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.

Double-Modal Locomotion of a Hydrogel Ultra-Soft Magnetic Miniature Robot with Switchable Forms.

Flexible miniature robots are expected to enter difficult-to-reach areas in vivo to carry out targeted operations, attracting widespread attention. However, it is challenging for the existing soft miniature robots to substantially alter their stable shape once the structure is designed. This limitation leads to a fixed motion mode, which subsequently restricts their operating environment. In this study, we designed a biocompatible flexible miniature robot with a variable stable form that is capable of adapting to complex terrain environments through multiple movement modes. Inspired by the reversible stretching reaction of alginate saline gel stimulated by changes in environmental ion concentration, we manufactured a morphologically changeable super-soft hydrogel miniature robot body. According to the stretch and contraction shapes of the flexible hydrogel miniature robot, we designed magnetic fields for swing and rolling motion modes to realize multi-shape movement. The experimental results demonstrate that the deflection angle of the designed flexible miniature robot is reversible and can reach a maximum of 180°. The flexible miniature robot can complete forward swinging in the bar stretch state and tumbling motion in the spherical state. We anticipate that flexible hydrogel miniature robots with multiple morphologies and multimodal motion have great potential for biomedical applications in complex, unstructured, and enclosed living environments.

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.

Encapsulation of Gas Sensors to Operate in the Gastrointestinal Tract for Continuous Monitoring.

Recent advances in ingestible sensors have enabled in situ detection of gastrointestinal (GI) biomarkers which shows great potential in shifting the paradigm of diagnosing GI and systemic diseases. However, the humid, acidic gastric environment is extremely harsh to electrically powered sensors, which limits their capacity for long term, continuous monitoring. Here, we propose an encapsulation approach for a gas sensor integrated into a nasogastric (NG) tube that overcomes chemical corrosion, electrical short, and mechanical collision in a gastric environment to enable continuous gaseous biomarkers monitoring. The coating effects on the sensitivity, signal latency, and repeatability are investigated. Our long-term continuous monitoring in vitro results show that the proposed coating method enables the gas sensors to function reliably and consistently in the simulated GI environment for more than 1 week. The encapsulation is composed of Polycaprolactone (PCL) to protect against mechanical scratching and Parylene C to prevent a sensor from chemical corrosion and electrical short. The average life-time of the sensor with 10 micrometers Parylene coating is about 3.6 days. Increasing the coating thickness to 20 micrometers results in 10.0 days. In terms of repeatability, 10 micrometers and 20 micrometers Parylene C coated sensors have a standard deviation of 1.30% and 2.10% for its within sensor response, and 5.19% and 3.06% between sensors respectively.

Cost-Effective Solution of Remote Photoplethysmography Capable of Real-Time, Multi-Subject Monitoring with Social Distancing.

Recent advances in remote-photoplethysmography (rPPG) have enabled the measurement of heart rate (HR), oxygen saturation (SpO2), and blood pressure (BP) in a fully contactless manner. These techniques are increasingly applied clinically given a desire to minimize exposure to individuals with infectious symptoms. However, accurate rPPG estimation often leads to heavy loading in computation that either limits its real-time capacity or results in a costly setup. Additionally, acquiring rPPG while maintaining protective distance would require high resolution cameras to ensure adequate pixels coverage for the region of interest, increasing computational burden. Here, we propose a cost-effective platform capable of the real-time, continuous, multi-subject monitoring while maintaining social distancing. The platform is composed of a centralized computing unit and multiple low-cost wireless cameras. We demonstrate that the central computing unit is able to simultaneously handle continuous rPPG monitoring of five subjects with social distancing without compromising the frame rate and rPPG accuracy.

In Situ Detection of Gastrointestinal Inflammatory Biomarkers Using Electrochemical Gas Sensors.

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.

Mobile Robotic Platform for Contactless Vital Sign Monitoring.

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.

