Catherine M. Meis

Bio: Catherine M. Meis is an academic researcher from Stanford University. The author has contributed to research in topics: Insulin & Self-healing hydrogels. The author has an hindex of 7, co-authored 12 publications receiving 132 citations. Previous affiliations of Catherine M. Meis include Iowa State University.

A co-formulation of supramolecularly stabilized insulin and pramlintide enhances mealtime glucagon suppression in diabetic pigs.

Abstract: Treatment of patients with diabetes with insulin and pramlintide (an amylin analogue) is more effective than treatment with insulin only. However, because mixtures of insulin and pramlintide are unstable and have to be injected separately, amylin analogues are only used by 1.5% of people with diabetes needing rapid-acting insulin. Here, we show that the supramolecular modification of insulin and pramlintide with cucurbit[7]uril-conjugated polyethylene glycol improves the pharmacokinetics of the dual-hormone therapy and enhances postprandial glucagon suppression in diabetic pigs. The co-formulation is stable for over 100 h at 37 °C under continuous agitation, whereas commercial formulations of insulin analogues aggregate after 10 h under similar conditions. In diabetic rats, the administration of the stabilized co-formulation increased the area-of-overlap ratio of the pharmacokinetic curves of pramlintide and insulin from 0.4 ± 0.2 to 0.7 ± 0.1 (mean ± s.d.) for the separate administration of the hormones. The co-administration of supramolecularly stabilized insulin and pramlintide better mimics the endogenous kinetics of co-secreted insulin and amylin, and holds promise as a dual-hormone replacement therapy. The co-administration of insulin and pramlintide stabilized with cucurbit[7]uril-conjugated polyethylene glycol in diabetic pigs improves the mealtime suppression of glucagon over the separate administration of the two hormones.

An ultrafast insulin formulation enabled by high-throughput screening of engineered polymeric excipients.

Abstract: Insulin has been used to treat diabetes for almost 100 years; yet, current rapid-acting insulin formulations do not have sufficiently fast pharmacokinetics to maintain tight glycemic control at mealtimes. Dissociation of the insulin hexamer, the primary association state of insulin in rapid-acting formulations, is the rate-limiting step that leads to delayed onset and extended duration of action. A formulation of insulin monomers would more closely mimic endogenous postprandial insulin secretion, but monomeric insulin is unstable in solution using present formulation strategies and rapidly aggregates into amyloid fibrils. Here, we implement high-throughput-controlled radical polymerization techniques to generate a large library of acrylamide carrier/dopant copolymer (AC/DC) excipients designed to reduce insulin aggregation. Our top-performing AC/DC excipient candidate enabled the development of an ultrafast-absorbing insulin lispro (UFAL) formulation, which remains stable under stressed aging conditions for 25 ± 1 hours compared to 5 ± 2 hours for commercial fast-acting insulin lispro formulations (Humalog). In a porcine model of insulin-deficient diabetes, UFAL exhibited peak action at 9 ± 4 min, whereas commercial Humalog exhibited peak action at 25 ± 10 min. These ultrafast kinetics make UFAL a promising candidate for improving glucose control and reducing burden for patients with diabetes.

Stable Monomeric Insulin Formulations Enabled by Supramolecular PEGylation of Insulin Analogues.

Abstract: Current "fast-acting" insulin analogues contain amino acid modifications meant to inhibit dimer formation and shift the equilibrium of association states toward the monomeric state. However, the insulin monomer is highly unstable and current formulation techniques require insulin to primarily exist as hexamers to prevent aggregation into inactive and immunogenic amyloids. Insulin formulation excipients have thus been traditionally selected to promote insulin association into the hexameric form to enhance formulation stability. This study exploits a novel excipient for the supramolecular PEGylation of insulin analogues, including aspart and lispro, to enhance the stability and maximize the prevalence of insulin monomers in formulation. Using multiple techniques, it is demonstrated that judicious choice of formulation excipients (tonicity agents and parenteral preservatives) enables insulin analogue formulations with 70-80% monomer and supramolecular PEGylation imbued stability under stressed aging for over 100 h without altering the insulin association state. Comparatively, commercial "fast-acting" formulations contain less than 1% monomer and remain stable for only 10 h under the same stressed aging conditions. This simple and effective formulation approach shows promise for next-generation ultrafast insulin formulations with a short duration of action that can reduce the risk of post-prandial hypoglycemia in the treatment of diabetes.

