Tear glucose measurements have been suggested as a potential alternative to blood glucose monitoring for diabetic patients. While previous work has reported that there is a correlation between blood and tear glucose levels in humans, this link has not been thoroughly established and additional clinical studies are needed. Herein, we evaluate the potential of using commercial blood glucose test strips to measure glucose in tears. Of several blood glucose strips evaluated, only one brand exhibits the low detection limit required for quantitating glucose in tears. Calibration of these strips in the range of 0-100 μM glucose with an applied potential of 150 mV to the working electrode yields a sensitivity of 0.127 nA/μM and a limit of quantitation (LOQ) of 9 μM. The strips also exhibit ≤13% error (n = 3) for 25, 50, and 75 μM glucose in the presence of 10 μM acetaminophen, 100 μM ascorbic acid, and 100 μM uric acid. Measurements of glucose in tears from nine normal (nondiabetic) fasting human subjects using strips yielded glucose values within the range of 5-148 μM (mean = 47 μM, median = 43 μM), similar to those for human tears reported by others with more complex LC-MS methods. The glucometer strip method could facilitate more clinical studies to determine whether tear glucose and blood glucose levels sufficiently correlate for application to routine measurements in tears to supplement blood glucose testing. This would be especially helpful for children, adolescents, other Type 1 diabetics, and also for Type 2 diabetics who require treatment with insulin and cannot tolerate multiple finger sticks per day.

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Mucoadhesive polymers are of significant interest to the pharmaceutical, medical device, and cosmetic industries. Polysaccharides possessing charged functional groups, such as chitosan, are known for mucoadhesive properties but suffer from poor chemical definition and solubility, while the chemical synthesis of polysaccharides is challenging with few reported examples of synthetic carbohydrate polymers with engineered‐in ionic functionality. We report the design, synthesis, and evaluation of a synthetic, cationic, enantiopure carbohydrate polymer inspired by the structure of chitosan. These water‐soluble, cytocompatible polymers are prepared via an anionic ring‐opening polymerization of a bicyclic β‐lactam sugar monomer. The synthetic method provides control over the site of amine functionalization and the length of the polymer while providing narrow dispersities. These well‐defined polymers are mucoadhesive as documented in single‐molecule scale (AFM), bulk solution phase (FRAP), and ex vivo tissue experiments. Polymer length and functionality affects bioactivity as long, charged polymers display higher mucoadhesivity than long, neutral polymers or short, charged polymers.

The alkene-isocyanate cycloaddition method affords β-lactams from glycals with high regio- and stereoselectivity, but the factors that determine substrate reactivity are poorly understood. Thus, we synthesized a library of 17 electron-rich alkenes (glycals) with varied protecting groups to systematically elucidate the factors that influence their reactivity toward the electron-poor trichloroacetyl isocyanate. The experimentally determined reaction rates exponentially correlate with the computationally determined highest occupied molecular orbital–lowest unoccupied molecular orbital (HOMO–LUMO) gap and natural bond orbital (NBO) valence energies. The electron-withdrawing ability of the protecting groups, but not bulk, impacts the electron density of the glycal allyloxocarbenium system when oriented pseudo-axially (i.e., stereoelectronics). In this conformation, ring σC–O* orbitals oriented antiperiplanar to the allyloxocarbenium system decrease glycal reactivity via negative hyperconjugation as protecting group electron withdrawal increases. Transition-state calculations reveal that protecting group stereoelectronics direct the reaction to proceed via an asynchronous one-step mechanism through a zwitterionic species. The combined experimental and computational findings, along with experimental validation on an unknown glycal, provide insight on the reaction mechanism and the role of distant protecting groups in glycal reactivity. Together, these studies will aid in the synthesis of new β-lactam antibiotics, β-lactamase inhibitors, and bicyclic carbohydrate-β-lactam monomers prepared by the alkene-isocyanate method.

Metrics & MoreArticle Recommendations CONSPECTUS:Carbohydrates are ubiquitous in nature, playing vital roles in all organisms ranging from metabolism to intercellular signaling. Polysaccharides, repeating units of small molecule carbohydrates, are hydrophilic, densely functionalized, stereoregular, and rigid macromolecules, and these characteristics are simultaneously advantageous in biomedical applications while presenting major hurdles for synthetic methodology and development of structure property relationships. While naturally obtained polysaccharides are widely utilized in the biochemical and medical literature, their poor physicochemical definition and the potential for contaminated samples hinders the clinical translation of this work. To address the need for new methods to synthesize carbohydrate polymers, we reported a novel class of biomaterials (Poly-Amido-Saccharides; PAS) in 2012. PASs share many properties with natural polysaccharides, such as hydrophilicity, dense hydroxyl functionality, stereoregularity, and a rigid backbone. PASs are connected by an α-1,2-amide linkage, instead of an ether linkage, that confers resistance to enzymatic and hydrolytic degradation and leads to a unique helical conformation. Importantly, our synthetic methodology affords control over molecular weight distribution resulting in pure, welldefined polymers. This Account provides an overview of the development of PAS, from the factors that initially motivated our research to current efforts to translate functional PAS to biomedical applications. We detail the synthesis of glucose-and galactosebased PAS and their biophysical properties including conformation analysis, lectin interactions, cell internalization, and water solubility. Additionally, we describe postpolymerization modification strategies to afford PASs that act as protein stabilizers. We also highlight our recent efforts toward a mechanistic understanding of monomer synthesis via [2 + 2] cycloaddition reactions in order to develop novel monomers with different stereochemistry and amine or alkyl functionality, thereby accessing functional carbohydrate polymers. Throughout our work, we apply computational and theoretical analysis to explain how properties at the monomer level (e.g., stereochemistry, functionality) significantly impact polymer properties, helical conformation, and bioactivities. Collectively, the results from the theoretical, synthetic, and applied aspects of this research advance us toward our goal of utilizing PASs in key biomedical applications as alternatives to natural polysaccharides. The importance of carbohydrates in nature and the versatility of their functions continue to inspire our investigation of new monomers, polymers, and copolymers, leveraging the advantageous properties of PAS to develop potential therapies.