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Respiratory infections caused by multi-drug-resistant Pseudomonas aeruginosa often yield poor outcomes if not detected right away. However, detecting this pathogen in respiratory samples with a rapid diagnostic test is challenging because the protective biofilms created by the pathogen are themselves surrounded by a high-viscosity sputum matrix. Here, we introduce a method for liquefying respiratory samples and disrupting bacterial biofilms on the spot within a minute. It relies on the generation of oxygen bubbles by bacterial catalase through the addition of hydrogen peroxide. When coupled with a mobile biosensor made of paper, the resulting diagnostic kit was able to detect P. aeruginosa infections in sputa from patients with excellent sensitivity and specificity within 8 min. The quick turnaround time along with few infrastructure requirements make this method ideal for the rapid screening of P. aeruginosa infections at the point of care.

A serendipitous discovery has led to the generation of a family of four compounds in which six components combine to form symmetric metal-cyclotricatechylene (H6ctc) cages. The four compounds, which have the compositions, [Cs((CH3)2CO)6][K4(H6ctc)4(H2O)8][Cs4(H2O)6](PO4)3, [Rb((CH3)2CO)6][Rb2K2(H6ctc)4(H2O)6][Rb4(H2O)6](PO4)3, [Cs((CH3)2CO)6][K4(H6ctc)4(H2O)8]-[Cs(H2O)9](SO4)3 and [Rb((CH3)2CO)6][Rb2K2(H6ctc)4(H2O)6][Rb(H2O)9](SO4)3 possess cubic symmetry that arises from the complementary interactions that govern the assembly of the components. The cage cavities contain water molecules and either one or four large alkali metal ions (either Rb+ or Cs+) which interact with the internal aromatic surfaces of the cage. Each cage is linked to six tetrahedral anions (PO43&minus, or SO42&minus, ) through 24 equivalent hydrogen bonds and each anion bridges a pair of cages through eight such hydrogen bonds. An unusual octahedral complex M((CH3)2CO)6+ (M = Rb or Cs), in which the M-C=O link is linear, appears to be a key structural component. A feature of this family of crystalline compounds is the presence of a range of complementary interactions which combine to generate materials that exhibit high crystallographic symmetry.

Severe infections can cause a dysregulated response leading to organ dysfunction known as sepsis. Sepsis can be lethal if not identified and treated right away. This requires measuring biomarkers and pathogens rapidly at the different points where sepsis care is provided. Current commercial approaches for sepsis diagnosis are not fast, sensitive, and/or specific enough for meeting this medical challenge. In this article, we review recent advances in the development of diagnostic tools for sepsis management based on micro- and nanostructured materials. We start with a brief introduction to the most popular biomarkers for sepsis diagnosis (lactate, procalcitonin, cytokines, C-reactive protein, and other emerging protein and non-protein biomarkers including miRNAs and cell-based assays) and methods for detecting bacteremia. We then highlight the role of nano- and microstructured materials in developing biosensors for detecting them taking into consideration the particular needs of every point of sepsis care (e.g., ultrafast detection of multiple protein biomarkers for diagnosing in triage, emergency room, ward, and intensive care unit; quantitative detection to de-escalate treatment; ultrasensitive and culture-independent detection of blood pathogens for personalized antimicrobial therapies; robust, portable, and web-connected biomarker tests outside the hospital). We conclude with an overview of the most utilized nano- and microstructured materials used thus far for solving issues related to sepsis diagnosis and point to new challenges for future development. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1007/s00604-022-05171-2.

Stratifying patients according to disease severity has been a major hurdle during the COVID-19 pandemic. This usually requires evaluating the levels of several biomarkers, which may be cumbersome when rapid decisions are required. In this manuscript we show that a single nanoparticle aggregation test can be used to distinguish patients that require intensive care from those that have already been discharged from the intensive care unit (ICU). It consists of diluting a platelet-free plasma sample and then adding gold nanoparticles. The nanoparticles aggregate to a larger extent when the samples are obtained from a patient in the ICU. This changes the color of the colloidal suspension, which can be evaluated by measuring the pixel intensity of a photograph. Although the exact factor or combination of factors behind the different aggregation behavior is unknown, control experiments demonstrate that the presence of proteins in the samples is crucial for the test to work. Principal component analysis demonstrates that the test result is highly correlated to biomarkers of prognosis and inflammation that are commonly used to evaluate the severity of COVID-19 patients. The results shown here pave the way to develop nanoparticle aggregation assays that classify COVID-19 patients according to disease severity, which could be useful to de-escalate care safely and make a better use of hospital resources.

