Caitlin L. Maikawa

Bio: Caitlin L. Maikawa is an academic researcher from Stanford University. The author has contributed to research in topics: Insulin & Biology. The author has an hindex of 10, co-authored 31 publications receiving 308 citations. Previous affiliations of Caitlin L. Maikawa include University of Massachusetts Amherst & University of Toronto.

Injectable Hydrogels for Sustained Codelivery of Subunit Vaccines Enhance Humoral Immunity.

Abstract: Vaccines aim to elicit a robust, yet targeted, immune response. Failure of a vaccine to elicit such a response arises in part from inappropriate temporal control over antigen and adjuvant presentation to the immune system. In this work, we sought to exploit the immune system's natural response to extended pathogen exposure during infection by designing an easily administered slow-delivery vaccine platform. We utilized an injectable and self-healing polymer-nanoparticle (PNP) hydrogel platform to prolong the codelivery of vaccine components to the immune system. We demonstrated that these hydrogels exhibit unique delivery characteristics, whereby physicochemically distinct compounds (such as antigen and adjuvant) could be codelivered over the course of weeks. When administered in mice, hydrogel-based sustained vaccine exposure enhanced the magnitude, duration, and quality of the humoral immune response compared to standard PBS bolus administration of the same model vaccine. We report that the creation of a local inflammatory niche within the hydrogel, coupled with sustained exposure of vaccine cargo, enhanced the magnitude and duration of germinal center responses in the lymph nodes. This strengthened germinal center response promoted greater antibody affinity maturation, resulting in a more than 1000-fold increase in antigen-specific antibody affinity in comparison to bolus immunization. In summary, this work introduces a simple and effective vaccine delivery platform that increases the potency and durability of subunit vaccines.

Particulate oxidative burden as a predictor of exhaled nitric oxide in children with asthma

Abstract: Background:Epidemiological studies have provided strong evidence that fine particulate matter (PM2.5; aerodynamic diameter ≤ 2.5 μm) can exacerbate asthmatic symptoms in children. Pro-oxidant compo...

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.

Emerging concepts in the science of vaccine adjuvants.

Abstract: Adjuvants are vaccine components that enhance the magnitude, breadth and durability of the immune response. Following its introduction in the 1920s, alum remained the only adjuvant licensed for human use for the next 70 years. Since the 1990s, a further five adjuvants have been included in licensed vaccines, but the molecular mechanisms by which these adjuvants work remain only partially understood. However, a revolution in our understanding of the activation of the innate immune system through pattern recognition receptors (PRRs) is improving the mechanistic understanding of adjuvants, and recent conceptual advances highlight the notion that tissue damage, different forms of cell death, and metabolic and nutrient sensors can all modulate the innate immune system to activate adaptive immunity. Furthermore, recent advances in the use of systems biology to probe the molecular networks driving immune response to vaccines ('systems vaccinology') are revealing mechanistic insights and providing a new paradigm for the vaccine discovery and development process. Here, we review the 'known knowns' and 'known unknowns' of adjuvants, discuss these emerging concepts and highlight how our expanding knowledge about innate immunity and systems vaccinology are revitalizing the science and development of novel adjuvants for use in vaccines against COVID-19 and future pandemics.

Review of Acellular Assays of Ambient Particulate Matter Oxidative Potential: Methods and Relationships with Composition, Sources, and Health Effects

Abstract: Oxidative stress is a potential mechanism of action for particulate matter (PM) toxicity and can occur when the body's antioxidant capacity cannot counteract or detoxify harmful effects of reactive oxygen species (ROS) due to an excess presence of ROS. ROS are introduced to the body via inhalation of PM with these species present on and/or within the particles (particle-bound ROS) and/or through catalytic generation of ROS in vivo after inhaling redox-active PM species (oxidative potential, OP). The recent development of acellular OP measurement techniques has led to a surge in research across the globe. In this review, particle-bound ROS techniques are discussed briefly while OP measurements are the focus due to an increasing number of epidemiologic studies using OP measurements showing associations with adverse health effects in some studies. The most common OP measurement techniques, including the dithiothreitol assay, glutathione assay, and ascorbic acid assay, are discussed along with evidence for utility of OP measurements in epidemiologic studies and PM characteristics that drive different responses between assay types (such as species composition, emission source, and photochemistry). Overall, most OP assays respond to metals like copper than can be found in emission sources like vehicles. Some OP assays respond to organics, especially photochemically aged organics, from sources like biomass burning. Select OP measurements have significant associations with certain cardiorespiratory end points, such as asthma, congestive heart disease, and lung cancer. In fact, multiple studies have found that exposure to OP measured using the dithiothreitol and glutathione assays drives higher risk ratios for certain cardiorespiratory outcomes than PM mass, suggesting OP measurements may be integrating the health-relevant fraction of PM and will be useful tools for future health analyses. The compositional impacts, including species and emission sources, on OP could have serious implications for health-relevant PM exposure. Though more work is needed, OP assays show promise for health studies as they integrate the impacts of PM species and properties on catalytic redox reactions into one measurement, and current work highlights the importance of metals, organic carbon, vehicles, and biomass burning emissions to PM exposures that could impact health.

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.