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Localization and tracking of ingestible microdevices in the gastrointestinal (GI) tract is valuable for the diagnosis and treatment of GI disorders. Such systems require a large field-of-view of tracking, high spatiotemporal resolution, wirelessly operated microdevices and a non-obstructive field generator that is safe to use in practical settings. However, the capabilities of current systems remain limited. Here, we report three dimensional (3D) localization and tracking of wireless ingestible microdevices in the GI tract of large animals in real time and with millimetre-scale resolution. This is achieved by generating 3D magnetic field gradients in the GI field-of-view using high-efficiency planar electromagnetic coils that encode each spatial point with a distinct magnetic field magnitude. The field magnitude is measured and transmitted by the miniaturized, low-power and wireless microdevices to decode their location as they travel through the GI tract. This system could be useful for quantitative assessment of the GI transit-time, precision targeting of therapeutic interventions and minimally invasive procedures.

The surface mucosa that lines many of our organs houses myriad biometric signals and, therefore, has great potential as a sensor-tissue interface for high-fidelity and long-term biosensing. However, progress is still nascent for mucosa-interfacing electronics owing to challenges with establishing robust sensor-tissue interfaces; device localization, retention and removal; and power and data transfer. This is in sharp contrast to the rapidly advancing field of skin-interfacing electronics, which are replacing traditional hospital visits with minimally invasive, real-time, continuous and untethered biosensing. This Review aims to bridge the gap between skin-interfacing electronics and mucosa-interfacing electronics systems through a comparison of the properties and functions of the skin and internal mucosal surfaces. The major physiological signals accessible through mucosa-lined organs are surveyed and design considerations for the next generation of mucosa-interfacing electronics are outlined based on state-of-the-art developments in bio-integrated electronics. With this Review, we aim to inspire hardware solutions that can serve as a foundation for developing personalized biosensing from the mucosa, a relatively uncharted field with great scientific and clinical potential.

The gut-brain axis, which is mediated via enteric and central neurohormonal signaling, is known to regulate a broad set of physiological functions from feeding to emotional behavior. Various pharmaceuticals and surgical interventions, such as motility agents and bariatric surgery, are used to modulate this axis. Such approaches, however, are associated with off-target effects or post-procedure recovery time and expose patients to substantial risks. Electrical stimulation has also been used to attempt to modulate the gut-brain axis with greater spatial and temporal resolution. Electrical stimulation of the gastrointestinal (GI) tract, however, has generally required invasive intervention for electrode placement on serosal tissue. Stimulating mucosal tissue remains challenging because of the presence of gastric and intestinal fluid, which can influence the effectiveness of local luminal stimulation. Here, we report the development of a bioinspired ingestible fluid-wicking capsule for active stimulation and hormone modulation (FLASH) capable of rapidly wicking fluid and locally stimulating mucosal tissue, resulting in systemic modulation of an orexigenic GI hormone. Drawing inspiration from Moloch horridus, the “thorny devil” lizard with water-wicking skin, we developed a capsule surface capable of displacing fluid. We characterized the stimulation parameters for modulation of various GI hormones in a porcine model and applied these parameters to an ingestible capsule system. FLASH can be orally administered to modulate GI hormones and is safely excreted with no adverse effects in porcine models. We anticipate that this device could be used to treat metabolic, GI, and neuropsychiatric disorders noninvasively with minimal off-target effects.

The successful delivery of RNA therapeutics is the gating hurdle to greater clinical translation and utility of this novel class of therapeutics. Delivery strategies today are limited and predominantly rely on lipid nanoparticles or conjugates, which can facilitate hepatic delivery but are poor for achieving uptake outside the liver. The ability to deliver RNA to other organs outside the liver in a formulation-agnostic approach could serve to unlock the broader potential of these therapies and enable their use in a broader set of disease. Here we demonstrate this formulation-agnostic delivery of two model siRNAs using low-frequency ultrasound to the gastrointestinal (GI) tract. Unformulated siRNAs targeting β-catenin (Ctnnb 1) and Sjögren syndrome antigen B (SSB) genes were successfully delivered to colonic mucosa in mice, achieving robust knockdown of the target mRNA from whole-colon tissue samples. Indeed, the capacity to target and successfully suppress expression from genes underscores the power of this platform to rapidly deliver unformulated and unoptimized sequences against a range of targets in the GI tract.

