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This article discusses a new device that has been developed to improve the assessment of pancreatic cystic lesions (PCLs) during endoscopic ultrasound (EUS). The device, called a through-the-needle loop, was tested in an animal randomized controlled trial using artificial cysts. The results showed that the device was safe and had a higher cell yield compared to the standard procedure. The authors suggest that further clinical studies are needed to validate these findings. [Extracted from the article]

This article reports a broad-band optical shutter based on microdroplet actuation with zero optical insertion loss in the open state. These features are achieved by electrowetting-on-dielectric (EWOD) actuation of opaque ionic liquid microdroplets. The negligible vapor pressure of ionic liquids allows the device to robustly operate in open air, unlike previously proposed EWOD-based systems in which the light crosses several attenuating and reflective layers, preventing broad-band operation and creating insertion losses > 14%. The presented device provides an attenuation of 78 dB in the closed state and a transmission of >99.99999% in the open state and can operate in the visible and mid-infrared wavelength range. Moreover, the switch can sustain larger incoming laser powers (5 mW continuous exposure or up to 3 h of continuous exposure at ∼100 mW) compared to the values reported for other state-of-the-art EWOD-based shutters. Additionally, the proposed device is compact, operates with low voltage (<25 V peak voltage), and features zero static power consumption. [ABSTRACT FROM AUTHOR]

Adhesion energies are determined for three different polymers currently used in adhesive wafer bonding of silicon wafers. The adhesion energies of the polymer off-stoichiometry thiol-ene-epoxy OSTE+ and the nano-imprint resist mr-I 9150XP are determined. The results are compared to the adhesion energies of wafers bonded with benzocyclobutene, both with and without adhesion promoter. The adhesion energies of the bonds are studied by blister tests, consisting of delaminating silicon lids bonded to silicon dies with etched circular cavities, using compressed nitrogen gas. The critical pressure needed for delamination is converted into an estimate of the bond adhesion energy. The fabrication of test dies and the evaluation method are described in detail. The mean bond energies of OSTE+ were determined to be 2.1 and 20 J m-2 depending on the choice of the epoxy used. A mean bond energy of 1.5 J m-2 was measured for mr-I 9150XP. [ABSTRACT FROM AUTHOR]

Automatic wire bonding is a highly mature, cost-efficient and broadly available back-end process, intended to create electrical interconnections in semiconductor chip packaging. Modern production wire-bonding tools can bond wires with speeds of up to 30 bonds per second with placement accuracies of better than 2 μm, and the ability to form each wire individually into a desired shape. These features render wire bonding a versatile tool also for integrating wires in applications other than electrical interconnections. Wire bonding has been adapted and used to implement a variety of innovative microstructures. This paper reviews unconventional uses and applications of wire bonding that have been reported in the literature. The used wire-bonding techniques and materials are discussed, and the implemented applications are presented. They include the realization and integration of coils, transformers, inductors, antennas, electrodes, through silicon vias, plugs, liquid and vacuum seals, plastic fibers, shape memory alloy actuators, energy harvesters and sensors. [ABSTRACT FROM AUTHOR]

This paper reports on the realization of 17 μm × 17 μm pitch bolometer arrays for uncooled infrared imagers. Microbolometer arrays have been available in primarily defense applications since the mid-1980s and are typically based on deposited thin films on top of CMOS wafers that are surface-machined into sensor pixels. This paper instead focuses on the heterogeneous integration of monocrystalline Si/SiGe quantum-well-based thermistor material in a CMOS-compliant process using adhesive wafer bonding. The high-quality monocrystalline thermistor material opens up for potentially lower noise compared to commercially available uncooled microbolometer arrays together with a competitive temperature coefficient of resistance (TCR). Characterized bolometers had a TCR of -2.9% K-1 in vacuum, measured thermal conductances around 5 × 10-8 WK-1 and thermal time constants between 4.9 and 8.5 ms, depending on the design. Complications in the fabrication of stress-free bolometer legs and low-noise contacts are discussed and analyzed. [ABSTRACT FROM AUTHOR]

Through-silicon via (TSV) technology enables 3D-integrated devices with higher performance and lower cost as compared to 2D-integrated systems. This is mainly due to smaller dimensions of the package and shorter internal signal lengths with lower capacitive, resistive and inductive parasitics. This paper presents a novel low-cost fabrication technique for metal-filled TSVs with very high aspect ratios (>20). Nickel wires are placed in via holes of a silicon wafer by an automated magnetic assembly process and are used as a conductive path of the TSV. This metal filling technique enables the reliable fabrication of through-wafer vias with very high aspect ratios and potentially eliminates characteristic cost drivers in the TSV production such as advanced metallization processes, wafer thinning and general issues associated with thin-wafer handling. [ABSTRACT FROM AUTHOR]

Competing Interests: Supported by grants from the Swedish Research Council; the 10.13039/501100004359Swedish Research Council for 10.13039/100018696Health, Working Life, and Welfare; Formas; the Swedish Asthma and Allergy Research Foundation; the Swedish Heart-Lung Foundation; and Region Stockholm (the ALF project, and for cohort and database maintenance). Disclosure of potential conflict of interest: E. Melén reports personal fees from 10.13039/100004325AstraZeneca, Chiesi, Sanofi, and Novartis outside the submitted work. The rest of the authors declare that they have no relevant conflicts of interest.

