Drinkable in situ-forming tough hydrogels for gastrointestinal therapeutics.

Pills are a cornerstone of medicine but can be challenging to swallow. While liquid formulations are easier to ingest, they lack the capacity to localize therapeutics with excipients nor act as controlled release devices. Here we describe drug formulations based on liquid in situ-forming tough (LIFT) hydrogels that bridge the advantages of solid and liquid dosage forms. LIFT hydrogels form directly in the stomach through sequential ingestion of a crosslinker solution of calcium and dithiol crosslinkers, followed by a drug-containing polymer solution of alginate and four-arm poly(ethylene glycol)-maleimide. We show that LIFT hydrogels robustly form in the stomachs of live rats and pigs, and are mechanically tough, biocompatible and safely cleared after 24 h. LIFT hydrogels deliver a total drug dose comparable to unencapsulated drug in a controlled manner, and protect encapsulated therapeutic enzymes and bacteria from gastric acid-mediated deactivation. Overall, LIFT hydrogels may expand access to advanced therapeutics for patients with difficulty swallowing.

Development of a long-acting direct-acting antiviral system for hepatitis C virus treatment in swine.

Chronic hepatitis C virus (HCV) infection is a leading cause of cirrhosis worldwide and kills more Americans than 59 other infections, including HIV and tuberculosis, combined. While direct-acting antiviral (DAA) treatments are effective, limited uptake of therapy, particularly in high-risk groups, remains a substantial barrier to eliminating HCV. We developed a long-acting DAA system (LA-DAAS) capable of prolonged dosing and explored its cost-effectiveness. We designed a retrievable coil-shaped LA-DAAS compatible with nasogastric tube administration and the capacity to encapsulate and release gram levels of drugs while resident in the stomach. We formulated DAAs in drug-polymer pills and studied the release kinetics for 1 mo in vitro and in vivo in a swine model. The LA-DAAS was equipped with ethanol and temperature sensors linked via Bluetooth to a phone application to provide patient engagement. We then performed a cost-effectiveness analysis comparing LA-DAAS to DAA alone in various patient groups, including people who inject drugs. Tunable release kinetics of DAAs was enabled for 1 mo with drug-polymer pills in vitro, and the LA-DAAS safely and successfully provided at least month-long release of sofosbuvir in vivo. Temperature and alcohol sensors could interface with external sources for at least 1 mo. The LA-DAAS was cost-effective compared to DAA therapy alone in all groups considered (base case incremental cost-effectiveness ratio $39,800). We believe that the LA-DAA system can provide a cost-effective and patient-centric method for HCV treatment, including in high-risk populations who are currently undertreated.

Kirigami-inspired stents for sustained local delivery of therapeutics.

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.

Systematic review on chronic non-communicable disease in disaster settings.

BACKGROUND: Non-communicable diseases (NCDs) constitute the leading cause of mortality globally. Low and middle-income countries (LMICs) not only experience the largest burden of humanitarian emergencies but are also disproportionately affected by NCDs, yet primary focus on the topic is lagging. We conducted a systematic review on the effect of humanitarian disasters on NCDs in LMICs assessing epidemiology, interventions, and treatment. METHODS: A systematic search in MEDLINE, MEDLINE (PubMed, for in-process and non-indexed citations), Social Science Citation Index, and Global Health (EBSCO) for indexed articles published before December 11, 2017 was conducted, and publications reporting on NCDs and humanitarian emergencies in LMICs were included. We extracted and synthesized results using a thematic analysis approach and present the results by disease type. The study is registered at PROSPERO (CRD42018088769). RESULTS: Of the 85 included publications, most reported on observational research studies and almost half (48.9%) reported on studies in the Eastern Mediterranean Region (EMRO), with scant studies reporting on the African and Americas regions. NCDs represented a significant burden for populations affected by humanitarian crises in our findings, despite a dearth of data from particular regions and disease categories. The majority of studies included in our review presented epidemiologic evidence for the burden of disease, while few studies addressed clinical management or intervention delivery. Commonly cited barriers to healthcare access in all phases of disaster and major disease diagnoses studied included: low levels of education, financial difficulties, displacement, illiteracy, lack of access to medications, affordability of treatment and monitoring devices, and centralized healthcare infrastructure for NCDs. Screening and prevention for NCDs in disaster-prone settings was supported. Refugee status was independently identified both as a risk factor for diagnosis with an NCD and conferring worse morbidity. CONCLUSIONS: An increased focus on the effects of, and mitigating factors for, NCDs occurring in disaster-afflicted LMICs is needed. While the majority of studies included in our review presented epidemiologic evidence for the burden of disease, research is needed to address contributing factors, interventions, and means of managing disease during humanitarian emergencies in LMICs.