Table S1 - List of antibodies used

The aggressive primary brain tumor glioblastoma (GBM) is characterized by aberrant metabolism that fuels its malignant phenotype. Diverse genetic subtypes of malignant glioma are sensitive to selective inhibition of the NAD+ salvage pathway enzyme nicotinamide phosphoribosyltransferase (NAMPT). However, the potential impact of NAD+ depletion on the brain tumor microenvironment has not been elaborated. In addition, systemic toxicity of NAMPT inhibition remains a significant concern. Here we show that microparticle-mediated intratumoral delivery of NAMPT inhibitor GMX1778 induces specific immunologic changes in the tumor microenvironment of murine GBM, characterized by upregulation of immune checkpoint PD-L1, recruitment of CD3+, CD4+, and CD8+ T cells, and reduction of M2-polarized immunosuppressive macrophages. NAD+ depletion and autophagy induced by NAMPT inhibitors mediated the upregulation of PD-L1 transcripts and cell surface protein levels in GBM cells. NAMPT inhibitor modulation of the tumor immune microenvironment was therefore combined with PD-1 checkpoint blockade in vivo, significantly increasing the survival of GBM-bearing animals. Thus, the therapeutic impacts of NAMPT inhibition extended beyond neoplastic cells, shaping surrounding immune effectors. Microparticle delivery and release of NAMPT inhibitor at the tumor site offers a safe and robust means to alter an immune tumor microenvironment that could potentiate checkpoint immunotherapy for glioblastoma.Significance:Microparticle-mediated local inhibition of NAMPT modulates the tumor immune microenvironment and acts cooperatively with anti-PD-1 checkpoint blockade, offering a combination immunotherapy strategy for the treatment of GBM.

Supplemental figures 1-10. Supplementary Figure S1. Cell viability assay with NAMPT inhibitors. Supplementary Figure S2. NAMPT inhibitor induces PD-L1 upregulation on alive cells. Supplementary Figure S3. NAMPT inhibitor induces PD-L1 upregulation. Supplementary Figure S4. Tumor PD-L1 upregulation after injection of coumarin6GMX1778 co-loaded microparticles. Supplementary Figure S5. NAMPT inhibitor-induced autophagy underlies an increase in PD-L1 mRNA and protein levels. Supplementary Figure S6. Impact of local treatment with GMX1778 microparticles on cells labeled with Arg1 and CD68 in murine glioblastoma. Supplementary Figure S7. NAMPT inhibitor decreases glioblastoma-associated macrophages. Supplementary Figure S8. PD-L1 immunohistochemistry (brown) of GL261 glioblastoma after treatment with blank micro-particles (MP), blank MP and anti-PD-1, GMX1778 MP, and combination of GMX1778 MP and anti-PD-1. Supplementary Figure S9. Immunoflurescence of GL261 glioblastoma after treatment with blank micro-particles, anti-PD-1, GMX1778 micro-particles, and combination. Supplementary Figure S10. GranzymeB immunohistochemistry (brown) of GL261 glioblastoma after treatment with blank micro-particles (MP), blank MP and anti-PD-1, GMX1778 MP, and combination of GMX1778 MP and anti-PD-1.

The Covid-19 Pandemic has renewed interest in contactless vital signs monitoring using state-of-the-art computer vision, which can efficiently screen for symptoms while reducing the risk of disease transmission. Despite the promising perfor- mance, the use of static camera setups requires subjects to remain static inside a field of view (FoV) for a pre-specified duration. Due to inconsistent ambient environmental conditions, the transit of individuals through the FoV, and the time it may take to triage individuals, the widespread adoption of static camera systems to continuously monitor vital signs has had suboptimal uptake. Robotic systems enable autonomous and continuous monitoring, but these require expensive cameras, computers, and robotic platforms, limiting widespread deployment. In response, we propose a cost-effective and scalable robotic solution consisting of a suite of commercial, off-the-shelf wireless cameras for capturing photoplethysmography (PPG) on ambulatory subjects linked to a single computer that supervises the cameras to compute the vital signs of subjects. Throughout a set of careful investigations of each individual step of the wireless machine vision camera and computer, bottlenecks constraining wireless live-streaming of high-quality PPG information are identified and those are addressed by a hybrid centralized/decentralized wireless machine vision protocol. Our results demonstrate that the proposed cost-effective wireless camera achieves equivalent remote-PPG accuracy to its costly, USB3 counterparts (mean error: 5.0 BMP vs. 4.7 BPM) by means of the hybrid camera protocol which boosts the overall frame rate to 17 FPS. In contrast, using the standard method that captures the PPG with the same spatial resolution can only achieve 1 FPS. In addition, this work also elucidates how varying the distance, image pixel density, frame rate, image compression, image downsampling, and color depth affect the rPPG performance. For each of the effects, we also discuss potential solutions for the cost-effective setup.

