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.

Results of an Ocean Trial of the Symbiotic Machine for Ocean uRanium Extraction.

Amidoxime-based adsorbents have become highly promising for seawater uranium extraction. However, current deployment schemes are stand-alone, intermittent operation systems that have significant practical and economic challenges. This paper presents two 1:10 scale prototypes of a Symbiotic Machine for Ocean uRanium Extraction (SMORE) which pairs with an existing offshore structure. This pairing reduces mooring and deployment costs while enabling continuous, autonomous uranium extraction. Utilizing a shell enclosure to decouple the mechanical and chemical requirements of the adsorbent, one design concept prototyped continuously moves the shells through the water while the other keeps them stationary. Water flow in the shells on each prototype was determined using the measurement of radium adsorbed by MnO2 impregnated acrylic fibers contained within each enclosure. The results from a nine-week ocean trial show that while movement of the shells through the water may not have an effect on uranium adsorption by the fibers encased, it could help reduce biofouling if above a certain threshold speed (resulting in increased uptake), while also allowing for the incorporation of design elements to further mitigate biofouling such as bristle brushes and UV lamps. The trace metal uptake by the AI8 adsorbents in this trial also varied greatly from previous marine deployments, suggesting that uranium uptake may depend greatly upon the seawater concentrations of other elements such as vanadium and copper. The results from this study will be used to inform future work on the seawater uranium production cost from a full-scale SMORE system.

Centrifugal LabTube platform for fully automated DNA purification and LAMP amplification based on an integrated, low-cost heating system.

This paper introduces a disposable battery-driven heating system for loop-mediated isothermal DNA amplification (LAMP) inside a centrifugally-driven DNA purification platform (LabTube). We demonstrate LabTube-based fully automated DNA purification of as low as 100 cell-equivalents of verotoxin-producing Escherichia coli (VTEC) in water, milk and apple juice in a laboratory centrifuge, followed by integrated and automated LAMP amplification with a reduction of hands-on time from 45 to 1 min. The heating system consists of two parallel SMD thick film resistors and a NTC as heating and temperature sensing elements. They are driven by a 3 V battery and controlled by a microcontroller. The LAMP reagents are stored in the elution chamber and the amplification starts immediately after the eluate is purged into the chamber. The LabTube, including a microcontroller-based heating system, demonstrates contamination-free and automated sample-to-answer nucleic acid testing within a laboratory centrifuge. The heating system can be easily parallelized within one LabTube and it is deployable for a variety of heating and electrical applications.

A versatile-deployable bacterial detection system for food and environmental safety based on LabTube-automated DNA purification, LabReader-integrated amplification, readout and analysis.

Contamination of foods is a public health hazard that episodically causes thousands of deaths and sickens millions worldwide. To ensure food safety and quality, rapid, low-cost and easy-to-use detection methods are desirable. Here, the LabSystem is introduced for integrated, automated DNA purification, amplification and detection. It consists of a disposable, centrifugally driven DNA purification platform (LabTube) and a low-cost UV/vis-reader (LabReader). For demonstration of the LabSystem in the context of food safety, purification of Escherichia coli (non-pathogenic E. coli and pathogenic verotoxin-producing E. coli (VTEC)) in water and milk and the product-spoiler Alicyclobacillus acidoterrestris (A. acidoterrestris) in apple juice was integrated and optimized in the LabTube. Inside the LabReader, the purified DNA was amplified, readout and analyzed using both qualitative isothermal loop-mediated DNA amplification (LAMP) and quantitative real-time PCR. For the LAMP-LabSystem, the combined detection limits for purification and amplification of externally lysed VTEC and A. acidoterrestris are 10(2)-10(3) cell-equivalents. In the PCR-LabSystem for E. coli cells, the quantification limit is 10(2) cell-equivalents including LabTube-integrated lysis. The demonstrated LabSystem only requires a laboratory centrifuge (to operate the disposable, fully closed LabTube) and a low-cost LabReader for DNA amplification, readout and analysis. Compared with commercial DNA amplification devices, the LabReader improves sensitivity and specificity by the simultaneous readout of four wavelengths and the continuous readout during temperature cycling. The use of a detachable eluate tube as an interface affords semi-automation of the LabSystem, which does not require specialized training. It reduces the hands-on time from about 50 to 3 min with only two handling steps: sample input and transfer of the detachable detection tube.

Technical communication: design and in vitro testing of a pressure-sensing syringe for endotracheal tube cuffs.

