No abstract

The controlled delivery of therapeutics in a manner responsive to physiological indicators has promise in realizing new therapeutic approaches to combat disease. This approach is especially relevant in the context of diabetes. Natural fluctuations in blood glucose seen in the healthy state, complete with peaks and troughs, are poorly regulated as a result of detrimental production or ineffective signaling of the insulin hormone. While several manifestations of diabetes are treated with regularly administered exogenous insulin, the present standard of care results in suboptimal glycemic management that poorly recreates natural hormone control, leading to long‐term instability and a significantly increased risk for secondary health complications. New synthetic technologies that make insulin available only when needed, and at the exact dose required, have been explored under the broad vision of realizing a “fully synthetic pancreas.” Yet, many challenges remain to realizing a technology that is appropriately responsive, safe, and well integrated into a manageable routine. Herein, many of the approaches explored thus far to sense physiological blood glucose and elicit response through the release of therapeutic insulin are summarized. The approaches point to a new, autonomous approach to managing diabetes with biomimetic therapy.

A novel four-disulfide insulin analog was designed with retained bioactivity and increased fibrillation stability.

Natural proteins traverse complex free energy landscapes to assemble into hierarchically organized structures, often through stimuli-directed kinetic pathways in response to relevant biological cues. Bioinspired strategies have sought to emulate the complexity, dynamicity, and modularity exhibited in these natural processes with synthetic analogues. However, these efforts are limited by many factors that complicate the rational design and predictable assembly of synthetic constructs, especially in aqueous environments. Herein, a model discotic amphiphile gelator is described that undergoes pathway-dependent structural maturation when exposed to varying application rates of a pH stimulus, investigated by electron microscopy, spectroscopy, and X-ray scattering techniques. Under the direction of a slowly changing pH stimulus, complex hierarchical assemblies result, characterized by mesoscale elongated “superstructure” bundles embedded in a percolated mesh of narrow nanofibers. In contrast, the assembly under a rapidly applied pH stimulus is characterized by homogeneous structures that are reminiscent of the superstructures arising from the more deliberate path, except with significantly reduced scale and concomitantly large increases in bulk rheological properties. This synthetic system bears resemblance to the pathway complexity and hierarchical ordering observed for native structures, such as collagen, and points to fundamental design principles that might be applied toward enhanced control of the properties of supramolecular self-assembly across length scales.

The self-assembly of oppositely charged oligopeptide mixtures is evaluated, observing self-sorting into distinct, yet still interacting, nanostructures.

This study compares next-day forecasts of storm motion from convection-allowing models with 1- and 4-km grid spacing. A tracking algorithm is used to determine the motion of discrete storms in both the model forecasts and an analysis of radar observations. The distributions of both the raw storm motions and the deviations of these motions from the environmental flow are examined to determine the overall biases of the 1- and 4-km forecasts and how they compare to the observed storm motions. The mean storm speeds for the 1-km forecasts are significantly closer to the observed mean than those for the 4-km forecasts when viewed relative to the environmental flow/shear, but mostly for the shorter-lived storms. For storm directions, the 1-km forecast storms move similarly to the 4-km forecast storms on average. However, for the raw storm motions and those relative to the 0–6-km shear, results suggest that the 1-km forecasts may alleviate some of a clockwise (rightward) bias of the 4-km forecasts, particularly for those that do not deviate strongly from the 0–6-km shear vector. This improvement in a clockwise bias also is seen for the longer-lived storms, but is not seen when viewing the storm motions relative to the 850–300-hPa mean wind or Bunkers motion vector. These results suggest that a reduction from 4- to 1-km grid spacing can potentially improve forecasts of storm motion, but further analysis of closer storm analogs are needed to confirm these results and to explore specific hypotheses for their differences.

Stimuli-responsive hydrogels are an area of active discovery for approaches to deliver therapeutics in response to disease-specific indicators. Glucose-responsive delivery of insulin is of particular interest in better managing diabetes. Accordingly, hydrogels have been explored as platforms that enable both a rate and dose of insulin release aligning with the real-time physiological disease state; materials often include glucose sensing by dynamic-covalent cross-linking between phenylboronic acids (PBAs) and diols, with competition from ambient glucose reducing cross-link density of the material and accelerating release of encapsulated insulin. Yet, these materials historically have challenges with insulin leakage, offer limited glucose-responsive release of the insulin payload, and require unreasonably high injection pressures for syringe administration. Here, a thermogel platform prepared from temperature-induced micelles formed into a network by PBA–Diol cross-linking is optimized using a formulation-centered approach to maximize glucose-responsive insulin delivery. Importantly, the dual-responsive nature of this platform enables a low-viscosity sol at ambient temperature for facile injection, solidifying into a stable viscoelastic hydrogel network once in the body. The final optimized formulation affords acceleration in insulin release in response to glucose and enables single dose blood glucose control in diabetic rodents when subjected to multiple glucose challenges.

Insulin has been a life-saving drug for millions of people with diabetes. However, several challenges exist which limit therapeutic benefits and reduce patient convenience. One key challenge is the fibrillation propensity, which necessitates refrigeration for storage. To address this limitation, we chemically synthesized and evaluated a methylene thioacetal human insulin analogue (SCS-Ins). The synthesized SCS-Ins showed enhanced serum stability and aggregation resistance while retaining bioactivity compared with native insulin.