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., Advanced Materials, 35 (11), ISSN:0935-9648, ISSN:1521-4095

Increasing the intensity of tumor treating fields (TTF) within a tumor bed improves clinical efficacy, but reaching sufficiently high field intensities to achieve growth arrest remains challenging due in part to the insulating nature of the cranium. Using MRI-derived finite element models (FEMs) and simulations, we optimized an exhaustive set of intracranial electrode locations to obtain maximum TTF intensities in three clinically challenging high-grade glioma (HGG) cases (i.e., thalamic, left temporal, brainstem). Electric field strengths were converted into therapeutic enhancement ratios (TER) to evaluate the predicted impact of stimulation on tumor growth. Concurrently, conventional transcranial configurations were simulated/optimized for comparison. Optimized intracranial TTF were able to achieve field strengths that have previously been shown capable of inducing complete growth arrest, in 98–100% of the tumor volumes using only 0.54–0.64 A current. The reconceptualization of TTF as a targeted, intracranial therapy has the potential to provide a meaningful survival benefit to patients with HGG and other brain tumors, including those in surgically challenging, deep, or anatomically eloquent locations which may preclude surgical resection. Accordingly, such an approach may ultimately represent a paradigm shift in the use of TTFs for the treatment of brain cancer.

Best practices in Biomedical Engineering education seek to connect classroom knowledge to practical applications. MIT’s Medical Device Design course is comprised of in-class didactics, individual laboratory assignments, and a semester-long, team- based design and prototyping challenge, based in real unmet biomedical need. Students in the course represent a broad set of undergraduate and graduate students, from diverse educational backgrounds, with different levels of training and expertise. This year, as a precursor to the semester-long project, we designed, piloted, and evaluated a new experiential learning lab based around a syringe pump, selected because of its prevalence in the clinical setting, exemplification of core, multidisciplinary biomedical engineering concepts, and suitability for a team-based learning exercise. Students individually calculated patient dosing requirements and translated desired volume and flow rate into stepper motor commands. Then, during a single in-class session, teams worked from a custom-designed and fabricated kit to assemble a syringe pump, breadboard electronics, implement software controls, and finally close the design loop by evaluating their pumps' dispensing performance. A post-lab survey of the student cohort indicated that this pilot lab provided a sound biomedical learning and teamwork opportunity that improved technical literacy. The survey also identified key opportunities for improvement – students wanted more time and instructor-guided learning to increase their understanding of the mechanical engineering, electrical engineering, and software subtopics. Consequently, next year we will expand the lab into a multi-class exercise, with enhanced lectures and supplementary materials. Overall, we share this problem-based learning exercise, designed to exemplify key concepts, improve teamwork, and foster hands-on tinkering skills, with other biomedical engineering instructors.

ObjectivesMask adherence continues to be a critical public health measure to prevent transmission of aerosol pathogens, such as SARS-CoV-2. We aimed to develop and deploy a computer vision algorithm to provide real-time feedback of mask wearing among staff in a hospital.DesignSingle-site, observational cohort study.SettingAn urban, academic hospital in Boston, Massachusetts, USA.ParticipantsWe enrolled adult hospital staff entering the hospital at a key ingress point.InterventionsConsenting participants entering the hospital were invited to experience the computer vision mask detection system. Key aspects of the detection algorithm and feedback were described to participants, who then completed a quantitative assessment to understand their perceptions and acceptance of interacting with the system to detect their mask adherence.Outcome measuresPrimary outcomes were willingness to interact with the mask system, and the degree of comfort participants felt in interacting with a public facing computer vision mask algorithm.ResultsOne hundred and eleven participants with mean age 40 (SD15.5) were enrolled in the study. Males (47.7%) and females (52.3%) were equally represented, and the majority identified as white (N=54, 49%). Most participants (N=97, 87.3%) reported acceptance of the system and most participants (N=84, 75.7%) were accepting of deployment of the system to reinforce mask adherence in public places. One third of participants (N=36) felt that a public facing computer vision system would be an intrusion into personal privacy.Public-facing computer vision software to detect and provide feedback around mask adherence may be acceptable in the hospital setting. Similar systems may be considered for deployment in locations where mask adherence is important.

