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Implantable drug depots have the capacity to locally meet therapeutic requirements by maximizing local drug efficacy and minimizing potential systemic side effects. Tubular organs including the gastrointestinal tract, respiratory tract and vasculature all manifest with endoluminal disease. The anatomic distribution of localized drug delivery for these organs using existing therapeutic modalities is limited. Application of local depots in a circumferential and extended longitudinal fashion could transform our capacity to offer effective treatment across a range of conditions. Here we report the development and application of a kirigami-based stent platform to achieve this. The stents comprise a stretchable snake-skin-inspired kirigami shell integrated with a fluidically driven linear soft actuator. They have the capacity to deposit drug depots circumferentially and longitudinally in the tubular mucosa of the gastrointestinal tract across millimetre to multi-centimetre length scales, as well as in the vasculature and large airways. We characterize the mechanics of kirigami stents for injection, and their capacity to engage tissue in a controlled manner and deposit degradable microparticles loaded with therapeutics by evaluating these systems ex vivo and in vivo in swine. We anticipate such systems could be applied for a range of endoluminal diseases by simplifying dosing regimens while maximizing drug on-target effects through the sustained release of therapeutics and minimizing systemic side effects. A kirigami-inspired stent-based system has been developed for extended local drug delivery to the gastrointestinal and respiratory tracts as well as the vascular system.

Conventionally, the intestinal permeability of drugs is evaluated using cell monolayer models that lack morphological, physiological and architectural features, as well as realistic neonatal Fc receptor (FcRn) expression. In addition, it is time-consuming, expensive and excessive to use a large number of mice for large-scale screening of FcRn-targeted candidates. For preclinical validation, it is critical to use suitable models that mimic the human intestine; the porcine ex vivo model is widely used for intestinal permeability studies, due to its physiological and anatomical similarities to humans. This study intended to analyze the potential to measure the intestinal permeability of FcRn-targeted substances using a porcine ex vivo platform, which is able to analyze 96 samples at the same time. In addition, the platform allows the screening of FcRn-targeting substances for transmucosal delivery, taking into consideration (cross-species) receptor-ligand binding kinetics. After analyzing the morphology of the porcine tissue, the FcRn expression across the gastrointestinal tract was verified. By studying the stomach, duodenum and jejunum, it was demonstrated that FcRn expression is maintained for up to 7 days. When evaluating the duodenum permeability of free engineered human albumin variants, it was shown that the variant with the mutation K573P (KP) is more efficiently transported. Given this, the porcine ex vivo platform was revealed to be a potential model for the screening of FcRn-targeted oral drug formulations.

Infectious diseases are a major driver of morbidity and mortality globally. Treatment of malaria, tuberculosis and human immunodeficiency virus infection are particularly challenging, as indicated by the ongoing transmission and high mortality associated with these diseases. The formulation of new and existing drugs in nano-sized carriers promises to overcome several challenges associated with the treatment of these diseases, including low on-target bioavailability, sub-therapeutic drug accumulation in microbial sanctuaries and reservoirs, and low patient adherence due to drug-related toxicities and extended therapeutic regimens. Further, nanocarriers can be used for formulating vaccines, which represent a major weapon in our fight against infectious diseases. Here we review the current burden of infectious diseases with a focus on major drivers of morbidity and mortality. We then highlight how nanotechnology could aid in improving existing treatment modalities. We summarize our progress so far and outline potential future directions to maximize the impact of nanotechnology on the global population. This Review outlines the potential applications of nanotechnology-based treatments for infectious diseases, with a specific focus on the progress and challenges in developing nanomedicines against HIV, tuberculosis and malaria.

Oral vaccination enables pain-free and self-administrable vaccine delivery for rapid mass vaccination during pandemic outbreaks. Furthermore, it elicits systemic and mucosal immune responses. This protects against infection at mucosal surfaces, which may further enhance protection and minimize the spread of disease. The gastrointestinal (GI) tract presents a number of prospective mucosal inductive sites for vaccine targeting, including the oral cavity, stomach, and small intestine. However, currently available oral vaccines are effectively limited to live-attenuated and inactivated vaccines against enteric diseases. The GI tract poses a number of challenges,including degradative processes that digest biologics and mucosal barriers that limit their absorption. This review summarizes the approaches currently under development and future opportunities for oral vaccine delivery to established (intestinal) and relatively new (oral cavity, stomach) mucosal targets. Special consideration is given to recent advances in oral biologic delivery that offer promise as future platforms for the administration of oral vaccines.