Identifying the pathogen responsible for an infection is a requirement in order to personalize antimicrobial treatments. Detecting bacterial enzymes, such as proteases, lipases, and oxidoreductases, is a winning approach for detecting pathogens at the point of care. In this Article, a new method for detecting urease-producing bacteria rapidly and at ultralow concentrations is reported. In this method, longsome bacteriological culture steps are substituted for a 10 min capture procedure with positively charged magnetic beads. The presence of urease-positive bacteria on the particles is then queried with a plasmonic signal generation step that generates blue- or red-colored nanoparticle suspensions upon addition of the enzyme substrate. These colorimetric signals, which can be easily identified by eye, are generated by the NH3-dependent assembly of gold nanoparticles in the presence of bovine serum albumin (BSA). The proposed method can detect Proteus mirabilis with a limit of detection of 101 cells mL-1, with a total assay time of 40 min, even in the presence of a large excess of urease-negative bacteria ( Pseudomonas aeruginosa). Furthermore, it does not require bulky equipment, and it can detect P. mirabilis at clinically relevant concentrations within minutes, making it suitable for detecting urease-positive pathogens at the point of care.

Graphical abstract, Detecting SARS-CoV-2 antigens in respiratory tract samples has become a widespread method for screening new SARS-CoV-2 infections. This requires a nasopharyngeal swab performed by a trained healthcare worker, which puts strain on saturated healthcare services. In this manuscript we describe a new approach for non-invasive COVID-19 diagnosis. It consists of using mobile biosensors for detecting viral antigens trapped in surgical face masks worn by patients. The biosensors are made of filter paper containing a nanoparticle reservoir. The nanoparticles transfer from the biosensor to the mask on contact, where they generate colorimetric signals that are quantified with a smartphone app. Sample collection requires wearing a surgical mask for 30 minutes, and the total assay time is shorter than 10 min. When tested in a cohort of 27 patients with mild or no symptoms, an area under the receiving operating curve (AUROC) of 0.99 was obtained (96.2% sensitivity and 100% specificity). Serial measurements revealed a high sensitivity and specificity when masks were worn up to 6 days after diagnosis. Surgical face masks are inexpensive and widely available, which makes this approach easy to implement anywhere. The excellent sensitivity, even when tested with asymptomatic patient samples, along with the mobile detection scheme and non-invasive sampling procedure, makes this biosensor design ideal for mass screening.

Graphical abstract, Highlights • Detection of cytokine storm biomarkers with mobile biosensors. • Immunosensors are made solely of cellulose modified with antibody-decorated nanoparticles. • Turnaround time under 10 min. • Detection of biomarkers in respiratory samples allows monitoring local inflammation. • Compatible with decentralized health care schemes., Decentralizing COVID-19 care reduces contagions and affords a better use of hospital resources. We introduce biosensors aimed at detecting severe cases of COVID-19 in decentralized healthcare settings. They consist of a paper immunosensor interfaced with a smartphone. The immunosensors have been designed to generate intense colorimetric signals when the sample contains ultralow concentrations of IL-6, which has been proposed as a prognosis biomarker of COVID-19. This is achieved by combining a paper-based signal amplification mechanism with polymer-filled reservoirs for dispensing antibody-decorated nanoparticles and a bespoken app for color quantification. With this design we achieved a low limit of detection (LOD) of 10−3 pg mL-1 and semi-quantitative measurements in a wide dynamic range between 10−3 and 102 pg mL-1 in PBS. The assay time is under 10 min. The low LOD allowed us to dilute blood samples and detect IL-6 with an LOD of 1.3 pg mL-1 and a dynamic range up to 102 pg mL-1. Following this protocol, we were able to stratify COVID-19 patients according to different blood levels of IL-6. We also report on the detection of IL-6 in respiratory samples (bronchial aspirate, BAS) from COVID-19 patients. The test could be easily adapted to detect other cytokines such as TNF-α and IL-8 by changing the antibodies decorating the nanoparticles accordingly. The ability of detecting cytokines in blood and respiratory samples paves the way for monitoring local inflammation in the lungs as well as systemic inflammation levels in the body.