Background: Self-sampling of dried blood spots (DBS) offers new routes to gather valuable health-related information from the general population. Yet, the utility of using deep proteome profiling from home-sampled DBS to obtain clinically relevant insights about SARS-CoV-2 infections remains largely unexplored., Methods: Our study involved 228 individuals from the general Swedish population who used a volumetric DBS sampling device and completed questionnaires at home during spring 2020 and summer 2021. Using multi-analyte COVID-19 serology, we stratified the donors by their response phenotypes, divided them into three study sets, and analyzed 276 proteins by proximity extension assays (PEA). After normalizing the data to account for variances in layman-collected samples, we investigated the association of DBS proteomes with serology and self-reported information., Results: Our three studies display highly consistent variance of protein levels and share associations of proteins with sex (e.g., MMP3) and age (e.g., GDF-15). Studying seropositive (IgG + ) and seronegative (IgG - ) donors from the first pandemic wave reveals a network of proteins reflecting immunity, inflammation, coagulation, and stress response. A comparison of the early-infection phase (IgM + IgG - ) with the post-infection phase (IgM - IgG + ) indicates several proteins from the respiratory system. In DBS from the later pandemic wave, we find that levels of a virus receptor on B-cells differ between seropositive (IgG + ) and seronegative (IgG - ) donors., Conclusions: Proteome analysis of volumetric self-sampled DBS facilitates precise analysis of clinically relevant proteins, including those secreted into the circulation or found on blood cells, augmenting previous COVID-19 reports with clinical blood collections. Our population surveys support the usefulness of DBS, underscoring the role of timing the sample collection to complement clinical and precision health monitoring initiatives., (© 2024. The Author(s).)

Background: Asthma was initially described as a risk factor for severe coronavirus disease 2019 (COVID-19), but the uptake of COVID-19 vaccine among young adults with asthma is not well studied., Objective: The aims were to assess COVID-19 vaccine uptake among young adults in general and to explore potential determinants including sociodemographic factors and asthma., Methods: Participants from the population-based birth cohort BAMSE (Barn/Child, Allergy, Milieu, Stockholm, Epidemiology) were included: 4,064 in the study population, 3,064 in a follow-up at age 24 years, and 2,049 in a COVID-19 follow-up (mean age, 26.5 years). Asthma and asthma-associated characteristics were assessed through questionnaires and clinical data. Data on all COVID-19 vaccines registered between January 1, 2021, and February 15, 2023, were extracted from the National Vaccination Register., Results: In the study population (n = 4,064), 53.9% had ≥3 COVID-19 vaccine doses registered. In the 24-year follow-up population (n = 3,064), vaccine uptake differed in relation to education ( P  < .001). Among the participants with university/college education, 65.7% had an uptake of ≥3 doses of vaccine, compared to 54.1% among the participants with elementary school/high school education. Participants with asthma had decreased odds of receiving ≥3 doses (adjusted odds ratio = 0.62; 95% confidence interval, 0.41-0.92) and ≥2 compared to peers without asthma. Those with uncontrolled disease also had decreased odds of receiving ≥3 doses (adjusted odds ratio = 0.30; 95% confidence interval, 0.13-0.66) and ≥2 compared to participants with controlled asthma., Conclusions: COVID-19 vaccine uptake among young adults is lower in individuals from households with lower socioeconomic status and among those with asthma, including uncontrolled asthma., Competing Interests: Supported by grants from the 10.13039/501100004359Swedish Research Council, the 10.13039/501100006636Swedish Research Council for Health, Working Life and Welfare, 10.13039/501100001862Formas, Swedish Asthma and Allergy Research Foundation, the Swedish Heart–Lung Foundation, and Region Stockholm (ALF project, and for cohort and database maintenance). Disclosure of potential conflict of interest: E. Melén reports personal fees from AstraZeneca, Chiesi, Sanofi, and Novartis outside the submitted work. The rest of the authors declare that they have no relevant conflicts of interest., (© 2024 The Authors.)

Cytobrushes are used for low-invasive sample collection and screening in multiple diseases, with a significant impact on early detection, prevention, and diagnosis. This study focuses on improving the safety of cell brushing in hard-to-reach locations by exploring brush construction from absorbable materials. We investigated the efficacy of loop brushes made of absorbable suture wires of Chirlac, Chirasorb, Monocryl, PDS II, Vicryl Rapid, Glycolon, and Catgut during their operation in conjunction with fine-needle aspiration in an artificial cyst model. PDS II brushes demonstrated the highest efficiency, while Monocryl and Catgut also provided a significant brushing effect. Efficient brushes portrayed higher flexural rigidity than their counterparts, and their efficiency was inversely proportional to their plastic deformation by the needle. Our results open avenues for safer cell biopsies in hard-to-reach locations by utilizing brushes composed of absorbable materials., (© 2023. The Author(s).)

Blood sampling is a common practice to monitor health, but it entails a series of drawbacks for patients including pain and discomfort. Thus, there is a demand for more convenient ways to obtain samples. Modern analytical techniques enable monitoring of multiple bioanalytes in smaller samples, opening possibilities for new matrices, and microsampling technologies to be adopted. Interstitial fluid (ISF) is an attractive alternative matrix that shows good correlation with plasma concentration dynamics for several analytes and can be sampled in a minimally invasive and painless manner from the skin at the point-of-care. However, there is currently a lack of sampling devices compatible with clinical translation. Here, to tackle state-of-the-art limitations, a cost-effective and compact single-microneedle-based device designed to painlessly collect precisely 1.1 µL of dermal ISF within minutes is presented. The fluid is volume-metered, dried, and stably stored into analytical-grade paper within the microfluidic device. The obtained sample can be mailed to a laboratory, quantitatively analyzed, and provide molecular insights comparable to blood testing. In a human study, the possibility to monitor various classes of molecular analytes is demonstrated in ISF microsamples, including caffeine, hundreds of proteins, and SARS-CoV-2 antibodies, some being detected in ISF for the first time., (© 2023 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.)