Exploring the effects of programmatic intervention on family planning health literacy and contraceptive utilization in eastern Uganda.

Uganda Village Project (UVP) implemented the Healthy Village Initiative (HVI) and conducted household surveys to assess the effects of the initiative. This data adds to the limited body of knowledge regarding the efficacy of community health interventions for reproductive health in rural east Africa. As part of the HVI, UVP surveys rural Ugandan households before and after a 3-year programmatic intervention to assess changes in family planning health literacy, and contraception utilization. Results showed that there was an increase in contraceptive utilization, an increase in family planning health literacy, and a decrease in unmet need for contraception. Community-based outreaches led by community members and health workers can contribute to improving access to contraception, utilization of contraception, and health literacy surrounding contraception.

Pushing for IV Push Medications: Cost-Effectiveness Model of Switching from IV Piggyback to IV Push for Frequently Used Emergency Department Medications.

In considering the potential to reduce the carbon footprint of our emergency department (ED) via decreasing plastic waste, we aimed to evaluate the effects of changing certain common emergency department medications from an intravenous (IV) piggyback administration route to IV push. Our team queried hospital pharmacy data to determine the number of doses of several frequently utilized antibiotics administered over a six-month time period, then calculated the resultant cost savings of a switch to IV push. Based upon our modeling calculations, switching certain medication administration routes to IVP can have significant impacts on cost, with an estimated cost savings of about $47,000 every six months. Maximizing the use of push administration could result in even more dramatic cost savings. In some scenarios, using IVP administration results in less than half the amount of plastic waste generated. Future research including a full life-cycle analysis is needed in order to precisely determine the impact on carbon footprint created by making this change.

Open cranium model for the study of cerebrovascular dynamics in intracranial hypertension.

BACKGROUND: Significant research has been devoted to developing noninvasive approaches to neuromonitoring. Clinical validation of such approaches is often limited, with minimal data available in the clinically relevant elevated ICP range. NEW METHOD: To allow ultrasound-guided placement of an intraventricular catheter and to perform simultaneous long-duration ICP and ultrasound recordings of cerebral blood flow, we developed a large unilateral craniectomy in a swine model. We also used a microprocessor-controlled actuator for intraventricular saline infusion to reliably and reversibly manipulate ICP according to pre-determined profiles. RESULTS: The model was reproducible, resulting in over 80 hours of high-fidelity, multi-parameter physiological waveform recordings in twelve animals, with ICP ranging from 2 to 78 mmHg. ICP elevations were reversible and reproducible according to two predetermined profiles: a stepwise elevation up to an ICP of 30-35 mmHg and return to normotension, and a clinically significant plateau wave. Finally, ICP was elevated to extreme levels of greater than 60 mmHg, simulating extreme clinical emergency. COMPARISON WITH EXISTING METHODS: Existing methods for ICP monitoring in large animals typically relied on burr-hole approaches for catheter placement. Accurate catheter placement can be difficult in pigs, given the thickness of their skull. Additionally, ultrasound is significantly attenuated by the skull. The open cranium model overcomes these limitations. CONCLUSIONS: The hemicraniectomy model allowed for verified placement of the intraventricular catheter, and reversible and reliable ICP manipulation over a wide range. The large dural window additionally allowed for long-duration recording of cerebral blood flow velocity from the middle cerebral artery.

