3D printing at the macroscale has evolved from making plastic prototypes to the production of high-performance functional metal parts for industries such as medical and aerospace. By contrast, MEMS devices today are produced in large quantities using semiconductor manufacturing processes. However, the semiconductor manufacturing paradigm is not cost-effective for producing customized MEMS devices in small to medium volumes (tens to thousands of units per year), and related applications are difficult to address efficiently. 3D printing of functional MEMS devices could play an important role in filling this gap. Here, we discuss recent advances in 3D- printed functional MEMS, addressing the challenges of economical customization at smaller production volumes.

Aims/hypothesis: Type 1 diabetes manifests after irreversible beta cell damage, highlighting the crucial need for markers of the presymptomatic phase to enable early and effective interventions. Current efforts to identify molecular markers of disease-triggering events lack resolution and convenience. Analysing frequently self-collected dried blood spots (DBS) could enable the detection of early disease-predictive markers and facilitate tailored interventions. Here, we present a novel strategy for monitoring transient molecular changes induced by environmental triggers that enable timely disease interception.

Methods: Whole blood (10 μl) was sampled regularly (every 1–5 days) from adult NOD mice infected with Coxsackievirus B3 (CVB3) or treated with vehicle alone. Blood samples (5 μl) were dried on filter discs. DBS samples were analysed by proximity extension assay. Generalised additive models were used to assess linear and non-linear relationships between protein levels and the number of days post infection (p.i.). A multi-layer perceptron (MLP) classifier was developed to predict infection status. CVB3-infected SOCS-1-transgenic (tg) mice were treated with immune- or non-immune sera on days 2 and 3 p.i., followed by monitoring of diabetes development.

Results: Frequent blood sampling and longitudinal measurement of the blood proteome revealed transient molecular changes in virus-infected animals that would have been missed with less frequent sampling. The MLP classifier predicted infection status after day 2 p.i. with over 90% accuracy. Treatment with immune sera on day 2 p.i. prevented diabetes development in all (100%) of CVB3-infected SOCS-1-tg NOD mice while five out of eight (62.5%) of the CVB3-infected controls treated with non-immune sera developed diabetes.

Conclusions/interpretation: Our study demonstrates the utility of frequently collected DBS samples to monitor dynamic proteome changes induced by an environmental trigger during the presymptomatic phase of type 1 diabetes. This approach enables disease interception and can be translated into human initiatives, offering a new method for early detection and intervention in type 1 diabetes.

Data and code availability: Additional data available at https://doi.org/10.17044/scilifelab.27368322 . Additional visualisations are presented in the Shiny app interface https://mouse-dbs-profiling.serve.scilifelab.se/

Microphysiological systems (MPS) are advanced in vitro platforms engineered to replicate in vivo conditions for studying human biology, disease mechanisms, and drug responses with greater physiological relevance. Fluorescence sensing is widely used as a functional readout in MPS due to its high sensitivity, selectivity, and stability. However, conventional fluorescence sensing systems often rely on bulky instrumentation with limited integration, which restricts continuous in situ monitoring, scalable high-throughput analysis, and spatially resolved investigation in multi-organ-on-a-chip models. To address these limitations, we present a highly miniaturized, fully integrated optical system with a 1 mm² footprint, enabling continuous in situ fluorescence monitoring of three-dimensional microtissues in close proximity. The system integrates microscale illumination and sensing units for fluorescence excitation and selective detection, an optical element for guided light propagation, and a microcage for mechanical confinement of microtissues. To demonstrate its capabilities, we integrated the miniaturized optical system with an MPS-relevant platform to monitor fluorescence signals in transgenic mouse pancreatic islets expressing genetically encoded calcium indicators. The integrated platform enables real-time, continuous monitoring of islet responses to potassium chloride stimulation and tracking of calcium oscillations for over two hours, providing valuable information about the functional status of the pancreatic islets. Our work enhances the analytical capabilities of MPS through the integration of miniaturized on-chip quantitative assessment tools, enabling precise, in situ, and continuous monitoring of biological activities in close proximity.

Lithium is the first-line treatment for bipolar disorder. However, the narrow therapeutic window of serum (s-)lithium is near its toxicity range, necessitating continuous monitoring of patients, a process involving regular hospital visits. On-demand home sampling could allow for more frequent testing, possibly resulting in safer patient outcomes, further dosage optimization, and increased compliance. This article presents a device that measures the s-lithium concentration from whole blood. The device consists of a single-use cartridge able to conduct on-chip serum filtration, volume-metering and an on-chip colorimetric assay. Spiked whole blood shows good linearity (Pearson's r = 0.96, R2 = 0.92), a limit-of-detection of 0.3 mmol L-1, and an average deviation of 0.05 mmol L-1 (+/- 6%) compared to atomic absorption spectroscopy. The on-chip colorimetric assay has shown to be a promising technique for measuring s-lithium concentration from whole blood and could allow patients to assess lithium levels at home and make the treatment available for new patient groups.

Topical drug delivery offers a localized and patient-friendly method for treating skin diseases and subcutaneous lesions. However, the outermost skin barrier - the stratum corneum (SC) - hinders the delivery of large molecules such as biopharmaceuticals. This study introduces rolling ultraminiaturized microneedle spheres (RUMS) as a novel solution that enables topical delivery of messenger RNA (mRNA) without the need for chemical enhancers or techniques like electroporation, iontophoresis, or microneedle patches. RUMS are engineered spherical microparticles that gently roll over the skin, creating numerous micropores while minimizing tissue damage. In ex vivo porcine skin experiments, 25 RUMS generated approximately 4,500 pores within 10 seconds, achieving penetration depths of around 20 micrometers and increasing skin permeability by up to 100-fold. In vivo studies in mice showed that combining RUMS with topical doxycycline led to a ~50% tumor size reduction within two weeks and full recovery by four weeks. In contrast, doxycycline or RUMS alone offered limited therapeutic benefit. Rapid skin healing was observed due to the small pore size. Additionally, topical delivery of lipid nanoparticle-encapsulated luciferase (luc)-encoding mRNA was successfully demonstrated in mice. Overall, use of RUMS presents a simple, painless, and potentially well-tolerated technique for enabling transdermal topical delivery of biologics.