Tablets and capsules are a cornerstone of medicine, but these solid dosage forms can be challenging to swallow for geriatric and pediatric patients. While liquid formulations are easier to ingest, these formulations lack the capacity to localize therapeutics and excipients nor act as controlled release devices. To bridge the advantages of solid and liquid dosage forms, here we describe drug formulations based on liquidin situ-forming and tough (LIFT) hydrogels. Drug-loaded LIFT hydrogels are formed directly in the stomach through the sequential ingestion of a crosslinker solution of calcium and dithiol crosslinkers, followed by the ingestion of a drug-containing polymer solution of alginate and 4-arm poly(ethylene glycol)-maleimide. We show that LIFT hydrogels are mechanically tough and able to robustly form in the presence of complex gastric fluid andin vivoin rat and porcine stomachs. LIFT hydrogels are retained within the porcine stomach for up to 24 h, biocompatible, and safely cleared. These hydrogels deliver a total dose comparable to unencapsulated drug but with delayed and lower maximum drug plasma concentrations, providing a method for controlled release that may mitigate drug toxicity. Co-encapsulation of lactase as a model biologic drug and calcium carbonate mitigated gastric-mediated deactivation of encapsulated enzyme in rat and porcine models. We also demonstrate the potential of these hydrogels to encapsulate and protect a model therapeutic bacterium,E. coliNissle 1917, against acid. LIFT hydrogels present a biocompatible means of tough, double-network hydrogel formationin situin the gastric cavity, and may expand medication access for patients with difficulty swallowing.

Microorganisms have been used for millennia to produce food and medicine and are now being developed as products themselves to treat disease and boost crop production. However, as required for these new applications, maintaining high viability throughout manufacturing, transportation and use remains a significant challenge requiring sophisticated cold-chains and packaging. In fact, we found that commercial microbial products (probiotics) provide a poor solution to this challenge, in particular for key industrial organisms likeE. coli. To overcome this technological gap, we report the development of synthetic extremophiles of industrially important gram-negative bacteria (E. coliNissle 1917,Ensifer meliloti), gram positive bacteria (Lactobacillusplantarum) and yeast (Saccharomyces boulardii). Specifically, we developed a high throughput pipeline to define species-specific materials that allow these organisms to survive drying, elevated temperatures, organic solvents and even ionizing radiation. We enhanced the stability ofE.coliNissle 1917 by >4 orders of magnitude over commercial formulations and demonstrate the capacity to remain viable while undergoing tableting and pharmaceutical methodologies involving organic solvents. The development of synthetic materials-based enhanced stabilization stands to transform our capacity to apply micro-organisms in extreme environments including those found on Earth as well as in space.One-Sentence SummaryFragile therapeutic bacteria can be made to survive the manufacturing extremes normally reserved for small molecule drugs.

Oral administration provides a simple and non-invasive approach for drug delivery. However, due to poor absorption and swift enzymatic degradation in the gastrointestinal tract, a wide range of molecules must be parenterally injected to attain required doses and pharmacokinetics. Here we present an orally dosed liquid auto-injector capable of delivering up to 4-mg doses of a bioavailable drug with the rapid pharmacokinetics of an injection, reaching an absolute bioavailability of up to 80% and a maximum plasma drug concentration within 30 min after dosing. This approach improves dosing efficiencies and pharmacokinetics an order of magnitude over our previously designed injector capsules and up to two orders of magnitude over clinically available and preclinical chemical permeation enhancement technologies. We administered the capsules to swine for delivery of clinically relevant doses of four commonly injected medications, including adalimumab, a GLP-1 analog, recombinant human insulin and epinephrine. These multi-day dosing experiments and oral administration in awake animal models support the translational potential of the system. Biologics are delivered by a pill that pricks the stomach wall.

Oral drug delivery of proteins is limited by the degradative environment of the gastrointestinal tract and poor absorption, requiring parenteral administration of these drugs. Luminal mucus represents the initial steric and dynamic barrier to absorption. To overcome this barrier, we report the development of the RoboCap, an orally ingestible, robotic drug delivery capsule that locally clears the mucus layer, enhances luminal mixing, and topically deposits the drug payload in the small intestine to enhance drug absorption. RoboCap’s mucus-clearing and churning movements are facilitated by an internal motor and by surface features that interact with small intestinal plicae circulares, villi, and mucus. Vancomycin (1.4 kilodaltons of glycopeptide) and insulin (5.8 kilodaltons of peptide) delivery mediated by RoboCap resulted in enhanced bioavailability 20- to 40-fold greater in ex vivo and in vivo swine models when compared with standard oral delivery ( P

Recent advances in integrated circuits and micromachining have enabled the integration of battery-powered micro-actuators in miniaturized drug delivery systems. However, the power/energy management system that treats current overloading remains sub-optimal. Overloading not only deteriorates the actuators’ long-term performance but also attenuates battery capacity. In this work, we are proposing a simple yet powerful solution to manage current overloading to maximize battery-powered system life-time. The proposed solution consists of a digitally programmable soft starter and DC-DC converter that can dynamically balance the trade-off between inrush current amplitude and motor starting speed as well as maximally minimize the continuous current draw from a battery. Our experimental results show that the proposed soft starter alone can enhance the battery capacity by 18% and together with the DC-DC converter, they can increase the drug delivery cycles by 33% without sacrificing the system’s output performance.