Continuous glucose monitors (CGMs) and closed-loop drug delivery systems have revolutionized patient care in diabetes and anesthesia. Here, we review the current state of continuous chemical sensor development, titratable drug delivery systems, and closed-loop therapies to identify clinically meaningful trends that, if realized, can have significant impact on medical practice and patient outcome. In particular, we focus on novel wearable and implantable demonstrations that stand to redefine the patient experience. Finally, we put forth a roadmap towards identifying critical unmet clinical opportunities to motivate future technological development towards applications beyond glucose, to both improve patient care across diverse fields of medicine and realize the full potential of these technologies to improve therapeutic outcome.

ObjectivesTo compare the impact of respirator extended use and reuse strategies with regard to cost and sustainability during the COVID-19 pandemic.DesignCost analysis.SettingUSA.ParticipantsAll healthcare workers within the USA.InterventionsNot applicable.Main outcome measuresA model was developed to estimate usage, costs and waste incurred by several respirator usage strategies over the first 6 months of the pandemic in the USA. This model assumed universal masking of all healthcare workers. Estimates were taken from the literature, government databases and commercially available data from approved vendors.ResultsA new N95 respirator per patient encounter would require 7.41 billion respirators, cost $6.38 billion and generate 84.0 million kg of waste in the USA over 6 months. One respirator per day per healthcare worker would require 3.29 billion respirators, cost $2.83 billion and generate 37.22 million kg of waste. Decontamination by ultraviolet germicidal irradiation would require 1.64 billion respirators, cost $1.41 billion and accumulate 18.61 million kg of waste. H2O2 vapour decontamination would require 1.15 billion respirators, cost $1.65 billion and produce 13.03 million kg of waste. One reusable respirator with daily disposable filters would require 18 million respirators, cost $1.24 billion and generate 15.73 million kg of waste. Pairing a reusable respirator with H2O2 vapour-decontaminated filters would reduce cost to $831 million and generate 1.58 million kg of waste. The use of one surgical mask per healthcare worker per day would require 3.29 billion masks, cost $460 million and generate 27.92 million kg of waste.ConclusionsDecontamination and reusable respirator-based strategies decreased the number of respirators used, costs and waste generated compared with single-use or daily extended-use of disposable respirators. Future development of low-cost,simple technologies to enable respirator and/or filter decontamination is needed to further minimise the economic and environmental costs of masks.

The delivery of therapeutics to the gastrointestinal (GI) mucosa remains primarily a function of diffusion and rapid delivery is a significant goal in drug delivery science. However, delivery is hindered by the molecular barrier properties of the mucosa, as well as environmental factors. We hypothesized that low-frequency ultrasound can overcome these barriers, achieving rapid delivery in an engineered, clinically-relevant system for buccal administration. The hand-held system enabled delivery of macromolecules in short, 60-s treatment times ex vivo. Tolerability of the prototype was demonstrated in awake, (unsedated) dogs. Finally, this technology enhanced the efficacy of the anti-inflammatory agent, budesonide, allowing for prophylactic treatment in a hamster model of oral inflammatory lesions in vivo. The capacity to deliver therapeutics in a targeted and rapid manner in a clinically-relevant form-factor presents an intriguing capability to expand the repertoire of therapeutics that can be applied topically in the mouth and beyond.

Cancer patients undergoing therapeutic radiation routinely develop injury of the adjacent gastrointestinal (GI) tract mucosa due to treatment. To reduce radiation dose to critical GI structures including the rectum and oral mucosa, 3D‐printed GI radioprotective devices composed of high‐Z materials are generated from patient CT scans. In a radiation proctitis rat model, a significant reduction in crypt injury is demonstrated with the device compared to without (p, One of the most common side effects of radiation therapy is injury to the gastrointestinal (GI) tract. To reduce radiation‐induced injury, personalized 3D‐printed radioprotective devices made of high‐Z materials are developed that are shown to reduce radiation injury in two animal models, improve clinically significant dosimetry in at‐risk GI tissue in human cancer patients, and are more cost‐effective compared to standard‐of‐care therapy.

Continuous and minimally-invasive monitoring of inflammation in the gastrointestinal (GI) tract can be achieved via ingestible bioengineered sensors tailored to each disease, such as Crohn’s disease. High-resolution biomolecular sensing could indicate the onset of acute disease episodes and allow for early intervention and better disease management. Our work aims to detect important but labile biomarkers in the GI tract that quickly degrade in the digestive system. For example, bleeding in the upper GI tract cannot be easily detected from stool samples and requires invasive endoscopy or laboratory analysis. Alternatively, ingestible video capsule endoscopes leverage wireless cameras for image-based monitoring of the small intestine, which is traditionally difficult to access via endoscopy [1]. However, neither of these methods can directly measure molecular mediators of disease. In contrast, our approach can detect labile biomarkers in situ via an ingestible capsule consisting of cell-based biosensors and low-power electronics.