An ingestible self-propelling device for intestinal reanimation.

Postoperative ileus (POI) is the leading cause of prolonged hospital stay after abdominal surgery and is characterized by a functional paralysis of the digestive tract, leading to symptoms such as constipation, vomiting, and functional obstruction. Current treatments are mainly supportive and inefficacious and yield acute side effects. Although electrical stimulation studies have demonstrated encouraging pacing and entraining of the intestinal slow waves, no devices exist today to enable targeted intestinal reanimation. Here, we developed an ingestible self-propelling device for intestinal reanimation (INSPIRE) capable of restoring peristalsis through luminal electrical stimulation. Optimizing mechanical, material, and electrical design parameters, we validated optimal deployment, intestinal electrical luminal contact, self-propelling capability, safety, and degradation of the device in ex vivo and in vivo swine models. We compared the INSPIRE's effect on motility in models of normal and depressed motility and chemically induced ileus. Intestinal contraction improved by 44% in anesthetized animals and up to 140% in chemically induced ileus cases. In addition, passage time decreased from, on average, 8.6 days in controls to 2.5 days with the INSPIRE device, demonstrating significant improvement in motility. Luminal electrical stimulation of the intestine via the INSPIRE efficaciously restored peristaltic activity. This noninvasive option offers a promising solution for the treatment of ileus and other motility disorders.

Closed-loop automated drug infusion regulator: A clinically translatable, closed-loop drug delivery system for personalized drug dosing.

BACKGROUND: Dosing of chemotherapies is often calculated according to the weight and/or height of the patient or equations derived from these, such as body surface area (BSA). Such calculations fail to capture intra- and interindividual pharmacokinetic variation, which can lead to order of magnitude variations in systemic chemotherapy levels and thus under- or overdosing of patients. METHODS: We designed and developed a closed-loop drug delivery system that can dynamically adjust its infusion rate to the patient to reach and maintain the drug's target concentration, regardless of a patient's pharmacokinetics (PK). FINDINGS: We demonstrate that closed-loop automated drug infusion regulator (CLAUDIA) can control the concentration of 5-fluorouracil (5-FU) in rabbits according to a range of concentration-time profiles (which could be useful in chronomodulated chemotherapy) and over a range of PK conditions that mimic the PK variability observed clinically. In one set of experiments, BSA-based dosing resulted in a concentration 7 times above the target range, while CLAUDIA keeps the concentration of 5-FU in or near the targeted range. Further, we demonstrate that CLAUDIA is cost effective compared to BSA-based dosing. CONCLUSIONS: We anticipate that CLAUDIA could be rapidly translated to the clinic to enable physicians to control the plasma concentration of chemotherapy in their patients. FUNDING: This work was supported by MIT's Karl van Tassel (1925) Career Development Professorship and Department of Mechanical Engineering and the Bridge Project, a partnership between the Koch Institute for Integrative Cancer Research at MIT and the Dana-Farber/Harvard Cancer Center.

An ingestible, battery-free, tissue-adhering robotic interface for non-invasive and chronic electrostimulation of the gut.

Ingestible electronics have the capacity to transform our ability to effectively diagnose and potentially treat a broad set of conditions. Current applications could be significantly enhanced by addressing poor electrode-tissue contact, lack of navigation, short dwell time, and limited battery life. Here we report the development of an ingestible, battery-free, and tissue-adhering robotic interface (IngRI) for non-invasive and chronic electrostimulation of the gut, which addresses challenges associated with contact, navigation, retention, and powering (C-N-R-P) faced by existing ingestibles. We show that near-field inductive coupling operating near 13.56 MHz was sufficient to power and modulate the IngRI to deliver therapeutically relevant electrostimulation, which can be further enhanced by a bio-inspired, hydrogel-enabled adhesive interface. In swine models, we demonstrated the electrical interaction of IngRI with the gastric mucosa by recording conductive signaling from the subcutaneous space. We further observed changes in plasma ghrelin levels, the "hunger hormone," while IngRI was activated in vivo, demonstrating its clinical potential in regulating appetite and treating other endocrine conditions. The results of this study suggest that concepts inspired by soft and wireless skin-interfacing electronic devices can be applied to ingestible electronics with potential clinical applications for evaluating and treating gastrointestinal conditions.