Respiratory infections caused by multi-drug-resistant

Urinary tract infections (UTI) have a high prevalence and can yield poor patient outcomes if they progress to urosepsis. Here we introduce mobile origami biosensors that detect UTIs caused by E. coli at the bedside in less than 7 minutes. The origami biosensors are made of a single piece of paper that contains antibody-decorated nanoparticles. When the urine sample contains E. coli, the biosensors generate colored spots on the paper strip. These are then quantified with a mobile app that calculates the pixel intensity in real time. The tests are highly specific and do not cross-react with other common uropathogens. Furthermore, the biosensors only yielded one false negative result when queried with a panel containing 57 urine samples from patients, which demonstrates that they have excellent sensitivity and specificity. This, along with the rapid assay time and smartphone-based detection, makes them useful for aiding in the diagnosis of UTIs at the point of care., Dr de la Rica acknowledges financial support from grants FEDER/Ministerio de Ciencia, Innovacion y Universidades/Agencia Estatal de Investigacion/-Proyecto CTQ2017-82432-R and FEDER/Ministerio de Ciencia, Innovacion y Universidades/Agencia Estatal de Investigacion/-Proyecto CTQ2017-92226-EXP as well as a Radix fellowship from IdISBa/Impost turisme sostenible/Govern de les Illes Balears.

The global COVID-19 pandemic has oversaturated many intensive care units to the point of collapse, leading to enormous spikes in death counts. Before critical care becomes a necessity, identifying patients who are likely to become critically ill and providing prompt treatment is a strategy to avoid ICU oversaturation. There is a consensus that a hyperinflammatory syndrome or a "cytokine storm" is responsible for poor outcomes in COVID-19. Measuring cytokine levels at the point of care is required in order to better understand this process. In this Perspective, we summarize the main events behind the cytokine storm in COVID-19 as well as current experimental treatments. We advocate for a new biosensor-enabled paradigm to personalize the management of COVID-19 and stratify patients. Biosensor-guided dosing and timing of immunomodulatory therapies could maximize the benefits of these anti-inflammatory treatments while minimizing deleterious effects. Biosensors will also be essential in order to detect complications such as coinfections and sepsis, which are common in immunosuppressed patients. Finally, we propose the ideal features of these biosensors using some prototypes from the recent literature as examples. Multisensors, lateral flow tests, mobile biosensors, and wearable biosensors are seen as key players for precision medicine in COVID-19.

Saturated red emitting dendrimers have been prepared for use in organic light-emitting diodes (OLEDs). The dendrimers consist of a homoleptic core iridium(III) complex comprising a 2-(thiophen-2-yl)quinoline ligand and fluorenylcarbazolyl-based first generation dendrons with n-propyl surface groups. The dendrimers differ in the position the dendron is attached to the ligand. It was found that the dendrimers had solution photoluminescence quantum yields of up to 86 ± 9%, which is amongst the highest for saturated red phosphorescent emitters. The dendrons and surface groups were found to provide sufficient processing ability to enable good quality films when blended with 4,4′-bis(N-carbazolyl)-1,1′-biphenyl (CBP). The dendrimer with the dendron attached to the quinoline unit of the ligand via a phenyl ring was found to have a film PLQY of 87 ± 10% when blended with CBP at a concentration of 10 wt%. A simple two-layer device comprising an emissive layer containing 10 wt% of the dendrimer in CBP and an electron transport layer was found to have a maximum EQE of 12% with CIE co-ordinates of (0.65, 0.34).