Epithelial tissues line the organs of the body, providing an initial protective barrier as well as a surface for nutrient and drug absorption. Here we identified enzymatic components present in the gastrointestinal epithelium that can serve as selective means for tissue-directed polymerization. We focused on the small intestine, given its role in drug and nutrient absorption, and identified catalase as an essential enzyme with the potential to catalyze polymerization and growth of synthetic biomaterial layers. We demonstrated that the polymerization of dopamine by catalase yields strong tissue adhesion. We characterized the mechanism and specificity of the polymerization in segments of the gastrointestinal tracts of pigs and humans ex vivo. Moreover, we demonstrated proof-of-concept for application of these gastrointestinal synthetic epithelial linings (GSELs) for drug delivery, enzymatic immobilization for digestive supplementation, and nutritional modulation through transient barrier formation in pigs. This catalase-based approach to in situ biomaterial generation may have broad indications for gastrointestinal applications.

Alternative means for drug delivery are needed to facilitate drug adherence and administration. Microneedles (MNs) have been previously investigated transdermally for drug delivery. To date, drug loading into MNs has been limited by drug solubility in the polymeric blend. We designed a highly drug-loaded MN patch to deliver macromolecules and applied it to the buccal area, which allows for faster delivery than the skin. We successfully delivered 1-mg payloads of human insulin and human growth hormone to the buccal cavity of swine within 30 s. In addition, we conducted a trial in 100 healthy volunteers to assess potential discomfort associated with MNs when applied in the oral cavity, identifying the hard palate as the preferred application site. We envisage that MN patches applied on buccal surfaces could increase medication adherence and facilitate the painless delivery of biologics and other drugs to many, especially for the pediatric and elderly populations.

PURPOSE: A multitude of different versions of the same medication with different inactive ingredients are currently available. It has not been quantified how this has evolved historically. Furthermore, it is unknown whether healthcare professionals consider the inactive ingredient portion when prescribing medications to patients. METHODS: We used data mining to track the number of available formulations for the same medication over time and correlate the number of available versions in 2019 to the number of manufacturers, the years since first approval, and the number of prescriptions. A focused survey among healthcare professionals was conducted to query their consideration of the inactive ingredient portion of a medication during prescriptions. RESULTS: The number of available versions of a single medication have dramatically increased in the last 40 years. The number of available, different versions of medications are largely determined by the number of manufacturers producing this medication. Healthcare provides commonly do not consider these the inactive ingredient portion when prescribing a medication. CONCLUSIONS: A multitude of available versions of the same medications provides a potentially under-recognized opportunity to prescribe the most suitable formulation to a patient as a step towards personalized medicine and mitigating potential adverse events from inactive ingredients.

Targeting areas of inflammation offers potential therapeutic and diagnostic benefits by maximizing drug and imaging marker on-target effects while minimizing systemic exposure that can be associated with adverse side effects. This strategy is particularly beneficial in the management of inflammatory bowel disease (IBD). Here an inflammation-targeting (IT) approach based on heparin-coated human serum albumin nanoparticles (HEP-HSA NPs) that utilize the increased intestinal permeability and changes in electrostatic interaction at the site of intestinal inflammation is described. Using small-molecule and biologic drugs as a model for drug combination, the HEP-HSA NPs demonstrate the capacity to load both drugs simultaneously; the dual-drug loaded HEP-HSA NPs exhibit a higher anti-inflammatory effect than both of the single-drug loaded NPs in vitro and selectively bind to inflamed intestine after enema administration in vivo in a murine model of colitis. Importantly, analyses of the physicochemical characteristics and targeting capacities of these NPs indicate that HEP coating modulates NP binding to the inflamed intestine, providing a foundation for future IT-NP formulation development.

Light-triggerable hydrogels enable on-demand degradation of gastrointestinal-resident devices, reducing the need for invasive interventions., Triggerable materials capable of being degraded by selective stimuli stand to transform our capacity to precisely control biomedical device activity and performance while reducing the need for invasive interventions. Here, we describe the development of a modular and tunable light-triggerable hydrogel system capable of interfacing with implantable devices. We apply these materials to two applications in the gastrointestinal (GI) tract: a bariatric balloon and an esophageal stent. We demonstrate biocompatibility and on-demand triggering of the material in vitro, ex vivo, and in vivo. Moreover, we characterize performance of the system in a porcine large animal model with an accompanying ingestible LED. Light-triggerable hydrogels have the potential to be applied broadly throughout the GI tract and other anatomic areas. By demonstrating the first use of light-degradable hydrogels in vivo, we provide biomedical engineers and clinicians with a previously unavailable, safe, dynamically deliverable, and precise tool to design dynamically actuated implantable devices.