Endotracheal intubation is a frequently performed procedure in the prehospital setting, intensive care unit, and for patients undergoing surgery. The endotracheal tube cuff must be inflated to a pressure that prevents air leaks without compromising tracheal mucosal blood flow. For simultaneous endotracheal tube cuff inflation and measurement, we designed and tested a novel pressure-sensing syringe in vitro. The prototype was developed using a standard 10-mL polycarbonate syringe body that houses a plunger and a silicone rubber bellows, the pressure-sensing element. Bellow feasibility was determined and modeled using finite element analysis. Repeatability testing at each pressure measurement for each bellows (pressure versus deflection) was within an average standard deviation of 0.3 cm to 1.61 cm (1%-5% error). Using an aneroid manometer for comparison, there was excellent linear correlation with a Spearman rank of 0.99 (P < 0.001), up to 30 cm H(2)O.

Design of a mechanical clutch-based needle-insertion device.

Insertion of trocars, needles, and catheters into unintended tissues or tissue compartments results in hundreds of thousands of complications annually. Current methods for blood vessel cannulation or epidural, chest tube, and initial trocar placement often involve the blind pass of a needle through several layers of tissue and generally rely on distinguishable anatomic landmarks and a high degree of clinical skill. To address this simply and without the use of electronics, a purely mechanical clutch system was developed for use in medical devices that access tissue and tissue compartments. This clutch utilizes the surface contact of a buckled filament inside an S-shaped tube to transmit force from the filament (catheter/guide wire) to the tube (needle). Upon encountering sufficient resistance at the tip, such as dense tissue, the catheter buckles and locks within the tube, causing the filament and needle to advance as one. When the needle reaches the target tissue or fluid-filled cavity, the filament unlocks and slides freely into the target region while the needle remains stationary. A similar locking phenomenon has long been observed in drill strings inside drill shafts used by the oil-drilling industry, and oil industry models were adapted to describe the motion of this clutch system. A predictive analytical model was generated and validated with empirical data and used to develop prototypes of a complete device then tested in vitro on muscle tissue and in vivo on a porcine laparoscopic model with promising results.

Investigation of abrasive saw kickback.

Saw kickback can cause fatal injuries, but only woodcutting saws have regulations and assessment methodologies for kickback. These regulations do not apply to abrasive cutting saws, as their cutting mechanism and dominant kickback mode differ from those of woodcutting saws. This work combines theoretical and experimental tools to investigate abrasive saw kickback. A theoretical model based on frictional engagement during a pinch-based kickback event is shown to predict resultant kickback energy in good agreement with experimental measurements. These measurements were obtained using a specialized machine that generates pinch-based kickback events and measures resultant kickback energy. Upon validating the model, two representative saws, a circular cutoff saw and a chainsaw, were tested using the prototype machine to evaluate their comparative kickback risk. This work demonstrates that pinch-based kickback is a potential safety risk for abrasive cutting saw operators and provides a testing machine design and analytical framework for evaluating this risk.

A Novel Approach to Open Reduction and Internal Fixation of Distal Radius Fractures Utilizing a Multi-Degree-of-Freedom Traction and Stabilization Device.

Open reduction and internal fixation (ORIF) is a surgical procedure performed with the objectives of restoring normal alignment and providing stability to broken bone fragments after a fracture. This procedure is increasingly used to treat fractures of the distal end of the radius. Reduction is achieved by the surgeon pulling and manipulating the hand while looking at real-time X-rays, and frequently requires large forces to distract impacted fragments from the proximal bone. This study presents the design and preliminary testing of a multi-degree-of-freedom (DOF) device capable of performing both distraction and reduction of fractured bone fragments using a traction splint mechanism with locking ball joints. A prototype was manufactured, and tests were conducted by a practicing hand surgeon. Both qualitative and quantitative tests using a phantom arm were performed. Quantitative force testing found an 80% reduction in the maximum force required to create needed traction, while qualitative tests with a hand surgeon found the device's ability to reduce and stabilize bone fragments while the hardware is secured to be more intuitive and less obstructive than existing techniques.

Effects of hydraulically disconnecting consumer pumps in an intermittent water supply.

We estimate 250 million people receive water using private pumps connected directly to intermittently pressurized distribution networks. Yet no previous studies have quantified the presumed effects of these pumps. In this paper, we investigate the effects of installing pressure-sustaining valves at consumer connections. These valves mimic pump disconnection by restricting flow. Installing these valves during the dry season at 94% of connections in an affluent neighborhood in Delhi, India, cut the prevalence of samples with turbidity > 4 NTU by two thirds. But considering the poor reputation of pumps, installed valves had surprisingly small average effects on turbidity (-8%; p<0.01) and free chlorine (+0.05 mg/L; p<0.001; N = 1,031). These effects were much smaller than the high variability in water quality supplied to both control and valve-installed neighborhoods. Site-specific responses to this variability could have confounded our results. At the study site, installed valves increased network pressure during 88% of the typical supply window; valves had a maximum pressure effect of +0.62 m (95% CI [0.54, 0.71]; a 40% increase vs. control). Further research is needed to generalize beyond our study site. Nevertheless, this paper provides unique evidence showing how the deployed valves mitigated pump effects, increased network pressure and improved water safety.