Oral Carbon Monoxide Enhances Autophagy Modulation in Prostate, Pancreatic, and Lung Cancers.

Modulation of autophagy, specifically its inhibition, stands to transform the capacity to effectively treat a broad range of cancers. However, the clinical efficacy of autophagy inhibitors has been inconsistent. To delineate clinical and epidemiological features associated with autophagy inhibition and a positive oncological clinical response, a retrospective analysis of patients is conducted treated with hydroxychloroquine, a known autophagy inhibitor. A direct correlation between smoking status and inhibition of autophagy with hydroxychloroquine is identified. Recognizing that smoking is associated with elevated circulating levels of carbon monoxide (CO), it is hypothesized that supplemental CO can amplify autophagy inhibition. A novel, gas-entrapping material containing CO in a pre-clinical model is applied and demonstrated that CO can dramatically increase the cytotoxicity of autophagy inhibitors and significantly inhibit the growth of tumors when used in combination. These data support the notion that safe, therapeutic levels of CO can markedly enhance the efficacy of autophagy inhibitors, opening a promising new frontier in the quest to improve cancer therapies.

Gastrointestinal Delivery of an mRNA Vaccine Using Immunostimulatory Polymeric Nanoparticles.

mRNA vaccines can be translated into protein antigens, in vivo, to effectively induce humoral and cellular immunity against these proteins. While current mRNA vaccines have generated potent immune responses, the need for ultracold storage conditions (- 80 °C) and healthcare professionals to administer the vaccine through the parenteral route has somewhat limited their distribution in rural areas and developing countries. Overcoming these challenges stands to transform future deployment of mRNA vaccines. In this study, we developed an mRNA vaccine that can trigger a systemic immune response through administration via the gastrointestinal (GI) tract and is stable at 4 °C. A library of cationic branched poly(ß-amino ester) (PBAE) polymers was synthesized and characterized, from which a polymer with high intracellular mRNA delivery efficiency and immune stimulation capacity was down-selected. mRNA vaccines made with the lead polymer-elicited cellular and humoral immunity in mice. Furthermore, lyophilization conditions of the formulation were optimized to enable storage under refrigeration. Our results suggest that PBAE nanoparticles are potent mRNA delivery platforms that can elicit B cell and T cell activation, including antigen-specific cellular and humoral responses. This system can serve as an easily administrable, potent oral mRNA vaccine.

Activated Metals to Generate Heat for Biomedical Applications.

Delivering heat in vivo could enhance a wide range of biomedical therapeutic and diagnostic technologies, including long-term drug delivery devices and cancer treatments. To date, providing thermal energy is highly power-intensive, rendering it oftentimes inaccessible outside of clinical settings. We developed an in vivo heating method based on the exothermic reaction between liquid-metal-activated aluminum and water. After establishing a method for consistent activation, we characterized the heat generation capabilities with thermal imaging and heat flux measurements. We then demonstrated one application of this reaction: to thermally actuate a gastric resident device made from a shape-memory alloy called Nitinol. Finally, we highlight the advantages and future directions for leveraging this novel in situ heat generation method beyond the showcased example.

Secure and Stable Wireless Communication for an Ingestible Device.