The gastrointestinal (GI) tract offers the opportunity to detect physiological and pathophysiological signals from the human body. Ingestible electronics can gain close proximity to major organs through the GI tract and therefore can serve as clinical tools for diagnostics and therapy. In this Review, we summarize the physiological and anatomical characteristics of the GI tract, which present both challenges and opportunities for the development of ingestible devices. We describe recent breakthroughs in materials science, electrical engineering and data science that have permitted the exploration of technologies for sensing and therapy via the GI tract. Novel sensing opportunities include electrochemical, electromagnetic, optical and acoustic protocols, which have the capacity to sense luminal or extra-luminal analytes in the GI tract. We review therapeutic interventions, such as anatomical targeting for drug delivery, delivery of macromolecules and electrical signals. Finally, we investigate major challenges associated with ingestible electronics, including safety, communication, powering, steering and tissue interactions. Ingestible electronics are an exciting area of scientific innovation and they may pave the way for a new era in medicine, enabling patients to receive remote, electronically assisted health care. Ingestible electronics can be used as clinical tools for diagnosis and therapy. In this Review, the authors discuss clinical applications of ingestible electronic devices and highlight materials and sensor technologies, drug delivery applications and major challenges and opportunities for clinical translation, such as safety, powering and communication.

INTRODUCTION: The development of oral sustained release dosage forms has been a longstanding goal due to the potential for ease of administration, improved pharmacokinetics, reduced dosing frequency, and improved adherence. The benefits of multi-day single dose drug delivery are evident in the success and patient adoption of injected or implanted dosage forms. However, in the space of oral medications, all current commercially-available gastric resident dosage forms, and most in development, are limited to gastric residence of less than one day. AREAS COVERED: Reviews of systems to extend gastric residence reveals that one-day or more residence has been an unmet challenge. New dosage forms are in development that seek to address many of the key physiological and design challenges of long-term gastric retention beyond 24 hours and up to a week or longer. The present analysis highlights the design, material considerations, and implications of unfolding dosage form systems with ultra-long-term gastric residence. EXPERT OPINION: The development of oral dosage forms providing sustained release of high potency medications over days or weeks could transform care, significantly decrease patient burden in chronic disease management and improve outcomes.

Covalently cross-linked gels are utilized in a broad range of biomedical applications though their synthesis often compromises easy implementation. Cross-linking reactions commonly utilize catalysts or conditions that can damage biologics and sensitive compounds, producing materials that require extensive post processing to achieve acceptable biocompatibility. As an alternative, we report a batch synthesis platform to produce covalently cross-linked materials appropriate for direct biomedical application enabled by green chemistry and commonly available food grade ingredients. Using caffeine, a mild base, to catalyze anhydrous carboxylate ring-opening of diglycidyl-ether functionalized monomers with citric acid as a tri-functional crosslinking agent we introduce a novel poly(ester-ether) gel synthesis platform. We demonstrate that biocompatible Caffeine Catalyzed Gels (CCGs) exhibit dynamic physical, chemical, and mechanical properties, which can be tailored in shape, surface texture, solvent response, cargo release, shear and tensile strength, among other potential attributes. The demonstrated versatility, low cost and facile synthesis of these CCGs renders them appropriate for a broad range of customized engineering applications including drug delivery constructs, tissue engineering scaffolds, and medical devices.

Diabetes mellitus is a chronic disease with an elevated risk of micro- and macrovascular complications, such as fibrosis. To prevent diabetes-associated fibrosis, the symptomatology of diabetes must be controlled, which is commonly done by subcutaneous injection of antidiabetic peptides. To minimize the pain and distress associated with such injections, there is an urgent need for non-invasive oral transmucosal drug delivery strategies. However, orally administered peptide-based drugs are exposed to harsh conditions in the gastrointestinal tract and poorly cross the selective intestinal epithelium. Thus, targeting of drugs to receptors expressed in epithelial cells, such as the neonatal Fc receptor (FcRn), may therefore enhance uptake and transport through mucosal barriers. This review compiles how in-depth studies of FcRn biology and engineering of receptor-binding molecules may pave the way for design of new classes of FcRn-targeted nanosystems. Tailored strategies may open new avenues for oral drug delivery and provide better treatment options for diabetes and, consequently, fibrosis prevention.

Improvements in ingestible electronics with the capacity to sense physiological and pathophysiological states have transformed the standard of care for patients. Yet, despite advances in device development, significant risks associated with solid, non-flexible gastrointestinal transiting systems remain. Here, we report the design and use of an ingestible, flexible piezoelectric device that senses mechanical deformation within the gastric cavity. We demonstrate the capabilities of the sensor in both in vitro and ex vivo simulated gastric models, quantify its key behaviours in the gastrointestinal tract using computational modelling and validate its functionality in awake and ambulating swine. Our proof-of-concept device may lead to the development of ingestible piezoelectric devices that might safely sense mechanical variations and harvest mechanical energy inside the gastrointestinal tract for the diagnosis and treatment of motility disorders, as well as for monitoring ingestion in bariatric applications.