Device Prototype for Vaginal Delivery of Extremely Preterm Fetuses in the Breech Presentation.

Vaginal delivery is typically avoided in the extremely preterm breech population due to the concern of entrapment by the cervix of the aftercoming head. A mechanical device concept is presented to enable vaginal delivery by preventing retraction of the cervix against the fetus during delivery. The two-part device was designed to dilate the cervix, prevent prolapse of small fetal parts and maintain sufficient dilation during delivery. The two-part device was designed and manufactured with the following modules: an inflatable saline-filled cervical balloon for dilation and a cervical retractor composed of semirigid beams to stabilize the cervix and maintain adequate dilation. The device was tested using a cervical phantom designed to simulate the compressive force the cervix exerts. The cervical balloon reached a maximum dilation of 8.5 cm, after which there was leakage of saline from the balloon. While this dilation was less than the target goal of 10 cm, the leaking was attributed to prototype manufacturing defects, which could be resolved with further development. The cervical retractor was able to withstand between 1-3 kPa. Although estimates of cervical pressure values can be upward of 30 kPa, there are no in vivo measurements to formally identify the pressure values for patients in preterm labor. This device serves as a viable proof-of-concept for utilizing an inflatable balloon device to prevent cervical retraction in the setting of extremely preterm vaginal breech delivery. Further manufacturing improvements and design changes could improve the device for continued development and testing.

MIT Emergency-Vent: An Automated Resuscitator Bag for the COVID-19 Crisis.

MIT's Emergency-Vent Project was launched in March 2020 to develop safe guidance and a reference design for a bridge ventilator that could be rapidly produced in a distributed manner worldwide. The system uses a novel servo-based robotic gripper to automate the squeezing of a manual resuscitator bag evenly from both sides to provide ventilation according to clinically specified parameters. In just one month, the team designed and built prototype ventilators, tested them in a series of porcine trials, and collaborated with industry partners to enable mass production. We released the design, including mechanical drawings, design spreadsheets, circuit diagrams, and control code into an open source format and assisted production efforts worldwide.Clinical relevance- This work demonstrated the viability of automating the compression of a manual resuscitator bag, with pressure feedback, to provide bridge ventilation support.

Design and Applicability of a Mechanical Impedance Sensor for Vein Penetration Detection.

Intravenous needle insertion is typically conducted manually, with needles guided into vessels by feel while looking for a brief flash of blood. This process is imprecise and leads to mispositioned needles, multiple reinsertion attempts, increased procedure time and higher costs for the hospital. We present a method for indicating that the needle has reached the vein by measuring the change in mechanical impedance of the needle as it passes through different tissue layers. Testing in a phantom indicated that this has the potential to identify transitions through tissue boundaries.

A gastric resident drug delivery system for prolonged gram-level dosing of tuberculosis treatment.

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

Permittivity measurements using adjustable microscale electrode gaps between millimeter-sized spherical electrodes.

This paper presents a technique for measuring the electrical permittivity of liquids and gases using millimeter-sized spherical electrodes with adjustable microscale separation. This technique eliminates the need for wet calibration by using the precise adjustment of electrode separation to remove the inherent errors of parasitic capacitance and electrode polarization. The spherical electrode geometry also eliminates the need for precise parallel adjustment of electrode separation, and enables small-volume, small-electrode-gap measurements where the applied electric field is constrained in a region of well-defined geometry. By further leveraging the fact that spherical electrodes can be obtained with extremely high diametrical accuracy, absolute permittivity measurement accuracies within 1% of the established values has been demonstrated. Finally, the apparatus also enables the creation of nanometer electrode gaps between macroscopic electrodes with precisely controlled separation, which can be used to study the electrical properties of liquids in highly confined states. The electrode gaps created in this manner can be adjusted from 20 nm to 50 microm, in increments of 0.25 nm.

Analytical scaling relations to evaluate leakage and intrusion in intermittent water supply systems.