Background: Lithium is a cornerstone in the treatment of bipolar disorder and is considered one of the most effective treatments in psychiatry at large. Lithium treatment requires individual dosing with frequent serum concentration measurements due to the narrow therapeutic window and risk of toxicity. There is need for patient-centric methods for lithium monitoring and the use of dried blood spots has recently been proposed for determination of lithium concentration. The purpose of the current study was to assess feasibility of this method by introducing a volumetric technique developed for home-sampling., Materials and Methods: Laboratory: Capillary blood was sampled by finger-prick using a volumetric device that collects 10 µL volumes as a dried blood spot. Lithium was measured in the dried blood spots using a validated atomic absorption spectroscopy method., Clinical: Thirty-nine lithium-treated patients were recruited, and dried blood spots and venous blood samples were collected. Routine serum analysis was performed for comparison., Results: The range of serum lithium concentrations was 0.41-1.22 mmol/L, and the dried blood spot/serum ratio was 0.78. A strong linear correlation between the two specimens was shown with Pearson's R = 0.95 (r 2 = 0.90). Adding hematocrit as a variable only minimally improved prediction., Conclusion: Volumetric dried blood spots is a promising technique for measurement of lithium concentrations. This will enable home-sampling and could potentially save resources, improve compliance, and make treatment safer. This may facilitate the use of lithium treatment in regions where monitoring via venous blood sampling remains difficult. However, the usability of dried blood spots for monitoring lithium treatment longitudinally remains to be examined., Competing Interests: Declaration of Competing Interest NR and OB are co-founders of Capitainer AB, a company commercializing Capitainer qDBS microsampling cards. All other authors declare no conflicts of interests., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Patient-centric sampling strategies, where the patient performs self-sampling and ships the sample to a centralized laboratory for readout, are on the verge of widespread adaptation. However, the key to a successful patient-centric workflow is user-friendliness, with few noncritical user interactions, and simple, ideally biohazard-free shipment. Here, we present a capillary-driven microfluidic device designed to perform the critical biomarker capturing step of a multiplexed immunoassay at the time of sample collection. On-chip sample drying enables biohazard-free shipment and allows us to make use of advanced analytics of specialized laboratories that offer the needed analytical sensitivity, reliability, and affordability. Using C-Reactive Protein, MCP1, S100B, IGFBP1, and IL6 as model blood biomarkers, we demonstrate the multiplexing capability and applicability of the device to a patient-centric workflow. The presented quantification of a biomarker panel opens up new possibilities for e-doctor and e-health applications.

Rapid on-site evaluation (ROSE) increases the diagnostic accuracy of fine-needle aspiration (FNA) samples from cysts, a sack-like fluid-containing tissue that sometimes can be precancerous, but is highly dependent on the skills and availability of cytopathologists. We present a semiautomated sample preparation device for ROSE. The device consists of a smearing tool and a capillary-driven chamber that allow smearing and staining of an FNA sample in a single platform. Here, we show the capability of the device to prepare samples for ROSE, using a human pancreatic cancer cell line (PANC-1) and liver, lymph node, and thyroid FNA model samples. Using microfluidics, the device reduces the equipment needed in an operating room for FNA sample preparation, which may lead to a wider implementation of ROSE in healthcare centers., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Pulmonary drug delivery by portable inhalers is the gold standard in lung disease therapy. An increasing focus on environmentally friendly inhalation currently spurs the development of propellant-free devices. However, the absence of propellants in the drug creates a need for suitable sealing systems that can ensure the pathogenic safety of devices. Traditionally, liquid drug inhalers incorporate a spray nozzle and a separate check valve. Here we show a fully integrated MEMS-based spray system for aqueous drug solutions and demonstrate its bacterial safety. The device comprises a thin silicon membrane with spray orifices, which self-seal against a compliant parylene valve seat underneath. This sealing system prevents bacterial ingrowth in its default closed state, while actuation lifts the membrane from the valve seat upon pressurization and sprays an inhalable aerosol from the nozzles. To seal against bacterial contamination effectively, we found that a contact force between the valve seat and the membrane (featuring the spray nozzles) is needed. In our testing, both self-sealing and an otherwise identical unvalved version of the spray chip can be bacterially safe in continued use when thoroughly cleaned of excess fluids and subjected to low bacterial loads for brief periods. However, when directly exposed to [Formula: see text] CFU/ml of our test organism Citrobacter rodentium for 24 h, unvalved systems become contaminated in nearly 90% of cases. In contrast, self-sealing spray chips reduced contamination probability by 70%. This development may enable preservative-free drug formulations in portable inhalers that use propellant-free aqueous drug solutions., (© 2022. The Author(s).)

Rapid on-site evaluation (ROSE) significantly improves the diagnostic yield of fine needle aspiration (FNA) samples but critically depends on the skills and availability of cytopathologists. Here, we introduce a portable device for semi-automated sample preparation for ROSE. In a single platform, the device combines a smearing tool and a capillary-driven chamber for staining FNA samples. Using a human pancreatic cancer cell line (PANC-1) and liver, lymph node, and thyroid FNA model samples, we demonstrate the capability of the device to prepare samples for ROSE. By minimizing the equipment needed in the operating room, the device may simplify the performance of FNA sample preparation and lead to a wider implementation of ROSE.

Background: Performing complete blood counts from patients' homes could have a transformative impact on e-based healthcare. Blood microsampling and sample drying are enabling elements for patient-centric healthcare. The aim of this study was to investigate the potential of dry blood samples for image-based cell quantification of red and white blood cells. Methods: A manual sample preparation method was developed and tested for image-based red and white blood cell counting. Results & conclusion: Dry blood samples enable image-based cell counting of red and white blood cells with a good correlation to gold standard hematology analyzer data (average coefficient of variation <6.5%; R 2  >0.8) and resolve the basic morphology of white blood cell nuclei. The presented proof-of-principle study is a first step toward patient-centric complete blood counts.