Evidence of counterion migration in ionic polymer actuators via investigation of electromechanical performance

Abstract: Functional ionomeric polymer membranes are the backbone of a wide range of ionic devices; the mobility of ions through the ionomeric membrane is the principle of operation of these devices. Drift and diffusion of ions through ionomeric membranes strongly depend on the ionic properties of host membrane, as well as the physical and chemical properties of the ions. It is well-established that cations and anions provided via a dopant (e.g. electrolyte or ionic liquid) are mobilized under stimulation. However, in this study, we report that in addition to ions sourced by the dopant, counterions of the ionomeric membrane are also mobilized when stimulated. In particular, we have investigated the electromechanical response of ionic electroactive polymer actuators consisting of Nafion ionomeric membranes with different counterions and have demonstrated that those with cation counterions of larger Van der Waals volume exhibit stronger actuation due to motion of the larger cation counterions compared to actuators consisting of Nafion with counterion of smaller Van der Waals volumes.

Self-Assembled, Dilution-Responsive Hydrogels for Enhanced Thermal Stability of Insulin Biopharmaceuticals.

Abstract: Biotherapeutics currently dominate the landscape of new drugs because of their exceptional potency and selectivity. Yet, the intricate molecular structures that give rise to these beneficial qualities also render them unstable in formulation. Hydrogels have shown potential as stabilizing excipients for biotherapeutic drugs, providing protection against harsh thermal conditions experienced during distribution and storage. In this work, we report the utilization of a cellulose-based supramolecular hydrogel formed from polymer-nanoparticle (PNP) interactions to encapsulate and stabilize insulin, an important biotherapeutic used widely to treat diabetes. Encapsulation of insulin in these hydrogels prevents insulin aggregation and maintains insulin bioactivity through stressed aging conditions of elevated temperature and continuous agitation for over 28 days. Further, insulin can be easily recovered by dilution of these hydrogels for administration at the point of care. This supramolecular hydrogel system shows promise as a stabilizing excipient to reduce the cold chain dependence of insulin and other biotherapeutics.

Translational Applications of Hydrogels.

Abstract: Advances in hydrogel technology have unlocked unique and valuable capabilities that are being applied to a diverse set of translational applications. Hydrogels perform functions relevant to a range of biomedical purposes-they can deliver drugs or cells, regenerate hard and soft tissues, adhere to wet tissues, prevent bleeding, provide contrast during imaging, protect tissues or organs during radiotherapy, and improve the biocompatibility of medical implants. These capabilities make hydrogels useful for many distinct and pressing diseases and medical conditions and even for less conventional areas such as environmental engineering. In this review, we cover the major capabilities of hydrogels, with a focus on the novel benefits of injectable hydrogels, and how they relate to translational applications in medicine and the environment. We pay close attention to how the development of contemporary hydrogels requires extensive interdisciplinary collaboration to accomplish highly specific and complex biological tasks that range from cancer immunotherapy to tissue engineering to vaccination. We complement our discussion of preclinical and clinical development of hydrogels with mechanical design considerations needed for scaling injectable hydrogel technologies for clinical application. We anticipate that readers will gain a more complete picture of the expansive possibilities for hydrogels to make practical and impactful differences across numerous fields and biomedical applications.

One-Step Synthesis of Cross-Linked Ionic Polymer Thin Films in Vapor Phase and Its Application to an Oil/Water Separation Membrane.

Abstract: In spite of the huge research interest, ionic polymers could not have been synthesized in the vapor phase because the monomers of ionic polymers contain nonvolatile ionic salts, preventing the monomers from vaporization. Here, we suggest a new, one-step synthetic pathway to form a series of cross-linked ionic polymers (CIPs) in the vapor phase via initiated chemical vapor deposition (iCVD). 2-(Dimethylamino)ethyl methacrylate (DMAEMA) and 4-vinylbenzyl chloride (VBC) monomers are introduced into the iCVD reactor in the vapor phase to form a copolymer film. Simultaneously in the course of the deposition process, the tertiary amine in DMAEMA and benzylic chloride in VBC undergo a Menshutkin nucleophilic substitution reaction to form an ionic ammonium–chloride complex, forming a highly cross-linked ionic copolymer film of p(DMAEMA-co-VBC). To the best of our knowledge, this is the first report on the synthesis of CIP films in the vapor phase. The newly developed CIP thin film is further applied to the surfac...

Graphene as a flexible electrode: review of fabrication approaches

Abstract: In recent years, the technological advancement of supercapacitors has been increasing exponentially due to the high demand in electronic consumer products. As so, researchers have found a way to meet that demand by fabricating graphene. As developments are made toward the future, two big advancements to be made are large-scale fabrication of graphene and fabricating graphene as a flexible electrode. This would allow for use in larger products and for manipulation of the unique properties of graphene to accommodate superior design alternatives. While large scale production is still mentioned, this review is specifically focusing on different methods used to fabricate graphene as a flexible electrode. Various fabrication methods, such as Hummers' method, chemical vapor deposition, epitaxial growth, and exfoliation of graphite oxide, used to fabricate graphene in such a way that allows flexibility and utilization of graphene's mechanical and electrical properties are discussed. Additionally, a section on environmentally friendly fabrication approaches is presented and discussed.