Probing the luminal microenvironment of reconstituted epithelial microtissues.

Polymeric microparticles can serve as carriers or sensors to instruct or characterize tissue biology. However, incorporating microparticles into tissues for in vitro assays remains a challenge. We exploit three-dimensional cell-patterning technologies and directed epithelial self-organization to deliver microparticles to the lumen of reconstituted human intestinal microtissues. We also develop a novel pH-sensitive microsensor that can measure the luminal pH of reconstituted epithelial microtissues. These studies offer a novel approach for investigating luminal microenvironments and drug-delivery across epithelial barriers

Development and Implementation of Tennessee Nonresidential Buprenorphine Treatment Guidelines

Objective: To describe the recent legislation in Tennessee and subsequent development and implementation of state-wide buprenorphine treatment guidelines. Practice Innovation: In 2016, Tennessee began licensing office-based opioid treatment (OBOT) clinics. Due to initial licensing criteria, not all providers were required to be licensed with the Department of Mental Health and Substance Abuse Services (TDMHSAS). The gap in licensing made it difficult to ensure an appropriate standard of care was being met by all addiction treatment providers. Therefore, the state developed legislation that allowed for the creation of best practice guidelines to encompass all providers of buprenorphine in the state of Tennessee, not just the licensed OBOT clinics. The guidelines define what the standard of care should entail while treating this vulnerable addiction population. Results: Tennessee legislation granted the formation of a committee to create the Tennessee Nonresidential Buprenorphine Treatment Guidelines. The committee was comprised of physicians, pharmacists, lawyers, law enforcement, and state officials. The finalized guidelines were published and effective January 1, 2018, and adopted as policy by the boards of medical examiners, osteopathic examination, and pharmacy shortly thereafter. The guidelines are now enforceable by the boards and give them the ability to discipline physicians who practice outside the standard of care. Conclusion: Tennessee legislation provides a model for other states to take action in combating this opioid crisis by not only increasing access to addiction treatment, but increasing access to quality care.   Article Type: Commentary   &nbsp

The Thin Film Polycaprolactone Device: A platform technology for biodegradable and tunable long acting drug delivery implants.

As healthcare costs rise, demand for reduced healthcare visits and improved efficacy, safety, and user acceptability grow. Among solutions, researchers seek to develop and commercialize long-acting controlled release drug delivery systems. The global revenue for these systems was estimated at $181.9 billion in 2013 with projected revenue growth to$212.8 billion by 2018. [1] Demand for such systems is broad and encompasses applications in the delivery of small molecule pharmaceuticals as well as biologics. Advancements in this area rely on the development of reproducible and controllable fabrication technologies and the availability of materials that are suitable for system duration and design. Such drug delivery systems benefit from an understanding of the underlying mechanisms of controlled release and from easily tunable release kinetics to accommodate pre-clinical through clinical development. Here we introduce the Thin-Film Polycaprolactone Device (TFPD), a tunable and biodegradable long-acting implant platform technology. The platform is based on the use of porous and nonporous thin-film (< 50 µm) Polycaprolactone (PCL), a bioresorbable and biocompatible polymer, as a membrane for controlled or sustained release of an API from a reservoir. The platform is highly versatile, allowing for delivery of small and large molecules alike, in sizes relevant to both ocular and subcutaneous implants. A deep understanding of the fundamental mechanisms related to both membrane and device design leads to the use of empirical models to easily design and tune devices for any given API and indication. As this delivery platform is so diverse in its potential applications, tunability and design models are key platform features and the focus of this dissertation. The following sections lay out practical approaches to tuning PCL degradation, the fabrication and characterization of various styles of PCL thin-film membranes, the design and tunability of membranes to control release and of reservoir devices according to target product profiles for specific indications. These concepts are then applied to the early development of three long-acting implant systems: an ocular implant for protein therapeutics, a subcutaneous implant for antiretroviral HIV pre-exposure prophylaxis, and a miniaturized subcutaneous contraceptive implant

A Tunable, Biodegradable, Thin-Film Polymer Device as a Long-Acting Implant Delivering Tenofovir Alafenamide Fumarate for HIV Pre-exposure Prophylaxis

PurposeThe effectiveness of Tenofovir based HIV pre-exposure prophylaxis (PrEP) is proven, but hinges on correct and consistent use. User compliance and therapeutic effectiveness can be improved by long acting drug delivery systems. Here we describe a thin-film polymer device (TFPD) as a biodegradable subcutaneous implant for PrEP.MethodsA thin-film polycaprolactone (PCL) membrane controls drug release from a reservoir. To achieve membrane controlled release, TAF requires a formulation excipient such as PEG300 to increase the dissolution rate and reservoir solubility. Short-term In vitro release studies are used to develop an empirical design model, which is applied to the production of in vitro prototype devices demonstrating up to 90-days of linear release and TAF chemical stability.ResultsThe size and shape of the TFPD are tunable, achieving release rates ranging from 0.5 to 4.4 mg/day in devices no larger than a contraceptive implant. Based on published data for oral TAF, subcutaneous constant-rate release for HIV PrEP is estimated at <2.8 mg/day. Prototype devices demonstrated linear release at 1.2 mg/day for up to 90 days and at 2.2 mg/day for up to 60 days.ConclusionsWe present a biodegradable TFPD for subcutaneous delivery of TAF for HIV PrEP. The size, shape and release rate of the device are tunable over a >8-fold range

Fabrication of Micropatterned Polymeric Nanowire Arrays for High-Resolution Reagent Localization and Topographical Cellular Control

Herein, we present a novel approach for the fabrication of micropatterned polymeric nanowire arrays that addresses the current need for scalable and customizable polymer nanofabrication. We describe two variations of this approach for the patterning of nanowire arrays on either flat polymeric films or discrete polymeric microstructures and go on to investigate biological applications for the resulting polymeric features. We demonstrate that the micropatterned arrays of densely packed nanowires facilitate rapid, low-waste drug and reagent localization with micron-scale resolution as a result of their high wettability. We also show that micropatterned nanowire arrays provide hierarchical cellular control by simultaneously directing cell shape on the micron scale and influencing focal adhesion formation on the nanoscale. This nanofabrication approach has potential applications in scaffold-based cellular control, biological assay miniaturization, and biomedical microdevice technology

Device design methodology and formulation of a protein therapeutic for sustained release intraocular delivery.

Despite years of effort, sustained delivery of protein therapeutics remains an unmet need due to three primary challenges - dose, duration, and stability. The work presented here provides a design methodology for polycaprolactone reservoir-based thin film devices suitable for long-acting protein delivery to the back of the eye. First, the challenge of formulating highly concentrated protein in a device reservoir was addressed by improving stability with solubility-reducing excipients. Next, predictive correlations between design parameters and device performance were developed to provide a methodology to achieve a target product profile. Prototype devices were designed using this methodology to achieve desired device size, release rate, therapeutic payload, and protein stability, assessed by in vitro studies. Finally, prototype tolerability was established in a non-human primate model. The design methodology presented here is widely applicable to reservoir-based sustained delivery devices for proteins and provides a general device design framework