Orally administered devices could enable the systemic uptake of biologic therapeutics by engineering around the physiological barriers present in the gastrointestinal (GI) tract. Such devices aim to shield cargo from degradative enzymes and increase the diffusion rate of medication through the GI mucosa. In order to achieve clinical relevance, these designs must significantly increase systemic drug bioavailability, deliver a clinically relevant dose and remain safe when taken frequently. Such an achievement stands to reduce our dependence on needle injections, potentially increasing patient adherence and reducing needle-associated complications. Here we discuss the physical and chemical constraints imposed by the GI organs and use these to develop a set of boundary conditions on oral device designs for the delivery of macromolecules. We critically examine how device size affects the rate of intestinal obstruction and hinders the loading capacity of poorly soluble protein drugs. We then discuss how current orally administered devices could solve the problem of tissue permeation and conclude that these physical methods stand to provide an efficacious set of alternatives to the classic hypodermic needle. ©2017 Elsevier Ltd, National Institutes of Health (EB-000244)

Poor patient adherence to oral contraceptives is the predominant cause of failure of these therapies, leading to unplanned pregnancies that can negatively affect female health worldwide. To improve patient adherence, we developed an oral contraceptive that is administered once a month. Here, we describe the design and report in vivo characterization of a levonorgestrel-releasing gastric resident dosage form in pigs., Bill & Melinda Gates Foundation (Grant OPP1139927)

Submucosal elevation, the process of instilling material in the submucosal space for separation of the surface mucosa and deeper muscularis layer, is a significant aspect of the endoscopic mucosal resection of large lesions performed to facilitate lesion removal and maximize safety. Submucosal injection, when applied, has historically been performed with normal saline, though this is limited by its rapid dissipation; solutions ideally need to be easily injectable, biocompatible, and provide a long‐lasting submucosal cushion with a desirable height. Here, reported is a new set of materials, endoscopically injectable shear‐thinning hydrogels, meeting these requirements because of their biocompatible components and ability to form a solid hydrogel upon injection. These findings are supported by evaluation in a large animal model and ultimately demonstrate the potential of these shear‐thinning hydrogels to serve as efficient submucosal injection fluids for cushion development. Given these unique characteristics, their broad application in mucosal resection techniques is anticipated.

Nanoformulations are transforming our capacity to effectively deliver and treat a myriad of conditions. However, many nanoformulation approaches still suffer from high production complexity and low drug loading. One potential solution relies on harnessing co-assembly of drugs and small molecular excipients to facilitate nanoparticle formation through solvent exchange without the need for chemical synthesis, generating nanoparticles with up to 95% drug loading. However, there is currently no understanding which of the millions of possible combinations of small molecules can result in the formation of these nanoparticles. Here we report the development of a high-throughput screening platform coupled to machine learning to enable the rapid evaluation of such nanoformulations. Our platform identified 101 novel self-assembling drug nanoparticles from 2.1 million pairings derived from 788 candidate drugs with one of 2686 excipients, spanning treatments for multiple diseases and often harnessing well-known food additives, vitamins, or approved drugs as carrier materials – with potential for accelerated approval and translation. Given their long-term stability and potential for clinical impact, we further characterize novel sorafenib-glycyrrhizin and terbinafine-taurocholic acid nanoparticles ex vivo and in vivo. We anticipate that this platform could accelerate the development of safer and more efficacious nanoformulations with high drug loadings for a wide range of therapeutics.

We hypothesized that ingested warm fluids could act as triggers for biomedical devices. We investigated heat dissipation throughout the upper gastrointestinal (GI) tract by administering warm (55°C) water to pigs and identified two zones in which thermal actuation could be applied: esophageal (actuation through warm water ingestion) and extra-esophageal (protected from ingestion of warm liquids and actuatable by endoscopically administered warm fluids). Inspired by a blooming flower, we developed a capsule-sized esophageal system that deploys using elastomeric elements and then recovers its original shape in response to thermal triggering of shape-memory nitinol springs by ingestion of warm water. Degradable millineedles incorporated into the system could deliver model molecules to the esophagus. For the extra-esophageal compartment, we developed a highly flexible macrostructure (mechanical metamaterial) that deforms into a cylindrical shape to safely pass through the esophagus and deploys into a fenestrated spherical shape in the stomach, capable of residing safely in the gastric cavity for weeks. The macrostructure uses thermoresponsive elements that dissociate when triggered with the endoscopic application of warm (55°C) water, allowing safe passage of the components through the GI tract. Our gastric-resident platform acts as a gram-level long-lasting drug delivery dosage form, releasing small-molecule drugs for 2 weeks. We anticipate that temperature-triggered systems could usher the development of the next generation of stents, drug delivery, and sensing systems housed in the GI tract.