Wireless communication enables an ingestible device to send sensor information and support external on-demand operation while in the gastrointestinal (GI) tract. However, it is challenging to maintain stable wireless communication with an ingestible device that travels inside the dynamic GI environment as this environment easily detunes the antenna and decreases the antenna gain. In this paper, we propose an air-gap based antenna solution to stabilize the antenna gain inside this dynamic environment. By surrounding a chip antenna with 1 ~ 2 mms of air, the antenna is isolated from the environment, recovering its antenna gain and the received signal strength by 12 dB or more according to our in vitro and in vivo evaluation in swine. The air gap makes margin for the high path loss, enabling stable wireless communication at 2.4 GHz that allows users to easily access their ingestible devices by using mobile devices with Bluetooth Low Energy (BLE). On the other hand, the data sent or received over the wireless medium is vulnerable to being eavesdropped on by nearby devices other than authorized users. Therefore, we also propose a lightweight security protocol. The proposed protocol is implemented in low energy without compromising the security level thanks to the base protocol of symmetric challenge-response and Speck, the cipher that is optimized for software implementation.

Coronial postmortem reports and indirect COVID-19 pandemic-related mortality.

AIMS: Widespread disruption of healthcare services and excess mortality not directly attributed to COVID-19 occurred between March and May 2020. We undertook the first UK multicentre study of coroners' autopsies before and during this period using postmortem reports. METHODS: We reviewed reports of non-forensic coroners' autopsies performed during the first COVID-19 lockdown (23 March to 8 May 2020), and the same period in 2018. Deaths were categorised as natural non-COVID-19, COVID-19-related, non-natural (suicide, drug and alcohol-related, traumatic, other). We provided opinion regarding whether delayed access to medical care or changes in behaviour due to lockdown were a potential factor in deaths. RESULTS: Seven centres covering nine coronial jurisdictions submitted a total of 1100 coroners' autopsies (498 in 2018, 602 in 2020). In only 54 autopsies was death attributed to COVID-19 (9%). We identified a significant increase in cases where delays in accessing medical care potentially contributed to death (10 in 2018, 44 in 2020). Lockdown was a contributing factor in a proportion of suicides (24%) and drug and alcohol-related deaths (12%). CONCLUSIONS: Postmortem reports have considerable utility in evaluating excess mortality due to healthcare and wider societal disruption during a pandemic. They provide information at an individual case level that is not available from assessment of death certification data. Detailed evaluation of coroners' autopsy reports, supported by appropriate regulatory oversight, is recommended to mitigate disruption and indirect causes of mortality in future pandemics. Maintaining access to healthcare, including substance misuse and mental health services, is an important consideration.

A Vibrating Ingestible BioElectronic Stimulator Modulates Gastric Stretch Receptors for Illusory Satiety.

Effective therapies for obesity either require invasive surgical or endoscopic interventions or high patient adherence, making it challenging for the nearly 42% of American adults who suffer from obesity to effectively manage their disease. Gastric mechanoreceptors sense distension of the stomach and perform volume-dependent vagal signaling to initiate the gastric phase and influence satiety. In this study, we developed a new luminal stimulation modality to specifically activate these gastric stretch receptors to elicit a vagal afferent response commensurate with mechanical distension. Here we developed the Vibrating Ingestible BioElectronic Stimulator (VIBES) pill - an ingestible device that performs luminal vibratory stimulation to activate mechanoreceptors and stroke mucosal receptors, which induces serotonin release as well as yields a hormonal metabolic response commensurate with a fed state. We evaluated VIBES across 108 meals in swine which consistently led to diminished food intake (~40%, p< 0.0001) and minimized the weight gain rate (p< 0.03) as compared to untreated controls. Application of mechanoreceptor biology could transform our capacity to help patients suffering from nutritional disorders.

Enzyme-Triggered Intestine-Specific Targeting Adhesive Platform for Universal Oral Drug Delivery.

Patient adherence to chronic therapies can be suboptimal, leading to poor therapeutic outcomes. Dosage forms that enable reduction in dosing frequency stand to improve patient adherence. Variation in gastrointestinal transit time, inter-individual differences in gastrointestinal physiology and differences in physicochemical properties of drugs represent challenges to the development of such systems. To this end, a small intestine-targeted drug delivery system is developed, where prolonged gastrointestinal retention and sustained release are achieved through tissue adhesion of drug pills mediated by an essential intestinal enzyme catalase. Here proof-of-concept pharmacokinetics is demonstrated in the swine model for two drugs, hydrophilic amoxicillin and hydrophobic levodopa. It is anticipated that this system can be applicable for many drugs with a diverse of physicochemical characteristics.