Biocompatibility of medical implants poses a significant challenge in medical technology. Neural implants, integral to curative therapies, initially exhibit efficacy but can lead to unforeseen long-term side effects. The material composition and dimensions of implants are critical factors influencing their biocompatibility within brain tissue. Typically, neural implants are identified as foreign entities by the patient's immune system, triggering persistent inflammation and severe adverse effects. In this study, we investigate the host response in mouse brain tissue of implanted microscale constructs measuring 0.1 x 0.1 x 1 mm3 fabricated from common microfabrication materials. Magnetic Resonance Imaging (MRI) analysis reveals rapid recovery of brain parenchyma at 6 week interval post-implantation, accompanied by negligible or mild adverse immune responses during the experimental period. Histological assessments and cell marker stainings targeting astroglia, macrophages, and microglia demonstrate minimal impacts of the microconstructs on mouse brain tissue throughout the 24-week implantation period. Our findings indicate that untethered microimplants of this scale may have potential applications in medical technology and medical treatment for various brain diseases. In summary, this study supports the development of potentially biocompatible brain microimplants that could be useful for the long-term management of chronic brain disorders.

Smart agriculture and environmental monitoring claim innovative wearable sensing technologies suitable for real-time, in-situ biochemical analysis for non-specialized users in plants. Current strategies measure physical parameters, ions or hormones by amperometry or potentiometry. Among these, plant hormones serve as stress biomarkers due to their role in stress response mechanisms. While electrocatalysis has been explored for their detection, early-stage stress monitoring at low concentrations demands higher selectivity and specificity. Therefore, new strategies integrating biorecognition elements, such as antibodies, with autonomous sample collection and bioassay performance are required. In this regard, this work proposes a novel wearable immunosensor device based on an electrochemical lateral flow assay (eLF) that includes an autonomous microsampling technology for minimally invasive in-situ sap extraction and abscisic acid (ABA) detection. This sap device collects, processes and analyzes plant sap with low sample volume (<10 μL) and short assay time (9min) using immunosensing for the first time in ABA wearable detection. Validation in drought-stressed cucumber plants demonstrated 78 % sensitivity and 71 % specificity in detecting subtle water stress with 77 % accuracy. These findings highlight the potential of this plant-wearable biosensor for early stress detection and its versatility to be adapted for the detection of other relevant molecules (proteins or DNA), key for smart agriculture and environmental monitoring.

Aims: Current endoscopic ultrasound (EUS) is suboptimal in the assessment of pancreatic cystic lesions (PCLs). We developed a new through-the needle loop device, to improve the cellular yield, and thereby sensitivity, of EUS fine needle aspiration (EUS-FNA) of pancreatic cysts.

In this in-vivo animal randomized controlled trial (RCT), we aim to test the cell yield and safety profile of this through the needle loop device using artificial cysts, comparing it with the standard procedure, EUS-FNA.

Methods: This was an in-vivo randomized controlled trial in pigs using artificial cysts. In one group, the new device was deployed through a 22G EUS-FNA needle into the cysts. In the control group, cystic punction was performed with standard EUS-FNA. New devices were visually inspected post-procedure. Cytological assessment, cell counting, and hemoglobin analysis were performed in samples from both groups.

Results: Artificial cysts (n=114) were punctured in six pigs, 57 in each group. Neither adverse events nor significant device malfunction occurred during brushing with the new loop device. Samples collected with the loop had non-detectable concentrations of hemoglobin in 72% (41/57) of cases, and 26% (16/57) had less than 0.6 g/dL, with no significant difference to the controls (p=0.32). There was significantly increased cell counts with the new device (11.7×median difference, p<.0001). Cytological smears were diagnostic in 77% of cases in the device group, while 54% in the control group (p=0.01, Fisher’s exact test; p=0.006, Chi-square test).

Conclusions: This novel loop device appears to be safe, causing neither significant bleeding nor device malfunction. Samples obtained with the loop brush were suitable for cytological analysis and showed significantly higher cell yield than controls. Further clinical studies are warranted.

Needle-based injections currently enable the administration of a wide range of biomacromolecule therapies across the body, including the gastrointestinal tract^{1, 2–3}, through recent developments in ingestible robotic devices^{4, 5, 6–7}. However, needles generally require training, sharps management and disposal, and pose challenges for autonomous ingestible systems. Here, inspired by the jetting systems of cephalopods, we have developed and evaluated microjet delivery systems that can deliver jets in axial and radial directions into tissue, making them suitable for tubular and globular segments of the gastrointestinal tract. Furthermore, they are implemented in both tethered and ingestible formats, facilitating endoscopic applications or patient self-dosing. Our study identified suitable pressure and nozzle dimensions for different segments of the gastrointestinal tract and applied microjets in a variety of devices that support delivery across the various anatomic segments of the gastrointestinal tract. We characterized the ability of these systems to administer macromolecules, including insulin, a glucagon-like peptide-1 (GLP1) analogue and a small interfering RNA (siRNA) in large animal models, achieving exposure levels similar to those achieved with subcutaneous delivery. This research provides key insights into jetting design parameters for gastrointestinal administration, substantially broadening the possibilities for future endoscopic and ingestible drug delivery devices.