Oral forms of medications contain "inactive" ingredients to enhance their physical properties. Using data analytics, we characterized the abundance and complexity of inactive ingredients in approved medications. A majority of medications contain ingredients that could cause adverse reactions, underscoring the need to maximize the tolerability and safety of medications and their inactive ingredients., National Instutites of Health (Grant EB000244)

Multigram drug depot systems for extended drug release could transform our capacity to effectively treat patients across a myriad of diseases. For example, tuberculosis (TB) requires multimonth courses of daily multigram doses for treatment. To address the challenge of prolonged dosing for regimens requiring multigram drug dosing, we developed a gastric resident system delivered through the nasogastric route that was capable of safely encapsulating and releasing grams of antibiotics over a period of weeks. Initial preclinical safety and drug release were demonstrated in a swine model with a panel of TB antibiotics. We anticipate multiple applications in the field of infectious diseases, as well as for other indications where multigram depots could impart meaningful benefits to patients, helping maximize adherence to their medication.

Biomacromolecules have transformed our capacity to effectively treat diseases; however, their rapid degradation and poor absorption in the gastrointestinal (GI) tract generally limit their administration to parenteral routes. An oral biologic delivery system must aid in both localization and permeation to achieve systemic drug uptake. Inspired by the leopard tortoise’s ability to passively reorient, we developed an ingestible self-orienting millimeter-scale applicator (SOMA) that autonomously positions itself to engage with GI tissue. It then deploys milliposts fabricated from active pharmaceutical ingredients directly through the gastric mucosa while avoiding perforation. We conducted in vivo studies in rats and swine that support the applicator’s safety and, using insulin as a model drug, demonstrated that the SOMA delivers active pharmaceutical ingredient plasma levels comparable to those achieved with subcutaneous millipost administration., National Institutes of Health (U.S.) (grant EB-000244)

The rapid, effective, and safe delivery of a broad range of therapeutics via the gastrointestinal (GI) tract remains a significant challenge in the field of drug delivery. The mucus layer coating t...

Biomolecular monitoring in the gastrointestinal tract could offer rapid, precise disease detection and management but is impeded by access to the remote and complex environment. Here, we present an ingestible micro-bio-electronic device (IMBED) for in situ biomolecular detection based on environmentally resilient biosensor bacteria and miniaturized luminescence readout electronics that wirelessly communicate with an external device. As a proof of concept, we engineer heme-sensitive probiotic biosensors and demonstrate accurate diagnosis of gastrointestinal bleeding in swine. Additionally, we integrate alternative biosensors to demonstrate modularity and extensibility of the detection platform. IMBEDs enable new opportunities for gastrointestinal biomarker discovery and could transform the management and diagnosis of gastrointestinal disease., Office of Naval Research (Grant N00014-13-1-0424), National Institutes of Health (Grant EB-000244)

Devices resident in the stomach -- which are used for a variety of clinical applications including nutritional modulation for bariatrics, ingestible electronics for diagnosis and monitoring, and gastric retentive dosage forms for prolonged drug delivery -- typically incorporate elastic polymers to compress the devices during delivery through the esophagus and other narrow orifices in the digestive system. However, in the event of accidental device fracture or migration, the non-degradable nature of these materials risks intestinal obstruction. Here, we show that an elastic, pH-responsive supramolecular gel remains stable and elastic in the acidic environment of the stomach but can be dissolved in the neutral-pH environment of the small and large intestines. In a large animal model, prototype devices with these materials as the key component demonstrated prolonged gastric retention and safe passage. These enteric elastomers should increase the safety profile for a wide range of gastric retentive devices.

© 2017 Macmillan Publishers Limited. Designing therapeutics is a process with many challenges. Even if the first hurdle-designing a drug that modulates the action of a particular biological target in vitro-is overcome, selective delivery to that target in vivo presents a major barrier. Side-effects can, in many cases, result from the need to use higher doses without targeted delivery. However, the established use of macromolecules to encapsulate or conjugate drugs can provide improved delivery, and stands to enable better therapeutic outcomes. In this Review, we discuss how drug delivery approaches have evolved alongside our ability to prepare increasingly complex macromolecular architectures. We examine how this increased complexity has overcome the challenges of drug delivery and discuss its potential for fulfilling unmet needs in nanomedicine.