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., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Serological testing is essential to curb the consequences of the COVID-19 pandemic. However, most assays are still limited to single analytes and samples collected within healthcare. Thus, we establish a multianalyte and multiplexed approach to reliably profile IgG and IgM levels against several versions of SARS-CoV-2 proteins (S, RBD, N) in home-sampled dried blood spots (DBS). We analyse DBS collected during spring of 2020 from 878 random and undiagnosed individuals from the population in Stockholm, Sweden, and use classification approaches to estimate an accumulated seroprevalence of 12.5% (95% CI: 10.3%-14.7%). This includes 5.4% of the samples being IgG + IgM + against several SARS-CoV-2 proteins, as well as 2.1% being IgG - IgM + and 5.0% being IgG + IgM - for the virus' S protein. Subjects classified as IgG + for several SARS-CoV-2 proteins report influenza-like symptoms more frequently than those being IgG + for only the S protein (OR = 6.1; p < 0.001). Among all seropositive cases, 30% are asymptomatic. Our strategy enables an accurate individual-level and multiplexed assessment of antibodies in home-sampled blood, assisting our understanding about the undiagnosed seroprevalence and diversity of the immune response against the coronavirus.

Integrating two-dimensional (2D) materials into semiconductor manufacturing lines is essential to exploit their material properties in a wide range of application areas. However, current approaches are not compatible with high-volume manufacturing on wafer level. Here, we report a generic methodology for large-area integration of 2D materials by adhesive wafer bonding. Our approach avoids manual handling and uses equipment, processes, and materials that are readily available in large-scale semiconductor manufacturing lines. We demonstrate the transfer of CVD graphene from copper foils (100-mm diameter) and molybdenum disulfide (MoS 2 ) from SiO 2 /Si chips (centimeter-sized) to silicon wafers (100-mm diameter). Furthermore, we stack graphene with CVD hexagonal boron nitride and MoS 2 layers to heterostructures, and fabricate encapsulated field-effect graphene devices, with high carrier mobilities of up to [Formula: see text]. Thus, our approach is suited for backend of the line integration of 2D materials on top of integrated circuits, with potential to accelerate progress in electronics, photonics, and sensing.

Alternative means for drug delivery are needed to facilitate drug adherence and administration. Microneedles (MNs) have been previously investigated transdermally for drug delivery. To date, drug loading into MNs has been limited by drug solubility in the polymeric blend. We designed a highly drug-loaded MN patch to deliver macromolecules and applied it to the buccal area, which allows for faster delivery than the skin. We successfully delivered 1-mg payloads of human insulin and human growth hormone to the buccal cavity of swine within 30 s. In addition, we conducted a trial in 100 healthy volunteers to assess potential discomfort associated with MNs when applied in the oral cavity, identifying the hard palate as the preferred application site. We envisage that MN patches applied on buccal surfaces could increase medication adherence and facilitate the painless delivery of biologics and other drugs to many, especially for the pediatric and elderly populations., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Transmission electron microscopy (TEM) allows for visualizing and analyzing viral particles and has become a vital tool for the development of vaccines and biopharmaceuticals. However, appropriate TEM sample preparation is typically done manually which introduces operator-based dependencies and can lead to unreliable results. Here, we present a capillary-driven microfluidic single-use device that prepares a TEM grid with minimal and non-critical user interaction. The user only initiates the sample preparation process, waits for about one minute and then collects the TEM grid, ready for imaging. Using Adeno-associated virus (AAV) particles as the sample and NanoVan® as the stain, we demonstrate microfluidic consistency and show that the sample preparation quality is sufficient for automated image analysis. We further demonstrate the versatility of the microfluidic device by preparing two protein complexes for TEM investigations using two different stain types. The presented TEM sample preparation concept could alleviate the problems associated with human inconsistency in manual preparation protocols and allow for non-specialists to prepare TEM samples.

Ingestible electronic devices enable noninvasive evaluation and diagnosis of pathologies in the gastrointestinal (GI) tract but generally cannot therapeutically interact with the tissue wall. Here, we report the development of an orally administered electrical stimulation device characterized in ex vivo human tissue and in in vivo swine models, which transiently anchored itself to the stomach by autonomously inserting electrically conductive, hooked probes. The probes provided stimulation to the tissue via timed electrical pulses that could be used as a treatment for gastric motility disorders. To demonstrate interaction with stomach muscle tissue, we used the electrical stimulation to induce acute muscular contractions. Pulses conductively signaled the probes' successful anchoring and detachment events to a parenterally placed device. The ability to anchor into and electrically interact with targeted GI tissues controlled by the enteric nervous system introduces opportunities to treat a multitude of associated pathologies., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).)

The out-of-plane integration of microfabricated planar microchips into functional three-dimensional (3D) devices is a challenge in various emerging MEMS applications such as advanced biosensors and flow sensors. However, no conventional approach currently provides a versatile solution to vertically assemble sensitive or fragile microchips into a separate receiving substrate and to create electrical connections. In this study, we present a method to realize vertical magnetic-field-assisted assembly of discrete silicon microchips into a target receiving substrate and subsequent electrical contacting of the microchips by edge wire bonding, to create interconnections between the receiving substrate and the vertically oriented microchips. Vertical assembly is achieved by combining carefully designed microchip geometries for shape matching and striped patterns of the ferromagnetic material (nickel) on the backside of the microchips, enabling controlled vertical lifting directionality independently of the microchip's aspect ratio. To form electrical connections between the receiving substrate and a vertically assembled microchip, featuring standard metallic contact electrodes only on its frontside, an edge wire bonding process was developed to realize ball bonds on the top sidewall of the vertically placed microchip. The top sidewall features silicon trenches in correspondence to the frontside electrodes, which induce deformation of the free air balls and result in both mechanical ball bond fixation and around-the-edge metallic connections. The edge wire bonds are realized at room temperature and show minimal contact resistance (<0.2 Ω) and excellent mechanical robustness (>168 mN in pull tests). In our approach, the microchips and the receiving substrate are independently manufactured using standard silicon micromachining processes and materials, with a subsequent heterogeneous integration of the components. Thus, this integration technology potentially enables emerging MEMS applications that require 3D out-of-plane assembly of microchips., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© The Author(s) 2020.)