Adaptive conductive electrotherapeutic scaffolds for enhanced peripheral nerve regeneration and stimulation.

BACKGROUND: While peripheral nerve stimulation (PNS) has shown promise in applications ranging from peripheral nerve regeneration to therapeutic organ stimulation, clinical implementation has been impeded by various technological limitations, including surgical placement, lead migration, and atraumatic removal. METHODS: We describe the design and validation of a platform technology for nerve regeneration and interfacing: adaptive, conductive, and electrotherapeutic scaffolds (ACESs). ACESs are comprised of an alginate/poly-acrylamide interpenetrating network hydrogel optimized for both open surgical and minimally invasive percutaneous approaches. FINDINGS: In a rodent model of sciatic nerve repair, ACESs significantly improved motor and sensory recovery (p < 0.05), increased muscle mass (p < 0.05), and increased axonogenesis (p < 0.05). Triggered dissolution of ACESs enabled atraumatic, percutaneous removal of leads at forces significantly lower than controls (p < 0.05). In a porcine model, ultrasound-guided percutaneous placement of leads with an injectable ACES near the femoral and cervical vagus nerves facilitated stimulus conduction at significantly greater lengths than saline controls (p < 0.05). CONCLUSION: Overall, ACESs facilitated lead placement, stabilization, stimulation, and atraumatic removal, enabling therapeutic PNS as demonstrated in small- and large-animal models. FUNDING: This work was supported by K. Lisa Yang Center for Bionics at MIT.

A vibrating ingestible bioelectronic stimulator modulates gastric stretch receptors for illusory satiety.

Effective therapies for obesity require invasive surgical and endoscopic interventions or high patient adherence, making it challenging for patients with obesity to effectively manage their disease. Gastric mechanoreceptors sense distension of the stomach and perform volume-dependent vagal signaling to initiate the gastric phase and influence satiety. In this study, we developed a new luminal stimulation modality to specifically activate these gastric stretch receptors to elicit a vagal afferent response commensurate with mechanical distension. We designed the Vibrating Ingestible BioElectronic Stimulator (VIBES) pill, an ingestible device that performs luminal vibratory stimulation to activate mechanoreceptors and stroke mucosal receptors, which induces serotonin release and yields a hormonal metabolic response commensurate with a fed state. We evaluated VIBES across 108 meals in swine which consistently led to diminished food intake (~40%, P < 0.0001) and minimized the weight gain rate (P < 0.05) as compared to untreated controls. Application of mechanoreceptor biology could transform our capacity to help patients suffering from nutritional disorders.

Actively Triggerable Metals via Liquid Metal Embrittlement for Biomedical Applications.

Actively triggerable materials, which break down upon introduction of an exogenous stimulus, enable precise control over the lifetime of biomedical technologies, as well as adaptation to unforeseen circumstances, such as changes to an established treatment plan. Yet, most actively triggerable materials are low-strength polymers and hydrogels with limited long-term durability. By contrast, metals possess advantageous functional properties, including high mechanical strength and conductivity, that are desirable across several applications within biomedicine. To realize actively triggerable metals, a mechanism called liquid metal embrittlement is leveraged, in which certain liquid metals penetrate the grain boundaries of certain solid metals and cause them to dramatically weaken or disintegrate. In this work, it is demonstrated that eutectic gallium indium (EGaIn), a biocompatible alloy of gallium, can be formulated to reproducibly trigger the breakdown of aluminum within different physiologically relevant environments. The breakdown behavior of aluminum after triggering can further be readily controlled by manipulating its grain structure. Finally, three possible use cases of biomedical devices constructed from actively triggerable metals are demonstrated.