Ingestible electronic sensors to measure instantaneous medication adherence: A narrative review.

OBJECTIVE: Medication nonadherence contributes to significant morbidity and mortality worldwide. While many techniques to measure adherence exist, digital pill systems represent a novel, direct method of measuring adherence and a means of providing instantaneous adherence supports. In this narrative review, we discuss digital pill system research based on clinical trials and qualitative investigations conducted to date and potential future applications of digital pill system in medication adherence measurement. METHODS: We conducted a literature search in PubMed of English language peer-reviewed articles describing the use of digital pill system for medication adherence measurement between 2000 and 2021. We included all articles that described the deployment of ingestible sensors and those involving qualitative investigations of digital pill system with human subjects. RESULTS: A total of 95 articles were found on initial search; 75 were removed based on exclusion criteria. Included articles were categorized as investigations that deployed an ingestible sensor in human populations (n = 18), or those that conducted qualitative work (n = 3). For pilot studies, the mean accuracy of the sensor to successfully detect a medication ingestion event ranged from 68% to 100%. When digital pill systems were deployed in real-world clinical settings, accuracy ranged from 68% to 90% with lower accuracy due to nonadherence to digital pill system technology. Qualitative studies demonstrated that providers and patients perceive the digital pill system as a facilitator for improving adherence and as a potential platform for delivering adherence interventions. Additionally, ingestion data from digital pill system was viewed as useful in facilitating adherence discussions between clinicians and patients. CONCLUSIONS: This narrative review demonstrates that the use of digital pill system is broadly feasible across multiple disease states including human immunodeficiency virus, hepatitis C infection, solid organ transplants, tuberculosis, schizophrenia, cardiovascular disease, and acute fractures, where adherence is closely linked to significant morbidity and mortality. It also highlights key areas of research that are still needed prior to broad-scale clinical deployment of such systems.

An automated all-in-one system for carbohydrate tracking, glucose monitoring, and insulin 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.

Acceptance of a computer vision facilitated protocol to measure adherence to face mask use: a single-site, observational cohort study among hospital staff.

OBJECTIVES: Mask 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. DESIGN: Single-site, observational cohort study. SETTING: An urban, academic hospital in Boston, Massachusetts, USA. PARTICIPANTS: We enrolled adult hospital staff entering the hospital at a key ingress point. INTERVENTIONS: Consenting 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 MEASURES: Primary 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. RESULTS: One 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.

Powering Implantable and Ingestible Electronics.

Implantable and ingestible biomedical electronic devices can be useful tools for detecting physiological and pathophysiological signals, and providing treatments that cannot be done externally. However, one major challenge in the development of these devices is the limited lifetime of their power sources. The state-of-the-art of powering technologies for implantable and ingestible electronics is reviewed here. The structure and power requirements of implantable and ingestible biomedical electronics are described to guide the development of powering technologies. These powering technologies include novel batteries that can be used as both power sources and for energy storage, devices that can harvest energy from the human body, and devices that can receive and operate with energy transferred from exogenous sources. Furthermore, potential sources of mechanical, chemical, and electromagnetic energy present around common target locations of implantable and ingestible electronics are thoroughly analyzed; energy harvesting and transfer methods befitting each energy source are also discussed. Developing power sources that are safe, compact, and have high volumetric energy densities is essential for realizing long-term in-body biomedical electronics and for enabling a new era of personalized healthcare.

Implantable system for chronotherapy.

Diurnal variation in enzymes, hormones, and other biological mediators has long been recognized in mammalian physiology. Developments in pharmacobiology over the past few decades have shown that timing drug delivery can enhance drug efficacy. Here, we report the development of a battery-free, refillable, subcutaneous, and trocar-compatible implantable system that facilitates chronotherapy by enabling tight control over the timing of drug administration in response to external mechanical actuation. The external wearable system is coupled to a mobile app to facilitate control over dosing time. Using this system, we show the efficacy of bromocriptine on glycemic control in a diabetic rat model. We also demonstrate that antihypertensives can be delivered through this device, which could have clinical applications given the recognized diurnal variation of hypertension-related complications. We anticipate that implants capable of chronotherapy will have a substantial impact on our capacity to enhance treatment effectiveness for a broad range of chronic conditions.