More than two decades ago it was discovered that nitric oxide (NO) concentrations in gas aspirated during colonoscopy were more than 100 times higher in patients diagnosed with Ulcerative Colitis (UC) than controls. While this provides a diagnostic opportunity, it has not been possible to perform in situ detection of NO via a non-invasive manner. This work presents the feasibility of in situ detection of NO by means of a capsule-like electrochemical gas sensor. Our in vivo results in a large animal model of intestinal inflammation show that NO can be directly detected at the site of inflammation and that it quickly dissipates to surrounding tissues, demonstrating the importance of in situ detection.

While peripheral nerve stimulation (PNS) has shown promise in applications ranging from peripheral nerve regeneration after injury to therapeutic organ stimulation, clinical implementation has been impeded by various technological limitations, including surgical placement, lead migration, and atraumatic removal. Here, we describe the design and validation of a new platform for nerve regeneration and interfacing: Absorbable, Conductive, Electrotherapeutic Scaffolds (ACES). ACES are comprised of an alginate/poly-acrylamide interpenetrating network hydrogel optimized for both open and minimally invasive percutaneous approaches. In a rodent model of sciatic nerve repair, ACES significantly improved motor and sensory recovery (p < 0.05), increased muscle mass (p < 0.05), and increased axonogenesis (p < 0.05). Triggered dissolution of ACES 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). Overall, ACES facilitated lead placement, stabilization, stimulation and atraumatic removal enabling therapeutic PNS as demonstrated in small and large animal models.

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.

The trade-off between spatial and temporal resolution remains a fundamental challenge in machine vision. A captured image often contains a significant amount of redundant information, and only a small region of interest (ROI) is necessary for object detection and tracking. In this paper, we first systematically characterize the effects of ROI on camera capturing, data transmission, and image processing. We then present the closed-loop ROI algorithm capable of high spatial and temporal resolution as well as wide scanning field of view (FOV) in single and multi-object detection and tracking via real-time wireless video streaming. With the feedback from real-time object tracking, the wireless camera is able to capture and transmit only the ROI which in turn enhances both the spatial and temporal resolution in object tracking. In addition, the proposed approach can still maintain a large FOV by processing regions outside of the ROI at lower spatial and temporal resolutions. When applied to a high spatial resolution wireless stream (5 MegaPixels), the closed-loop ROI algorithm improves the temporal resolution by up to $10\times $ (from 2.4FPS to 22.5FPS). Specifically, camera processing is improved by up to $4.7\times $ , data transmission is improved by up to $160\times $ , and PC processing is improved by up to $2.5\times $ . In a person tracking experiment, the closed-loop ROI algorithm enables a wide-angle camera to outperform both a normal wide-angle camera–which suffers from poor temporal resolution and motion blur–and a pan & tilt camera–which cannot automatically refresh tracking after the tracking is lost.

Carbon monoxide (CO) has long been considered a toxic gas but is now a recognized bioactive gasotransmitter with potent immunomodulatory effects. Although inhaled CO is currently under investigation for use in patients with lung disease, this mode of administration can present clinical challenges. The capacity to deliver CO directly and safely to the gastrointestinal (GI) tract could transform the management of diseases affecting the GI mucosa such as inflammatory bowel disease or radiation injury. To address this unmet need, inspired by molecular gastronomy techniques, we have developed a family of gas-entrapping materials (GEMs) for delivery of CO to the GI tract. We show highly tunable and potent delivery of CO, achieving clinically relevant CO concentrations in vivo in rodent and swine models. To support the potential range of applications of foam GEMs, we evaluated the system in three distinct disease models. We show that a GEM containing CO dose-dependently reduced acetaminophen-induced hepatocellular injury, dampened colitis-associated inflammation and oxidative tissue injury, and mitigated radiation-induced gut epithelial damage in rodents. Collectively, foam GEMs have potential paradigm-shifting implications for the safe therapeutic use of CO across a range of indications.