Ingestible electronics have revolutionized the standard of care for a variety of health conditions. Extending the capacity and safety of these devices, and reducing the costs of powering them, could enable broad deployment of prolonged monitoring systems for patients. Although prior biocompatible power harvesting systems for in vivo use have demonstrated short minute-long bursts of power from the stomach, not much is known about the capacity to power electronics in the longer term and throughout the gastrointestinal tract. Here, we report the design and operation of an energy-harvesting galvanic cell for continuous in vivo temperature sensing and wireless communication. The device delivered an average power of 0.23 μW per mm2 of electrode area for an average of 6.1 days of temperature measurements in the gastrointestinal tract of pigs. This power-harvesting cell has the capacity to provide power for prolonged periods of time to the next generation of ingestible electronic devices located in the gastrointestinal tract.

© 2017 Elsevier Ltd Inflammatory bowel disease (IBD) is a chronic, idiopathic inflammatory set of conditions that can affect the entire gastrointestinal (GI) tract and is associated with an increased risk of colorectal cancer. To date there is no curative therapy for IBD; therefore life-long medication can be necessary for IBD management if surgery is to be avoided. Drug delivery systems specific to the colon have improved IBD treatment and several such systems are available to patients. However, current delivery systems for IBD do not target drugs to the site of inflammation, which leads to frequent dosing and potentially severe side effects that can adversely impact patients’ adherence to medication. There is a need for novel drug delivery systems that can target drugs to the site of inflammation, prolong local drug availability, improve therapeutic efficacy, and reduce drug side effects. Nanoparticulate (NP) systems are attractive in designing targeted drug delivery systems for the treatment of IBD because of their unique physicochemical properties and capability of targeting the site of disease. This review analyzes the microenvironment at the site of inflammation in IBD, highlighting the pathophysiological features as possible cues for targeted delivery; discusses different strategies and mechanisms of NP targeting IBD, including size-, charge-, ligand-receptor-, degradation- and microbiome-mediated approaches; and summarizes recent progress on using NPs towards improved therapies for IBD. Finally, challenges and future directions in this field are presented to advance the development of targeted drug delivery for IBD treatment.

Electronic devices placed in the gastrointestinal (GI) tract for prolonged periods have the potential to transform clinical evaluation and treatment. One challenge to the deployment of such gastroresident electronics is the difficulty in powering millimeter-sized electronics devices without using batteries, which compromise biocompatibility and long-term residence. We examined the feasibility of leveraging mid-field wireless powering to transfer power from outside of the body to electronics at various locations along the GI tract. Using simulations and ex vivo measurements, we designed mid-field antennas capable of operating efficiently in tissue at 1.2 GHz. These antennas were then characterized in vivo in five anesthetized pigs, by placing one antenna outside the body, and the other antenna inside the body endoscopically, at the esophagus, stomach, and colon. Across the animals tested, mean transmission efficiencies of −41.2, −36.1, and −34.6 dB were achieved in vivo while coupling power from outside the body to the esophagus, stomach, and colon, respectively. This corresponds to power levels of 37.5 μW, 123 μW and 173 μW received by antennas in the respective locations, while keeping radiation exposure levels below safety thresholds. These power levels are sufficient to wirelessly power a range of medical devices from outside of the body., Draper Fellowship, National Institutes of Health (U.S.) (Grant No. EB-000244), Brigham and Women's Hospital. Division of Gastroenterology

Background & Aims It is a challenge to deliver nucleic acids to gastrointestinal (GI) tissues due to their size and need for intracellular delivery. They are also extremely susceptible to degradation by nucleases, which are ubiquitous in the GI tract. We investigated whether ultrasound, which can permeabilize tissue through a phenomenon known as transient cavitation, can be used to deliver RNA to the colonic mucosa of living mice. Methods We investigated delivery of fluorescently labeled permeants to colon tissues of Yorkshire pigs ex vivo and mice in vivo. Colon tissues were collected and fluorescence was measured by confocal microscopy. We then evaluated whether ultrasound is effective in delivering small interfering (si)RNA to C57BL/6 mice with dextran sodium sulfate−induced colitis. Some mice were given siRNA against tumor necrosis factor (Tnf) mRNA for 6 days; colon tissues were collected and analyzed histologically and TNF protein levels measured by enzyme-linked immunosorbent assay. Feces were collected and assessed for consistency and occult bleeding. We delivered mRNA encoding firefly luciferase to colons of healthy C57BL/6 mice. Results Exposure of ex vivo pig colon tissues to 20 kHz ultrasound for 1 minute increased the level of delivery of 3 kDa dextran 7-fold compared with passive diffusion (P =.037); 40 kHz ultrasound application for 0.5 seconds increased the delivery 3.3-fold in living mice (P =.041). Confocal microscopy analyses of colon tissues from pigs revealed regions of punctuated fluorescent dextran signal, indicating intracellular delivery of macromolecules. In mice with colitis, ultrasound delivery of unencapsulated siRNA against Tnf mRNA reduced protein levels of TNF in colon tissues, compared with mice with colitis given siRNA against Tnf mRNA without ultrasound (P ≤.014), and reduced features of inflammation (P ≤ 4.1 × 10−5). Separately, colons of mice administered an mRNA encoding firefly luciferase with ultrasound and the D-luciferin substrate had levels of bioluminescence 11-fold greater than colons of mice given the mRNA alone (P =.0025). Ultrasound exposures of 40 kHz ultrasound for 0.5 seconds were well tolerated, even in mice with acute colitis. Conclusions Ultrasound can be used to deliver mRNAs and siRNAs to the colonic mucosa of mice and knock down expression of target mRNAs. Keywords: Antisense Therapy; Ulcerative Colitis; Inflammatory Bowel Disease; Ultrasound-Mediated Gastrointestinal Drug Delivery, National Institutes of Health (U.S.) (Grant EB-000244)