Insulin and other injectable biologic drugs have transformed the treatment of patients suffering from diabetes 1,2 , yet patients and healthcare providers often prefer to use and prescribe less effective orally dosed medications 3-5 . Compared with subcutaneously administered drugs, oral formulations create less patient discomfort 4 , show greater chemical stability at high temperatures 6 , and do not generate biohazardous needle waste 7 . An oral dosage form for biologic medications is ideal; however, macromolecule drugs are not readily absorbed into the bloodstream through the gastrointestinal tract 8 . We developed an ingestible capsule, termed the luminal unfolding microneedle injector, which allows for the oral delivery of biologic drugs by rapidly propelling dissolvable drug-loaded microneedles into intestinal tissue using a set of unfolding arms. During ex vivo human and in vivo swine studies, the device consistently delivered the microneedles to the tissue without causing complete thickness perforations. Using insulin as a model drug, we showed that, when actuated, the luminal unfolding microneedle injector provided a faster pharmacokinetic uptake profile and a systemic uptake >10% of that of a subcutaneous injection over a 4-h sampling period. With the ability to load a multitude of microneedle formulations, the device can serve as a platform to orally deliver therapeutic doses of macromolecule drugs.

Obtaining plasma from a blood sample and preparing it for subsequent analysis is currently a laborious process involving experienced health-care professionals and centrifugation. We circumvent this by utilizing capillary forces and microfluidic engineering to develop an autonomous plasma sampling device that filters and stores an exact amount of plasma as a dried plasma spot (DPS) from a whole blood sample in less than 6 min. We tested 24 prototype devices with whole blood from 10 volunteers, various input volumes (40-80 μL), and different hematocrit levels (39-45%). The resulting mean plasma volume, assessed gravimetrically, was 11.6 μL with a relative standard deviation similar to manual pipetting (3.0% vs 1.4%). LC-MS/MS analysis of caffeine concentrations in the generated DPS (12 duplicates) showed a strong correlation ( R 2 = 0.99) to, but no equivalence with, concentrations prepared from corresponding plasma obtained by centrifugation. The presented autonomous DPS device may enable patient-centric plasma sampling through minimally invasive finger-pricking and allow generatation of volume-defined DPS for quantitative blood analysis.

Dried blood spot (DBS) sampling is a promising method for collection of microliter blood samples. However, hematocrit-related bias in combination with subpunch analysis can result in inaccurate quantification of analytes in DBS samples. In this study we use a microfluidic DBS card, designed to automatically collect fixed volume DBS samples irrespective of the blood hematocrit, to measure caffeine concentration in normal finger prick samples obtained from 44 human individuals. Caffeine levels originating from blood drops of unknown volume collected on the volumetric microfluidic DBS card were compared to volume-controlled pipetted DBS samples from the same finger prick. Hematocrit independence and volumetric sampling performances were also verified on caffeine-spiked blood samples in vitro, using both LC-MS/MS and gravimetric methods, on hematocrits from 26 to 62%. The gravimetric measurements show an excellent metering performance of the microfluidic DBS card, with a mean blood sample volume of 14.25 μL ± 3.0% ( n = 51). A measured mean bias below 2.9% compared to normal hematocrit (47%) demonstrates that there is no significant hematocrit-induced bias. LC-MS/MS measurements confirm low CV and hematocrit independence of the sampling system and exhibit no substantial mean bias compared to pipetted DBS. Tests with 44 individuals demonstrated applicability of the microfluidic DBS card for direct finger prick blood sampling, and measured caffeine concentrations show a good agreement with measurements of pipetted DBS. The presented concept demonstrates a good volumetric performance which can help to improve the accuracy of DBS analysis by analyzing a whole spot, equivalent to a defined volume of liquid blood.

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., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Biomacromolecules have transformed our capacity to effectively treat diseases; however, their rapid degradation and poor absorption in the gastrointestinal (GI) tract generally limit their administration to parenteral routes. An oral biologic delivery system must aid in both localization and permeation to achieve systemic drug uptake. Inspired by the leopard tortoise's ability to passively reorient, we developed an ingestible self-orienting millimeter-scale applicator (SOMA) that autonomously positions itself to engage with GI tissue. It then deploys milliposts fabricated from active pharmaceutical ingredients directly through the gastric mucosa while avoiding perforation. We conducted in vivo studies in rats and swine that support the applicator's safety and, using insulin as a model drug, demonstrated that the SOMA delivers active pharmaceutical ingredient plasma levels comparable to those achieved with subcutaneous millipost administration., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

A new analytical all-solid-state platform for intradermal potentiometric detection of potassium in interstitial fluid is presented here. Solid microneedles are modified with different coatings and polymeric membranes to prepare both the potassium-selective electrode and reference electrode needed for the potentiometric readout. These microneedle-based electrodes are fixed in an epidermal patch suitable for insertion into the skin. The analytical performances observed for the potentiometric cell (Nernstian slope, limit of detection of 10 -4.9 potassium activity, linear range of 10 -4.2 to 10 -1.1 , drift of 0.35 ± 0.28 mV h -1 ), together with a fast response time, adequate selectivity, and excellent reproducibility and repeatability, are appropriate for potassium analysis in interstitial fluid within both clinical and harmful levels. The potentiometric response is maintained after several insertions into animal skin, confirming the resiliency of the microneedle-based sensor. Ex vivo tests based on the intradermal detection of potassium in chicken and porcine skin demonstrate that the microneedle patch is suitable for monitoring potassium changes inside the skin. In addition, the dimensions of the microneedles modified with the corresponding layers necessary to enhance robustness and provide sensing capabilities (1000 μm length, 45° tip angle, 15 μm thickness in the tip, and 435 μm in the base) agree with the required ranges for a painless insertion into the skin. In vitro cytotoxicity experiments showed that the patch can be used for at least 24 h without any side effect for the skin cells. Overall, the developed concept constitutes important progress in the intradermal analysis of ions related to an electrolyte imbalance in humans, which is relevant for the control of certain types of diseases.