Dynamic Monitoring of Systemic Biomarkers with Gastric Sensors.

Continuous monitoring in the intensive care setting has transformed the capacity to rapidly respond with interventions for patients in extremis. Noninvasive monitoring has generally been limited to transdermal or intravascular systems coupled to transducers including oxygen saturation or pressure. Here it is hypothesized that gastric fluid (GF) and gases, accessible through nasogastric (NG) tubes, commonly found in intensive care settings, can provide continuous access to a broad range of biomarkers. A broad characterization of biomarkers in swine GF coupled to time-matched serum is conducted . The relationship and kinetics of GF-derived analyte level dynamics is established by correlating these to serum levels in an acute renal failure and an inducible stress model performed in swine. The ability to monitor ketone levels and an inhaled anaesthetic agent (isoflurane) in vivo is demonstrated with novel NG-compatible sensor systems in swine. Gastric access remains a main stay in the care of the critically ill patient, and here the potential is established to harness this establishes route for analyte evaluation for clinical management.

Devices for drug delivery in the gastrointestinal tract: A review of systems physically interacting with the mucosa for enhanced delivery.

The delivery of macromolecules via the gastrointestinal (GI) tract remains a significant challenge. A variety of technologies using physical modes of drug delivery have been developed and investigated to overcome the epithelial cell layer of the GI tract for local and systemic delivery. These technologies include direct injection, jetting, ultrasound, and iontophoresis, which have been largely adapted from transdermal drug delivery. Direct injection of agents using needles through endoscopy has been used clinically for over a century. Jetting, a needle-less method of drug delivery where a high-speed stream of fluid medication penetrates tissue, has been evaluated pre-clinically for delivery of agents into the buccal mucosa. Ultrasound has been shown to be beneficial in enhancing delivery of macromolecules, including nucleic acids, in pre-clinical animal models. The application of an electric field gradient to drive drugs into tissues through the technique of iontophoresis has been shown to deliver highly toxic chemotherapies into GI tissues. Here in, we provide an in-depth overview of these physical modes of drug delivery in the GI tract and their clinical and preclinical uses.

Assessment of the Acceptability and Feasibility of Using Mobile Robotic Systems for Patient Evaluation.