The COVID-19 pandemic has accelerated methods to facilitate contactless evaluation of patients in hospital settings. By minimizing in-person contact with individuals who may have COVID-19, healthcare workers can prevent disease transmission and conserve personal protective equipment. Obtaining vital signs is a ubiquitous task that is commonly done in person by healthcare workers. To eliminate the need for in-person contact for vital sign measurement in the hospital setting, we developed Dr. Spot, a mobile quadruped robotic system. The system includes IR and RGB cameras for vital sign monitoring and a tablet computer for face-to-face medical interviewing. Dr. Spot is teleoperated by trained clinical staff to simultaneously measure the skin temperature, respiratory rate, and heart rate while maintaining social distancing from patients and without removing their mask. To enable accurate, contactless measurements on a mobile system without a static black body as reference, we propose novel methods for skin temperature compensation and respiratory rate measurement at various distances between the subject and the cameras, up to 5 m. Without compensation, the skin temperature MAE is 1.3°C. Using the proposed compensation method, the skin temperature MAE is reduced to 0.3°C. The respiratory rate method can provide continuous monitoring with a MAE of 1.6 BPM in 30 s or rapid screening with a MAE of 2.1 BPM in 10 s. For the heart rate estimation, our system is able to achieve a MAE less than 8 BPM in 10 s measured in arbitrary indoor light conditions at any distance below 2 m.

The aggressive primary brain tumor glioblastoma (GBM) is characterized by aberrant metabolism that fuels its malignant phenotype. Diverse genetic subtypes of malignant glioma are sensitive to selective inhibition of the NAD+ salvage pathway enzyme nicotinamide phosphoribosyltransferase (NAMPT). However, the potential impact of NAD+ depletion on the brain tumor microenvironment has not been elaborated. In addition, systemic toxicity of NAMPT inhibition remains a significant concern. Here we show that microparticle-mediated intratumoral delivery of NAMPT inhibitor GMX1778 induces specific immunologic changes in the tumor microenvironment of murine GBM, characterized by upregulation of immune checkpoint PD-L1, recruitment of CD3+, CD4+, and CD8+ T cells, and reduction of M2-polarized immunosuppressive macrophages. NAD+ depletion and autophagy induced by NAMPT inhibitors mediated the upregulation of PD-L1 transcripts and cell surface protein levels in GBM cells. NAMPT inhibitor modulation of the tumor immune microenvironment was therefore combined with PD-1 checkpoint blockade in vivo, significantly increasing the survival of GBM-bearing animals. Thus, the therapeutic impacts of NAMPT inhibition extended beyond neoplastic cells, shaping surrounding immune effectors. Microparticle delivery and release of NAMPT inhibitor at the tumor site offers a safe and robust means to alter an immune tumor microenvironment that could potentiate checkpoint immunotherapy for glioblastoma. Significance: Microparticle-mediated local inhibition of NAMPT modulates the tumor immune microenvironment and acts cooperatively with anti-PD-1 checkpoint blockade, offering a combination immunotherapy strategy for the treatment of GBM.

Monolayers of cancer-derived cell lines are widely used in the modelling of the gastrointestinal (GI) absorption of drugs and in oral drug development. However, they do not generally predict drug absorption in vivo. Here, we report a robotically handled system that uses large porcine GI tissue explants that are functionally maintained for an extended period in culture for the high-throughput interrogation (several thousand samples per day) of whole segments of the GI tract. The automated culture system provided higher predictability of drug absorption in the human GI tract than a Caco-2 Transwell system (Spearman’s correlation coefficients of 0.906 and 0.302, respectively). By using the culture system to analyse the intestinal absorption of 2,930 formulations of the peptide drug oxytocin, we discovered an absorption enhancer that resulted in a 11.3-fold increase in the oral bioavailability of oxytocin in pigs in the absence of cellular disruption of the intestinal tissue. The robotically handled whole-tissue culture system should help advance the development of oral drug formulations and might also be useful for drug screening applications. A robotically handled culture system using porcine gastrointestinal tissue explants for the high-throughput interrogation of the gastrointestinal tract predicts the absorption of oral drugs in the human gut better than Caco-2 Transwells.

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.

The fixation and manipulation of fibroids during laparoscopic myomectomy is a persistent issue for gynecologic surgeons. In this paper, we present a laparoscopic grasper that, through a sheath-based deployment mechanism, opens into a larger multitoothed grasper within the patient and collapses back for removal. Due to the increased number of contact points with the tumor, the expanded grasper allows for reliable fixation, aiding in manipulation during excision. We describe the nature-inspired design of the grasper from a physical foundation, establish the design theory and practical issues, and present manufacturing and testing of a full-scale 5 mm grasper. The unit was tested on synthetic fibroid models and was able to sustain a 50% higher load before tearing than a common single-tooth tenaculum. This development not only promises to improve fibroid fixation in myomectomy but also its design could be adapted to aid in the fixation of other difficult tissues in laparoscopic surgery.