Continuous glucose monitoring (CGM) has the potential to greatly improve diabetes management. The aim of this work is to show a proof-of-concept CGM device which performs minimally invasive and minimally delayed in-situ glucose sensing in the dermal interstitial fluid, combining the advantages of microneedle-based and commercially available CGM systems. The device is based on the integration of an ultra-miniaturized electrochemical sensing probe in the lumen of a single hollow microneedle, separately realized using standard silicon microfabrication methods. By placing the sensing electrodes inside the lumen facing an opening towards the dermal space, real-time measurement purely can be performed relying on molecular diffusion over a short distance. Furthermore, the device relies only on passive capillary lumen filling without the need for complex fluid extraction mechanisms. Importantly, the transdermal portion of the device is 50 times smaller than that of commercial products. This allows access to the dermis and simultaneously reduces tissue trauma, along with being virtually painless during insertion. The three-electrode enzymatic sensor alone was previously proven to have satisfactory sensitivity (1.5 nA/mM), linearity (up to 14 mM), selectivity, and long-term stability (up to 4 days) in-vitro. In this work we combine this sensor technology with microneedles for reliable insertion in forearm skin. In-vivo human tests showed the possibility to correctly and dynamically track glycaemia over time, with approximately 10 min delay with respect to capillary blood control values, in line with the expected physiological lag time. The proposed device can thus reduce discomfort and potentially enable less invasive real-time CGM in diabetic patients.

Bad breath or halitosis affects a majority of the population from time to time, causing personal discomfort and social embarrassment. Here, we report on a miniaturized, microelectromechanical systems (MEMS)-based, amperometric hydrogen sulfide (H₂S) sensor that potentially allows bad breath quantification through a small handheld device. The sensor is designed to detect H₂S gas in the order of parts-per-billion (ppb) and has a measured sensitivity of 0.65 nA/ppb with a response time of 21 s. The sensor was found to be selective to NO and NH₃ gases, which are normally present in the oral breath of adults. The ppb-level detection capability of the integrated sensor, combined with its relatively fast response and high sensitivity to H₂S, makes the sensor potentially applicable for oral breath monitoring.

Whole-blood microsampling provides many benefits such as remote, patient-centric, and minimally invasive sampling. However, blood plasma, and not whole blood, is the prevailing matrix in clinical laboratory investigations. The challenge with plasma microsampling is to extract plasma volumes large enough to reliably detect low-concentration analytes from a small finger prick sample. Here we introduce a passive plasma filtration device that provides a high extraction yield of 65%, filtering 18 μL of plasma from 50 μL of undiluted human whole blood (hematocrit 45%) within less than 10 min. The enabling design element is a wedge-shaped connection between the blood filter and the hydrophilic bottom surface of a capillary channel. Using finger prick and venous blood samples from more than 10 healthy volunteers, we examined the filtration kinetics of the device over a hematocrit range of 35-55% and showed that 73 ± 8% of the total protein content was successfully recovered after filtration. The presented plasma filtration device tackles a major challenge toward patient-centric blood microsampling by providing high-yield plasma filtration, potentially allowing reliable detection of low-concentration analytes from a blood microsample.

An ultra-miniaturized electrochemical biosensor for continuous glucose monitoring (CGM) is presented. The aim of this work is to demonstrate the possibility of an overall reduction in sensor size to allow minimally invasive glucose monitoring in the interstitial fluid in the dermal region, in contrast to larger state-of-the-art systems, which are necessarily placed in the subcutaneous layer. Moreover, the reduction in size might be a key factor to improve the stability and reliability of transdermal sensors, due to the reduction of the detrimental foreign body reaction and of consequent potential failures. These advantages are combined with lower invasiveness and discomfort for patients. The realized device consists of a microfabricated three-electrode enzymatic sensor with a total surface area of the sensing portion of less than 0.04mm 2 , making it the smallest fully integrated planar amperometric glucose sensor area reported to date. The working electrode and counter electrode consist of platinum and are functionalized by drop casting of three polymeric membranes. The on-chip iridium oxide (IrOx) pseudo-reference electrode provides the required stability for measurements under physiological conditions. The device is able to dynamically and linearly measure glucose concentrations in-vitro over the relevant physiological range, while showing sufficient selectivity to known interfering species present in the interstitial fluid, with resolution and sensitivity (1.51nA/mM) comparable to that of state-of-art commercial CGM systems. This work can therefore enable less invasive and improved CGM in patients affected by diabetes., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Ingestible electronics have revolutionized the standard of care for a variety of health conditions. Extending the capacity and safety of these devices, and reducing the costs of powering them, could enable broad deployment of prolonged monitoring systems for patients. Although prior biocompatible power harvesting systems for in vivo use have demonstrated short minute-long bursts of power from the stomach, not much is known about the capacity to power electronics in the longer term and throughout the gastrointestinal tract. Here, we report the design and operation of an energy-harvesting galvanic cell for continuous in vivo temperature sensing and wireless communication. The device delivered an average power of 0.23 μW per mm 2 of electrode area for an average of 6.1 days of temperature measurements in the gastrointestinal tract of pigs. This power-harvesting cell has the capacity to provide power for prolonged periods of time to the next generation of ingestible electronic devices located in the gastrointestinal tract.