Intermittent water supplies (IWS) deliver piped water to one billion people; this water is often microbially contaminated. Contaminants that accumulate while IWS are depressurized are flushed into customers' homes when these systems become pressurized. In addition, during the steady-state phase of IWS, contaminants from higher-pressure sources (e.g., sewers) may continue to intrude where pipe pressure is low. To guide the operation and improvement of IWS, this paper proposes an analytic model relating supply pressure, supply duration, leakage, and the volume of intruded, potentially-contaminated, fluids present during flushing and steady-state. The proposed model suggests that increasing the supply duration may improve water quality during the flushing phase, but decrease the subsequent steady-state water quality. As such, regulators and academics should take more care in reporting if water quality samples are taken during flushing or steady-state operational conditions. Pipe leakage increases with increased supply pressure and/or duration. We propose using an equivalent orifice area (EOA) to quantify pipe quality. This provides a more stable metric for regulators and utilities tracking pipe repairs. Finally, we show that the volume of intruded fluid decreases in proportion to reductions in EOA. The proposed relationships are applied to self-reported performance indicators for IWS serving 108 million people described in the IBNET database and in the Benchmarking and Data Book of Water Utilities in India. This application shows that current high-pressure, continuous water supply targets will require extensive EOA reductions. For example, in order to achieve national targets, utilities in India will need to reduce their EOA by a median of at least 90%.

Suspended heated silicon platform for rapid thermal control of surface reactions with application to carbon nanotube synthesis.

Rapid continuous thermal control of chemical reactions such as those for chemical vapor deposition (CVD) growth of nanotubes and nanowires cannot be studied using traditional reactors such as tube furnaces, which have large thermal masses. We present the design, modeling, and verification of a simple, low-cost reactor based on resistive heating of a suspended silicon platform. This system achieves slew rates exceeding 100 degrees C/s, enabling studies of rapid heating and thermal cycling. Moreover, the reaction surface is available for optical monitoring. A first-generation CVD apparatus encapsulates the heated silicon platform inside a sealed quartz tube, and initial experiments demonstrate growth of films of tangled single-wall and aligned multiwall carbon nanotubes using this system. The reactor can be straightforwardly scaled to larger or smaller substrate sizes and may be extended for a wide variety of reactions, for performing in situ reaction diagnostics, for chip-scale growth of nanostructures, and for rapid thermal processing of microelectronic and micromechanical devices.

A New Phenomenon: Sub-Tg, Solid-State, Plasticity-Induced Bonding in Polymers.

Polymer self-adhesion due to the interdiffusion of macromolecules has been an active area of research for several decades. Here, we report a new phenomenon of sub-Tg, solid-state, plasticity-induced bonding; where amorphous polymeric films were bonded together in a period of time on the order of a second in the solid-state at ambient temperatures, up to 60 K below their glass transition temperature (Tg), by subjecting them to active plastic deformation. Despite the glassy regime, the bulk plastic deformation triggered the requisite molecular mobility of the polymer chains, causing interpenetration across the interfaces held in contact. Quantitative levels of adhesion and the morphologies of the fractured interfaces validated the sub-Tg, plasticity-induced, molecular mobilization causing bonding. No-bonding outcomes (i) during the uniaxial compressive straining of films (a near-hydrostatic setting which strongly limits plastic flow) and (ii) between an 'elastic' and a 'plastic' film further established the explicit role of plastic deformation in this newly reported sub-Tg solid-state bonding.

Low-profile self-sealing sample transfer flexure box.

A flexural bearing mechanism has enabled the development of a self-sealing box for protecting air sensitive samples during transfer between glove boxes, micro-machining equipment, and microscopy equipment. The simplicity and self-actuating feature of this design makes it applicable to many devices that operate under vacuum conditions. The models used to design the flexural mechanism are presented in detail. The device has been tested in a Zeiss Merlin GEMINI II scanning electron microscope with Li3PS4 samples, showing effective isolation from air and corrosion prevention.

Rapid growth and flow-mediated nucleation of millimeter-scale aligned carbon nanotube structures from a thin-film catalyst.

We discuss the rapid growth of films and lithographically templated microstructures of vertically aligned small-diameter multiwalled carbon nanotubes (VA-MWNTs), by atmospheric-pressure thermal chemical vapor deposition (CVD) of C2H4/H2/Ar on a Fe/Al2O3 catalyst film deposited by electron beam evaporation. The structures grow to 1 mm height in 15 min and reach close to 2 mm in 60 min. The growth rate and final height of CNT microstructures grown from catalyst patterns depend strongly on the local areal density of catalyst, representing a reverse analogue of loading effects which occur in plasma etching processes. Abrupt transitions between areas of micrometer-thick tangled CNT films and millimeter-scale aligned CNT structures are manipulated by changing the duration of pretreatment by H2/Ar prior to introduction of C2H4 and by changing the configuration of the substrate sample in the furnace tube. This demonstrates that the flow profile over the sample mediates the supply of reactants to the catalyst and that pretreatment using H2 significantly affects the initial activity of the catalyst.