Importance: Before the widespread implementation of robotic systems to provide patient care during the COVID-19 pandemic occurs, it is important to understand the acceptability of these systems among patients and the economic consequences associated with the adoption of robotics in health care settings. Objective: To assess the acceptability and feasibility of using a mobile robotic system to facilitate health care tasks. Design, Setting, and Participants: This study included 2 components: a national survey to examine the acceptability of using robotic systems to perform health care tasks in a hospital setting and a single-site cohort study of patient experiences and satisfaction with the use of a mobile robotic system to facilitate triage and telehealth tasks in the emergency department (ED). The national survey comprised individuals living in the US who participated in a sampling-based survey via an online analytic platform. Participants completed the national survey between August 18 and August 21, 2020. The single-site cohort study included patients living in the US who presented to the ED of a large urban academic hospital providing quaternary care in Boston, Massachusetts between April and August 2020. All data were analyzed from August to October 2020. Exposures: Participants in the national survey completed an online survey to measure the acceptability of using a mobile robotic system to perform health care tasks (facilitating telehealth interviews, acquiring vital signs, obtaining nasal or oral swabs, placing an intravenous catheter, performing phlebotomy, and turning a patient in bed) in a hospital setting in the contexts of general interaction and interaction during the COVID-19 pandemic. Patients in the cohort study were exposed to a mobile robotic system, which was controlled by an ED clinician and used to facilitate a triage interview. After exposure, patients completed an assessment to measure their satisfaction with the robotic system. Main Outcomes and Measures: Acceptability of the use of a mobile robotic system to facilitate health care tasks in a hospital setting (national survey) and feasibility and patient satisfaction regarding the use of a mobile robotic system in the ED (cohort study). Results: For the national survey, 1154 participants completed all acceptability questions, representing a participation rate of 35%. After sample matching, a nationally representative sample of 1000 participants (mean [SD] age, 48.7 [17.0] years; 535 women [53.5%]) was included in the analysis. With regard to the usefulness of a robotic system to perform specific health care tasks, the response of "somewhat useful" was selected by 373 participants (37.3%) for facilitating telehealth interviews, 350 participants (35.0%) for acquiring vital signs, 307 participants (30.7%) for obtaining nasal or oral swabs, 228 participants (22.8%) for placing an intravenous catheter, 249 participants (24.9%) for performing phlebotomy, and 371 participants (37.1%) for turning a patient in bed. The response of "extremely useful" was selected by 287 participants (28.7%) for facilitating telehealth interviews, 413 participants (41.3%) for acquiring vital signs, 192 participants (19.2%) for obtaining nasal or oral swabs, 159 participants (15.9%) for placing an intravenous catheter, 167 participants (16.7%) for performing phlebotomy, and 371 participants (37.1%) for turning a patient in bed. In the context of the COVID-19 pandemic, the median number of individuals who perceived the application of robotic systems to be acceptable for completing telehealth interviews, obtaining nasal and oral swabs, placing an intravenous catheter, and performing phlebotomy increased. For the ED cohort study, 51 individuals were invited to participate, and 41 participants (80.4%) enrolled. One participant was unable to complete the study procedures because of a signaling malfunction in the robotic system. Forty patients (mean [SD] age, 45.8 [2.7] years; 29 women [72.5%]) completed the mobile robotic system-facilitated triage interview, and 37 patients (92.5%) reported that the interaction was satisfactory. A total of 33 participants (82.5%) reported that their experience of receiving an interview facilitated by a mobile robotic system was as satisfactory as receiving an in-person interview from a clinician. Conclusions and Relevance: In this study, a mobile robotic system was perceived to be acceptable for use in a broad set of health care tasks among survey respondents across the US. The use of a mobile robotic system enabled the facilitation of contactless triage interviews of patients in the ED and was considered acceptable among participants. Most patients in the ED rated the quality of mobile robotic system-facilitated interaction to be equivalent to in-person interaction with a clinician.

Prospective Evaluation of the Transparent, Elastomeric, Adaptable, Long-Lasting (TEAL) Respirator.

N95 filtering facepiece respirators (FFR) and surgical masks are essential in reducing airborne disease transmission, particularly during the COVID-19 pandemic. However, currently available FFR's and masks have major limitations, including masking facial features, waste, and integrity after decontamination. In a multi-institutional trial, we evaluated a transparent, elastomeric, adaptable, long-lasting (TEAL) respirator to evaluate success of qualitative fit test with user experience and biometric evaluation of temperature, respiratory rate, and fit of respirator using a novel sensor. There was a 100% successful fit test among participants, with feedback demonstrating excellent or good fit (90% of participants), breathability (77.5%), and filter exchange (95%). Biometric testing demonstrated significant differences between exhalation and inhalation pressures among a poorly fitting respirator, well-fitting respirator, and the occlusion of one filter of the respirator. We have designed and evaluated a transparent elastomeric respirator and a novel biometric feedback system that could be implemented in the hospital setting.

Gastrointestinal synthetic epithelial linings.

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 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.

Injection Molded Autoclavable, Scalable, Conformable (iMASC) system for aerosol-based protection: a prospective single-arm feasibility study.