This paper demonstrates flexible and stretchable microneedle patches that combine soft and flexible base substrates with hard and sharp stainless steel microneedles. An elastomeric polymer base enables conformal contact between the microneedle patch and the complex topography and texture of the underlying skin, while robust and sharp stainless steel microneedles reliably pierce the outer layers of the skin. The flexible microneedle patches have been realized by magnetically assembling short stainless steel microneedles into a flexible polymer supporting base. In our experimental investigation, the microneedle patches were applied to human skin and an excellent adaptation of the patch to the wrinkles and deformations of the skin was verified, while at the same time the microneedles reliably penetrate the surface of the skin. The unobtrusive flexible and stretchable microneedle patches have great potential for transdermal biointerfacing in a variety of emerging applications such as transdermal drug delivery, bioelectric treatments and wearable bio-electronics for health and fitness monitoring., Competing Interests: Novo Nordisk A/S of Denmark has supported this study by providing stainless steel needles. This does not alter our adherence to PLOS ONE policies on sharing data and materials. We have no other potential competing or financial interests to report.

Solid state nanopores enable translocation and detection of single bio-molecules such as DNA in buffer solutions. Here, sub-10 nm nanopore arrays in silicon membranes were fabricated by using electron-beam lithography to define etch pits and by using a subsequent electrochemical etching step. This approach effectively decouples positioning of the pores and the control of their size, where the pore size essentially results from the anodizing current and time in the etching cell. Nanopores with diameters as small as 7 nm, fully penetrating 300 nm thick membranes, were obtained. The presented fabrication scheme to form large arrays of nanopores is attractive for parallel bio-molecule sensing and DNA sequencing using optical techniques. In particular the signal-to-noise ratio is improved compared to other alternatives such as nitride membranes suffering from a high-luminescence background.

Background: Inhomogeneous sample distribution in DBS is a problem for accurate quantitative analysis of DBS, and has often been explained by chromatographic effects., Results: We present a model describing formation of inhomogeneous DBS during drying of the spot caused by higher evaporation rates of water at the edge as compared with the center. Color intensity analysis shows that the relative humidity and DBS card position affect the homogeneity of DBS., Conclusion: The so-called 'coffee-stain effect' explains the typical distribution pattern of analytes with higher concentrations measured along the edge of DBS as compared with the center. The driving mechanism and potential influencing factors should be considered when addressing the inhomogeneity of DBS in the future.

Background: DBS samples collected from a fingerprick typically vary in volume and homogeneity and hence make an accurate quantitative analysis of DBS samples difficult., Results: We report a prototype which first defines a precise liquid volume and subsequently stores it to a conventional DBS matrix. Liquid volumes of 2.2 µl ± 7.1% (n = 21) for deionized water and 6.1 µl ± 8.8% (n = 15) for whole blood have been successfully metered and stored in DBS paper., Conclusion: The new method of collecting a defined volume of blood by DBS sampling has the potential to reduce assay bias for the quantitative evaluation of DBS samples while maintaining the simplicity of conventional DBS sampling.

We describe a simple but reliable approach to shrink silicon nanopores with nanometer precision for potential high throughput biomolecular sensing and parallel DNA sequencing. Here, nanopore arrays on silicon membranes were fabricated by a self-limiting shrinkage of inverted pyramidal pores using dry thermal oxidation at 850 °C. The shrinkage rate of the pores with various initial sizes saturated after 4 h of oxidation. In the saturation regime, the shrinkage rate is within ± 2 nm h(-1). Oxidized pores with an average diameter of 32 nm were obtained with perfect circular shape. By careful design of the initial pore size, nanopores with diameters as small as 8 nm have been observed. Statistics of the pore width show that the shrinkage process did not broaden the pore size distribution; in most cases the distribution even decreased slightly. The progression of the oxidation and the deformation of the oxide around the pores were characterized by focused ion beam and electron microscopy. Cross-sectional imaging of the pores suggests that the initial inverted pyramidal geometry is most likely the determining factor for the self-limiting shrinkage.

This paper reports a novel micro electro mechanical system (MEMS) valve with posture controlled flow characteristics for improved treatment of hydrocephalus, a disease that is characterized by elevated pressure in the cerebrospinal fluid (CSF) that surrounds the brain and spinal cord. In contrast to conventional differential pressure CSF valves, the CSF valve presented here features a third port which utilizes hydrostatic pressure from a pressure compensating catheter to adapt CSF drainage to optimized levels irrespective of body position. Prototypes have been fabricated using standard MEMS manufacturing processes and the experimental evaluation successfully showed that the flow rate was adjustable with a varying hydrostatic pressure on the third port. Measured data showed that flow rate was at near ideal values at laying body position and that the flow rate can be adjusted to optimal values at standing body position by selecting an appropriate length of the pressure compensating catheter. This is the first pressure balanced CSF valve intended for body position controlled CSF pressure regulation.