Efforts at elimination of scourges, such as malaria, are limited by the logistic challenges of reaching large rural populations and ensuring patient adherence to adequate pharmacologic treatment. We have developed an oral, ultra-long-acting capsule that dissolves in the stomach and deploys a star-shaped dosage form that releases drug while assuming a geometry that prevents passage through the pylorus yet allows passage of food, enabling prolonged gastric residence. This gastric-resident, drug delivery dosage form releases small-molecule drugs for days to weeks and potentially longer. Upon dissolution of the macrostructure, the components can safely pass through the gastrointestinal tract. Clinical, radiographic, and endoscopic evaluation of a swine largeanimal model that received these dosage forms showed no evidence of gastrointestinal obstruction or mucosal injury. We generated long-acting formulations for controlled release of ivermectin, a drug that targets malariatransmitting mosquitoes, in the gastric environment and incorporated these into our dosage form, which then delivered a sustained therapeutic dose of ivermectin for up to 14 days in our swine model. Further, by using mathematical models of malaria transmission that incorporate the lethal effect of ivermectin against malariatransmitting mosquitoes, we demonstrated that this system will boost the efficacy of mass drug administration toward malaria elimination goals. Encapsulated, gastric-resident dosage forms for ultra-long-acting drug delivery have the potential to revolutionize treatment options for malaria and other diseases that affect large populations around the globe for which treatment adherence is essential for efficacy., NIH (Grants EB-000244 and T32-5T32HL007604-29), Bill and Melinda Gates Foundation (Grants OPP1096734, OPP1139921 and OPP1068440)

A novel Janus device with omniphobic and mucoadhesive sides that exhibit the unique capacity for antifouling and extended gastrointestinal retention is fabricated. This system enables repulsion of the food and fluid stream by the luminal-facing omniphobic side and allows attachment to the gastrointestinal mucosa by the mucoadhesive side.

Rapid and effective drug delivery to the gastrointestinal (GI) tract can be a significant challenge. This is because of the harsh environment present in the GI tract and fast transit times in disease states. Physical enhancers, such as ultrasound(US), may enable the rapid delivery of therapeutics while circumventing the need for formulation development. Despite being investigated for other uses, low frequency US has not been studied for GI-based delivery previously. Our group has developed a hand-held device for the rapid delivery of therapeutics to the colonic mucosa. The device utilizes low-frequency US, which is able to painlessly and reversibly permeabilize the tissue. Short, 1-minute treatments in 80 kg Yorkshire pigs were found to enhance the delivery of mesalamine, a drug used for the treatment of inflammatory bowel disease, 22.4-fold over a conventional enema. The safety and efficacy of US were further validated in a rodent colitis model. The delivery of proteins was also possible. US-mediated GI delivery has many potential applications ranging from localized treatment with anti-inflammatories to the more broad delivery of macromolecules. This new technology could prove invaluable in both clinical and research settings, enabling improved therapies and expansion of research techniques applied to the GI tract.

Both patients and physicians prefer the oral route of drug delivery. The gastrointestinal (GI) tract, though, limits the bioavailability of certain therapeutics because of its protease and bacteria-rich environment as well as general pH variability from pH 1 to 7. These extreme environments make oral delivery particularly challenging for the biologic class of therapeutics. Here, we demonstrate proof-of-concept experiments in swine that microneedle-based delivery has the capacity for improved bioavailability of a biologically active macromolecule. Moreover, we show that microneedle-containing devices can be passed and excreted from the GI tract safely. These findings strongly support the success of implementation of microneedle technology for use in the GI tract., National Institutes of Health (U.S.) (Grant EB000244), National Institutes of Health (U.S.) (Grant T32DK7191-38-S1)