OBJECTIVE: To develop and test a new reusable, sterilisable N95 filtering facepiece respirator (FFR)-comparable face mask, known as the Injection Molded Autoclavable, Scalable, Conformable (iMASC) system, given the dire need for personal protective equipment within healthcare settings during the COVID-19 pandemic. DESIGN: Single-arm feasibility study. SETTING: Emergency department and outpatient oncology clinic. PARTICIPANTS: Healthcare workers who have previously undergone N95 fit testing. INTERVENTIONS: Fit testing of new iMASC system. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome is success of fit testing using an Occupational Safety and Health Administration (OSHA)-approved testing method, and secondary outcomes are user experience with fit, breathability and filter replacement. RESULTS: Twenty-four subjects were recruited to undergo fit testing, and the average age of subjects was 41 years (range of 21-65 years) with an average body mass index of 26.5 kg/m2. The breakdown of participants by profession was 46% nurses (n=11), 21% attending physicians (n=5), 21% resident physicians (n=5) and 12% technicians (n=3). Of these participants, four did not perform the fit testing due to the inability to detect saccharin solution on premask placement sensitivity test, lack of time and inability to place mask over hair. All participants (n=20) who performed the fit test were successfully fitted for the iMASC system using an OSHA-approved testing method. User experience with the iMASC system, as evaluated using a Likert scale with a score of 1 indicating excellent and a score of 5 indicating very poor, demonstrated an average fit score of 1.75, breathability of 1.6, and ease of replacing the filter on the mask was scored on average as 2.05. CONCLUSIONS: The iMASC system was shown to successfully fit multiple different face sizes and shapes using an OSHA-approved testing method. These data support further certification testing needed for use in the healthcare setting.

Controlled Delivery of Bile Acids to the Colon.

INTRODUCTION: Bile acids, such as chenodeoxycholic acid, play an important role in digestion but are also involved in intestinal motility, fluid homeostasis, and humoral activity. Colonic delivery of sodium chenodeoxycholate (CDC) has demonstrated clinical efficacy in treating irritable bowel syndrome with constipation but was associated with a high frequency of abdominal pain. We hypothesized that these adverse effects were triggered by local super-physiological CDC levels caused by an unfavorable pharmacokinetic profile of the delayed release formulation. METHODS: We developed novel release matrix systems based on hydroxypropyl methylcellulose (HPMC) for sustained release of CDC. These included standard HPMC formulations as well as bi-layered formulations to account for potential delivery failures due to low colonic fluid in constipated patients. We evaluated CDC release profiles in silico (pharmacokinetic modeling), in vitro and in vivo in swine (pharmacokinetics, rectal manometry). RESULTS: For the delayed release formulation in vitro release studies demonstrated pH triggered dose dumping which was associated with giant colonic contractions in vivo. Release from the bi-layered HPMC systems provided controlled release of CDC while minimizing the frequency of giant contractions and providing enhanced exposure as compared to standard HPMC formulations in vivo. DISCUSSION: Bi-phasic CDC release could help treat constipation while mitigating abdominal pain observed in previous clinical trials. Further studies are necessary to demonstrate the therapeutic potential of these systems in humans.

High-Resolution SPECT Imaging of Stimuli-Responsive Soft Microrobots.

Untethered small-scale robots have great potential for biomedical applications. However, critical barriers to effective translation of these miniaturized machines into clinical practice exist. High resolution tracking and imaging in vivo is one of the barriers that limit the use of micro- and nanorobots in clinical applications. Here, the inclusion of radioactive compounds in soft thermoresponsive magnetic microrobots is investigated to enable their single-photon emission computed tomography imaging. Four microrobotic platforms differing in hydrogel structure and four 99m Tc[Tc]-based radioactive compounds are investigated in order to achieve optimal contrast agent retention and optimal imaging. Single microrobot imaging of structures as low as 100 µm in diameter, as well as tracking of shape switching from tubular to planar configurations by inclusion of 99m Tc[Tc] colloid in the hydrogel structure, is reported.