Interval delivery of 5HT2A agonists using multilayered polymer films.

There is an urgent unmet medical need to develop therapeutic options for the ~50% of depression patients suffering from treatment-resistant depression, which is difficult to treat with existing psycho- and pharmaco-therapeutic options. Classical psychedelics, such as the 5HT2A agonists, have re-emerged as a treatment paradigm for depression. Recent clinical trials highlight the potential effectiveness of 5HT2A agonists to improve mood and psychotherapeutic growth in treatment-resistant depression patients, even in those who have failed a median of four previous medications in their lifetime. Moreover, microdosing could be a promising way to achieve long-term alleviation of depression symptoms without a hallucinogenic experience. However, there are a gamut of practical barriers that stymie further investigation of microdosing 5HT2A agonists, including: low compliance with the complicated dosing regimen, high risk of diversion of controlled substances, and difficulty and cost administering the long-term treatment regimens in controlled settings. Here, we developed a drug delivery system composed of multilayered cellulose acetate phthalate (CAP)/Pluronic F-127 (P) films for the encapsulation and interval delivery of 5HT2A agonists from a fully biodegradable and biocompatible implant. CAPP film composition, thickness, and layering strategies were optimized, and we demonstrated three distinct pulses from the multilayered CAPP films in vitro. Additionally, the pharmacokinetics and biodistribution of the 5HT2A agonist 2,5-Dimethoxy-4-iodoamphetamine (DOI) were quantified following the subcutaneous implantation of DOI-loaded single and multilayered CAPP films. Our results demonstrate, for the first time, the interval delivery of psychedelics from an implantable drug delivery system and open the door to future studies into the therapeutic potential of psychedelic delivery.

A simple atomic force microscope-based method for quantifying wear of sliding probes.

Sliding wear is particularly problematic for micro- and nano-scale devices and applications, and is often studied at the small scale to develop practical and fundamental insights. While many methods exist to measure and quantify the wear of a sliding atomic force microscope (AFM) probe, many of these rely on specialized equipment and/or assumptions from continuum mechanics. Here we present a methodology that enables simple, purely AFM-based measurement of wear, in cases where the AFM probe wears to a flat plateau. The rate of volume removal is recast into a form that depends primarily on the time-varying contact area. This contact area is determined using images of sharp spikes, which are analyzed with a simple thresholding technique, rather than requiring sophisticated computer algorithms or continuum mechanics assumptions. This approach enables the rapid determination of volume lost, rate of material removal, normal stress, and interfacial shear stress at various points throughout the wear experiment. The method is demonstrated using silicon probes sliding on an aluminum oxide substrate. As a validation for the present method, direct imaging in the transmission electron microscope is used to verify the method's parameters and results. Overall, it is envisioned that this purely AFM-based methodology will enable higher-throughput wear experiments and direct hypothesis-based investigation into the science of wear and its dependence on different variables.