Oral delivery of therapeutics is the preferred route of administration due to ease of administration which is associated with greater patient medication adherence. One major barrier to oral delivery and intestinal absorption is rapid clearance of the drug and the drug delivery system from the gastrointestinal (GI) tract. To address this issue, researchers have investigated using GI mucus to help maximize the pharmacokinetics of the therapeutic; while mucus can act as a barrier to effective oral delivery, it can also be used as an anchoring mechanism to improve intestinal residence. Nano-drug delivery systems that use materials which can interact with the mucus layers in the GI tract can enable longer residence time, improving the efficacy of oral drug delivery. This review examines the properties and function of mucus in the GI tract, as well as diseases that alter mucus. Three broad classes of mucus-interacting systems are discussed: mucoadhesive, mucus-penetrating, and mucolytic drug delivery systems. For each class of system, the basis for mucus interaction is presented, and examples of materials that inform the development of these systems are discussed and reviewed. Finally, a list of FDA-approved mucoadhesive, mucus-penetrating, and mucolytic drug delivery systems is reviewed. In summary, this review highlights the progress made in developing mucus-interacting systems, both at a research-scale and commercial-scale level, and describes the theoretical basis for each type of system.

While there have been rapid advances in developing new and more targeted drugs to treat cancer, much less progress has been made in individualizing dosing. Even though the introduction of immunotherapies such as CAR T-cells and checkpoint inhibitors, as well as personalized therapies that target specific mutations, have transformed clinical treatment of cancers, chemotherapy remains a mainstay in oncology. Chemotherapies are typically dosed on either a body surface area (BSA) or weight basis, which fails to account for pharmacokinetic differences between patients. Drug absorption, distribution, metabolism, and excretion rates can vary between patients, resulting in considerable differences in exposure to the active drugs. These differences result in suboptimal dosing, which can reduce efficacy and increase side-effects. Therapeutic drug monitoring (TDM), genotype guided dosing, and chronomodulation have been developed to address this challenge; however, despite improving clinical outcomes, they are rarely implemented in clinical practice for chemotherapies. Thus, there is a need to develop interventions that allow for individualized drug dosing of chemotherapies, which can help maximize the number of patients that reach the most efficacious level of drug in the blood while mitigating the risks of underdosing or overdosing. In this review, we discuss the history of the development of chemotherapies, their mechanisms of action and how they are dosed. We discuss substantial intraindividual and interindividual variability in chemotherapy pharmacokinetics. We then propose potential engineering solutions that could enable individualized dosing of chemotherapies, such as closed-loop drug delivery systems and bioresponsive biomaterials.

Description, We developed a dynamic omnidirectional adhesive microneedle system that improves the oral delivery of macromolecules., Oral drug administration remains the preferred route for patients and health care providers. Delivery of macromolecules through this route remains challenging because of limitations imposed by the transport across the gastrointestinal epithelium and the dynamic and degradative environment. Here, we present the development of a delivery system that combines physical (microneedle) and nonphysical (enhancer) modes of drug delivery enhancement for a macromolecule in a large animal model. Inspired by the thorny-headed intestinal worm, we report a dynamic omnidirectional mucoadhesive microneedle system capable of prolonged gastric mucosa fixation. Moreover, we incorporate sodium N-[8-(2-hydroxybenzoyl) amino] caprylate along with semaglutide and demonstrate enhanced absorption in swine resistant to physical displacement in the gastric cavity. Meanwhile, we developed a targeted capsule system capable of deploying intact microneedle-containing systems. These systems stand to enable the delivery of a range of drugs through the generation and maintenance of a privileged region in the gastrointestinal tract.

Bioplastics — typically plastics manufactured from bio-based polymers — stand to contribute to more sustainable commercial plastic life cycles as part of a circular economy, in which virgin polymers are made from renewable or recycled raw materials. Carbon-neutral energy is used for production and products are reused or recycled at their end of life (EOL). In this Review, we assess the advantages and challenges of bioplastics in transitioning towards a circular economy. Compared with fossil-based plastics, bio-based plastics can have a lower carbon footprint and exhibit advantageous materials properties; moreover, they can be compatible with existing recycling streams and some offer biodegradation as an EOL scenario if performed in controlled or predictable environments. However, these benefits can have trade-offs, including negative agricultural impacts, competition with food production, unclear EOL management and higher costs. Emerging chemical and biological methods can enable the ‘upcycling’ of increasing volumes of heterogeneous plastic and bioplastic waste into higher-quality materials. To guide converters and consumers in their purchasing choices, existing (bio)plastic identification standards and life cycle assessment guidelines need revision and homogenization. Furthermore, clear regulation and financial incentives remain essential to scale from niche polymers to large-scale bioplastic market applications with truly sustainable impact., Plastics support modern life but are also associated with environmental pollution. This Review discusses technologies for the production and recycling of bioplastics as part of a more sustainable and circular economy.

