categorized into four types: metals, inorganics, polymers, and hydrogels, have been elaborated with state-of-the-art bioengineering strategies for minimally invasive, continuous, and multiplexed sensing. Microneedle sensors have been employed to detect a wide range of biomarkers from electrolytes, metabolites, polysaccharides, nucleic acids, proteins to drugs. Insightful perspectives are outlined from biofluid, microneedles, biosensors, POC devices, and theragnostic instruments, which depict a bright future of the upcoming personalized and intelligent health management.

A wearable microneedle patch incorporating reversible FRET-based hydrogel sensors for continuous glucose monitoring.

Continuous glucose monitors are crucial for diabetes management, but invasive sampling, signal drift and frequent calibrations restrict their widespread usage. Microneedle sensors are emerging as a minimally-invasive platform for real-time monitoring of clinical parameters in interstitial fluid. Herein, a painless and flexible microneedle sensing patch is constructed by a mechanically-strong microneedle base and a thin layer of fluorescent hydrogel sensor for on-site, accurate, and continuous glucose monitoring. The Förster resonance energy transfer (FRET)-based hydrogel sensors are fabricated by facile photopolymerizations of acryloylated FRET pairs and glucose-specific phenylboronic acid. The optimized hydrogel sensor enables quantification of glucose with reversibility, high selectivity, and signal stability against photobleaching. Poly (ethylene glycol diacrylate)-co-polyacrylamide hydrogel is utilized as the microneedle base, facilitating effective skin piercing and biofluid extraction. The integrated microneedle sensor patch displays a sensitivity of 0.029 mM-1 in the (patho)physiological range, a low detection limit of 0.193 mM, and a response time of 7.7 min in human serum. Hypoglycemia, euglycemia and hyperglycemia are continuously monitored over 6 h simulated meal and rest activities in a porcine skin model. This microneedle sensor with high transdermal analytical performance offers a powerful tool for continuous diabetes monitoring at point-of-care settings.

Probing the guest-binding preference of three structurally similar and conformationally adaptive macrocycles.

A hybrid macrocycle was synthesized by combining the repeat units in oxatub[4]arene and zorb[4]arene, and its recognition behavior and conformational analysis were studied. Three structurally similar and conformationally adaptive macrocycles show different guest-binding selectivities and preferences even in a complex mixture containing three macrocycles and three guests.

Effects of side chains of oxatub[4]arene on its conformational interconversion, molecular recognition and macroscopic self-assembly.

A series of oxatub[4]arenes with different alkyl side chains have been synthesized. The conformational interconversion, molecular recognition and macroscopic self-assembly behaviour of oxatub[4]arene derivatives were investigated. The difference in side chains slightly changes the binding affinities, but results in different self-assembly morphologies at the solid state.

Protecting-Group-Free Total Synthesis of (-)-Jiadifenolide: Development of a [4 + 1] Annulation toward Multisubstituted Tetrahydrofurans.

A concise, protecting-group-free total synthesis of (-)-jiadifenolide, a synthetically challenging seco-prezizaane sesquiterpene with potent neurotrophic activity, is reported. The convergent route features a SmI2/H2O-mediated stereoselective reductive cyclization, an unprecedented formal [4 + 1] annulative tetrahydrofuran-forming reaction and programmed redox manipulations. The newly developed annulation of ß-hydroxy aldehydes or ketones with lithium trimethylsilyldiazomethane provides access to a diverse array of multisubstituted tetrahydrofurans. The synthetic jiadifenolide exhibited weak cytotoxicity against five human cancer cell lines.

Oxatub[4]arene: a smart macrocyclic receptor with multiple interconvertible cavities.

There are a large number of synthetic macrocyclic receptors in the literature. No particular one is suitable for all guests or purposes. For a broader guest binding scope or multiple purposes, a macrocycle with multiple interconvertible cavities will be advantageous. Here, we report a naphthalene-based macrocyclic receptor with an adaptable cavity, namely oxatub[4]arene. It has four representative conformations resulting from the flipping of naphthalene rings, each with a deep and well-defined cavity. Different guests select one host conformer or a combination of conformers. All the four conformers have been detected and characterized based on 2D NMR spectra and X-ray single crystal structures. Thermodynamically, these conformers constitute a reservoir, that responds to the structural changes of guests, and thus maximizes the association free energies. This smart macrocycle may provide a new platform for the construction of molecular machines and devices or stimuli-responsive materials.

FXR ligands protect against hepatocellular inflammation via SOCS3 induction.

Because of the anti-inflammatory actions of farnesoid X receptor (FXR) agonists, FXR has received much attention as a potential therapeutic target. However, the molecular mechanisms of actions have not yet been elucidated. In the present study, we reported that in the animal model of LPS-induced liver injury, administration of the FXR natural ligand CDCA could attenuate hepatocyte inflammatory damage, reduce transaminase activities, suppress inflammation mediators (IL-6, TNF-α and ICAM-1) expression and inhibit STAT3 phosphorylation. These protective effects of FXR were accompanied by an increased expression of suppressor of cytokine signaling 3 (SOCS3), which is a negative feedback regulator of cytokine-STAT3 signaling. We then demonstrated that the beneficial effects of FXR agonist in STAT3 activation were weakened by small interfering RNA-mediated SOCS3 knockdown in hepacytes. Moreover we observed both natural ligand CDCA and synthetic ligand GW4064 could upregulate SOCS 3 expression by enhancing the promoter activity in hepatocytes. These results suggest modulation of SOCS3 expression may represent a novel mechanism through which FXR activation could selectively affect cytokine bioactivity in inflammation response. FXR ligands may be potentially therapeutic in the treatment of liver inflammatory diseases via SOCS3 induction.