The incidence of insulinopenic diabetes mellitus is constantly increasing, and in addition, approximately a third of all hyperinsulinemic diabetic patients develop insulinopenia. Optimal glycemic control is essential to minimize the risk for diabetes-induced complications, but the majority of diabetic patients fail to achieve proper long-term glucose levels even in clinical trials, and even more so in clinical practice. Compliance with a treatment regimen is likely to be higher if the procedure is simple, painless, and discreet. Thus, insulin has been suggested for nasal, gastrointestinal, and inhalation therapy, but so far with considerable downsides in effect, side effects, or patient acceptance. The stratum corneum is the main barrier preventing convenient drug administration without the drawbacks of subcutaneous injections. Recently, devices with miniaturized needles have been developed that combine the simplicity and discretion of patch-based treatments, but with the potential of peptide and protein administration. As this review describes, initial comparisons with subcutaneous administration now suggest microneedle patches for active insulin delivery are efficient in maintaining glycemic control. Hollow microneedle technology could also prove to be efficient in systemic as well as local delivery of other macromolecular drugs, such as vaccines., (© 2014 Diabetes Technology Society.)

Functional nanoporous materials are promising for a number of applications ranging from selective biofiltration to fuel cell electrodes. This work reports the functionalization of nanoporous membranes using atomic layer deposition (ALD). ALD is used to conformally deposit platinum (Pt) and aluminum oxide (Al(2)O(3)) on Pt in nanopores to form a metal-insulator stack inside the nanopore. Deposition of these materials inside nanopores allows the addition of extra functionalities to nanoporous materials such as anodic aluminum oxide (AAO) membranes. Conformal deposition of Pt on such materials enables increased performances for electrochemical sensing applications or fuel cell electrodes. An additional conformal Al(2)O(3) layer on such a Pt film forms a metal-insulator-electrolyte system, enabling field effect control of the nanofluidic properties of the membrane. This opens novel possibilities in electrically controlled biofiltration. In this work, the deposition of these two materials on AAO membranes is investigated theoretically and experimentally. Successful process parameters are proposed for a reliable and cost-effective conformal deposition on high aspect ratio three-dimensional nanostructures. A device consisting of a silicon chip supporting an AAO membrane of 6 mm diameter and 1.3 μm thickness with 80 nm diameter pores is fabricated. The pore diameter is reduced to 40 nm by a conformal deposition of 11 nm Pt and 9 nm Al(2)O(3) using ALD.

This paper presents fabrication and testing of membrane-sealed hollow microneedles. This novel concept offers the possibility of a sealed microneedle-based transdermal drug delivery system in which the drug is stored and protected from the environment. Sealed microneedles were fabricated by covering the tip openings of out-of-plane silicon microneedles with thin gold membranes. In this way a leak-tight seal was established which hinders both contamination and evaporation. To allow drug release from the microneedles, three different methods of opening the seals were investigated: burst opening by means of pressure; opening by applying a small voltage in the presence of physiological saline; and opening as a result of microneedle insertion into the skin. It was found that a 170 nm thick gold membrane can withstand a pressure of approximately 120 kPa. At higher pressures the membranes burst and the microneedles are opened up. The membranes can also be electrochemically dissolved within 2 min in saline conditions similar to interstitial fluid present in the skin. Moreover, through in vivo tests, it was demonstrated that 170 nm thick membranes break when the microneedles were inserted into skin tissue. The proposed concept was demonstrated as a feasible option for sealing hollow microneedles. This enables the realization of a closed-package transdermal drug delivery system based on microneedles.

This paper presents the first microneedle-based transdermal patch with integrated active dispensing functionality. The electrically controlled system consists of a low-cost dosing and actuation unit capable of controlled release of liquid in the microliter range at low flow-rates and minimally invasive, side-opened, microneedles. The system was successfully tested in vivo by insulin administration to diabetic rats. Active infusion of insulin at 2 mul/h was compared to passive, diffusion-driven, delivery. Continuous active infusion caused significantly higher insulin concentrations in blood plasma. After a 3-h delivery period, the insulin concentration was five times larger compared to passive delivery. Consistent with insulin concentrations, actively administered insulin resulted in a significant decrease of blood glucose levels. Additionally, insertion and liquid injection was verified on human skin. This study shows the feasibility of a patch-like system with on-board liquid storage and dispensing capability. The proposed device represents a first step towards painless and convenient administration of macromolecular drugs such as insulin or vaccines.

Purpose: Good glycaemic control is essential to minimize the risk for diabetes-induced complications. Also, compliance is likely to be higher if the procedure is simple and painless. This study was designed to validate painless intradermal delivery via a patch-like microneedle array., Materials and Methods: Diabetes was induced by an intravenous injection of streptozotocin (50 mg/kg bw) in adult male Sprague Dawley rats. Plasma insulin and blood glucose were measured before, during and after subcutaneous or intradermal (microneedles) infusion of insulin (0.2 IU/h) under Inactin-anaesthesia., Results: Before insulin administration, all animals displayed a pronounced hyperglycaemia (19 +/- 1 mM; 359 mg/dl). Administration of insulin resulted in a reduced plasma glucose independently of administration route (subcutaneous 7.5 +/- 4.2, n = 9, and intradermal 11 +/- 1.8, n = 9 after 240 min), but with less errors of the mean in the intradermal group. In the intradermal group, plasma insulin was increased in all latter measurements (72 +/- 22, 81 +/- 34, and 87 +/- 20 microIU/ml), as compared to the first measurement (26 +/- 13). In the subcutaneous group, plasma insulin was elevated during the last measurement (to 154 +/- 3.5 microIU/ml from 21 +/- 18)., Conclusion: This study presents a novel possibility of insulin delivery that is controllable and requires minimal training. This treatment strategy could improve compliance, and thus be beneficial for patients' glycaemic control.

A novel microdevice for passively mixing liquid samples based on surface tension and a geometrical mixing chamber is presented. Due to the laminar flow regime on the microscale, mixing becomes difficult if not impossible. We present a micromixer where a constantly changing time dependent flow pattern inside a two sample liquid plug is created as the plug simply passes through the planar mixer chamber. The device requires no actuation during mixing and is fabricated using a single etch process. The effective mixing of two coloured liquid samples is demonstrated.