Gastrointestinal-based drug delivery is considered the preferred mode of drug administration owing to its convenience for patients, which improves adherence. However, unique characteristics of the gastrointestinal tract (such as the digestive environment and constraints on transport across the gastrointestinal mucosa) limit the absorption of drugs. As a result, many medications, in particular biologics, still exist only or predominantly in injectable form. In this Review, we examine the fundamentals of gastrointestinal drug delivery to inform clinicians and pharmaceutical scientists. We discuss general principles, including the challenges that need to be overcome for successful drug formulation, and describe the unique features to consider for each gastrointestinal compartment when designing drug formulations for topical and systemic applications. We then discuss emerging technologies that seek to address remaining obstacles to successful gastrointestinal-based drug delivery.

Glycemic control through titration of insulin dosing remains the mainstay of diabetes mellitus treatment. Insulin therapy is generally divided into dosing with long- and short-acting insulin, where long-acting insulin provides basal coverage and short-acting insulin supports glycemic excursions associated with eating. The dosing of short-acting insulin often involves several steps for the user including blood glucose measurement and integration of potential carbohydrate loads to inform safe and appropriate dosing. The significant burden placed on the user for blood glucose measurement and effective carbohydrate counting can manifest in substantial effects on adherence. Through the application of computer vision, we have developed a smartphone-based system that is able to detect the carbohydrate load of food by simply taking a single image of the food and converting that information into a required insulin dose by incorporating a blood glucose measurement. Moreover, we report the development of comprehensive all-in-one insulin delivery systems that streamline all operations that peripheral devices require for safe insulin administration, which in turn significantly reduces the complexity and time required for titration of insulin. The development of an autonomous system that supports maximum ease and accuracy of insulin dosing will transform our ability to more effectively support patients with diabetes.

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.

With over 40 clinical trials underway, we are nearing the first FDA approved live microbial therapeutic. Here, we discuss the significant challenges of reliably administering live microorganisms to patients and the opportunities for drug delivery of these new complex therapeutics., With >40 clinical trials underway, we are nearing the first FDA-approved live microbial therapeutic. Here, Giovanni Traverso, MIT and Harvard Medical School Assistant Professor, and colleagues Miguel Jimenez and Institute Professor Robert Langer from MIT discuss the significant challenges of administering live microorganisms to patients and the opportunities for drug delivery of these new complex therapeutics.

Intravesical instillation is an efficient drug delivery route for the local treatment of various urological conditions. Nevertheless, intravesical instillation is associated with several challenges, including pain, urological infection, and frequent clinic visits for catheterization; these difficulties support the need for a simple and easy intravesical drug delivery platform. Here, we propose a novel biodegradable intravesical device capable of long-term, local drug delivery without a retrieval procedure. The intravesical device is composed of drug encapsulating biodegradable polycaprolactone (PCL) microcapsules and connected by a bioabsorbable Polydioxanone (PDS) suture with NdFeB magnets in the end. The device is easily inserted into the bladder and forms a 'ring' shape optimized for maximal mechanical stability as informed by finite element analysis. In this study, inserted devices were retained in a swine model for 4 weeks. Using this device, we evaluated the system's capacity for delivery of lidocaine and resiquimod and demonstrated prolonged drug release. Moreover, a cost-effectiveness analysis supports device implementation compared to the standard of care. Our data support that this device can be a versatile drug delivery platform for urologic medications.

The evaluation of the tone and contractile patterns of the gastrointestinal (GI) tract via manometry is essential for the diagnosis of GI motility disorders. However, manometry is expensive and relies on complex and bulky instrumentation. Here we report the development and performance of an inexpensive and easy-to-manufacture catheter-like device for capturing manometric data across the dynamic range observed in the human GI tract. The device, which we designed to resemble the quipu-knotted strings used by Andean civilizations for the capture and transmission of information-consists of knotted piezoresistive pressure sensors made by infusing a liquid metal (eutectic gallium-indium) through thin silicone tubing. By exploring a range of knotting configurations, we identified optimal design schemes that led to sensing performances comparable to those of commercial devices for GI manometry, as we show for the sensing of GI motility in multiple anatomic sites of the GI tract of anaesthetized pigs. Disposable and customizable piezoresistive catheters may broaden the use of GI manometry in low-resource settings.