Detecting small variations in the levels of IL-6 is crucial for the early diagnosis of sepsis. To be useful in clinical decision-making, this requires detecting IL-6 rapidly in whole blood and with portable readers. Here we introduce immunosensors made of filter paper that use plasmonic nanoprobes to detect IL-6 rapidly in unprocessed blood with an unmodified smartphone. Key aspects of the biosensor fabrication were optimized in order to reduce the assay time without losing sensitivity. This included testing three bioconjugation routes for protein attachment to nanoprobes using gold nanoparticles covered with carboxylate or amine moieties, or polyvinylpyrrolidone (PVP), as starting materials, and using alternating layers of polyelectrolytes to bind the capture antibody to the paper substrate. Smartphone-based signal quantification was achieved with a custom-made app featuring a unique augmented reality guidance system that circumvents the need for smartphone attachments and automates all the steps involved in color quantification. The biosensors were able to detect IL-6 with a limit of detection of 0.1 pg mL(-1) and a total assay time within 17 min. They could also detect an increase in IL-6 of only 12.5 pg mL(-1) over basal levels in whole blood with 99% confidence. The high sensitivity and rapid turnaround time afforded by the optimized biosensors and the fully automated real-time densitometry app make our biosensors well suited for emergency healthcare situations such as the identification of potential sepsis cases., R. R. acknowledges financial support from FEDER/Ministerio de Ciencia, Innovacion y Universidades/Agencia Estatal de Investigacion/- Proyecto CTQ2017-82432-R (biosensor development) and Proyecto CTQ2017-92226-EXP (app development). R. R. and S. M. R. acknowledge funding from a Radix fellowship from IdISBa/Impost turisme sostenible/Govern de les Illes Balears. A. A. acknowledges a fellowship for doctoral studies from Roche (Stop fuga de cerebros program). R. A. A.-P. and N. P. P. acknowledge financial support from Spanish Ministerio de Economia y Competitividad (CTQ2017-88648R and RYC-2015-19107), the Generalitat de Cataluna (2017SGR883), the Universitat Rovira i Virgili (2018PFR-URV-B2-02), and the Universitat Rovira i Virgili and Banco Santander (2017EXIT-08).

Signal amplification in colorimetric biosensors usually requires labile reagents and/or additional steps, which are not ideal for in-field measurements. Here we show that the limit of detection of a gold nanoparticle-labeled colorimetric immunosensor can be decreased 10-fold by performing the assay on a folded piece of paper. In this approach, the intrinsic porosity of the substrate enables generating multiple signals with a single drop of reagent. This yields combined signals with higher optical density thanks to the semitransparent nature of the wet material. It will be shown that this method can decrease the limit of detection 10 times in a model immunosensor for the detection of immunoglobulins. The procedure is so straightforward that it could be easily implemented to decrease the limit of detection of microfluidic paper-based analytical devices with colorimetric readouts.

Detecting variations in the localized surface plasmon resonance (LSPR) of gold nanoparticles is a widespread approach for developing colorimetric biosensors. This is usually performed with a large spectrophotometer, which is not suitable for in-field measurements, or with the naked eye, which only allows detecting large spectral variations leading to clear changes in color. Here we demonstrate that patterns printed on paper can transduce LSPR variations caused by the aggregation of plasmonic nanosensors using a mobile device as the reader. The sensitivity of the proposed paper transducers is tested with a new enzyme-less signal generation mechanism for biosensors based on triggering the aggregation of gold nanoparticles in the presence of neutravidin. A competitive immunoassay using this mechanism and the proposed transducers can detect the model analyte C-reactive protein with a limit of detection of 3·10−8 g mL−1 within 1 h, which is comparable to an ELISA using a spectrophotometer to detect the signal. The fabrication of the transducers only requires a common toner printer, and the signal can be detected with the ubiquitous smartphone using a downloadable app, which makes the proposed detection platform ideal for developing mobile biosensors for global health applications.

Colorimetric tests are becoming increasingly popular in point-of-need analyses due to the possibility of detecting the signal with the naked eye, which eliminates the utilization of bulky and costly instruments only available in laboratories. However, colorimetric tests may be interpreted incorrectly by nonspecialists due to disparities in color perception or a lack of training. Here we solve this issue with a method that not only detects colorimetric signals but also interprets them so that the test outcome is understandable for anyone. It consists of an augmented reality (AR) app that uses a camera to detect the colored signals generated by a nanoparticle-based immunoassay, and that yields a warning symbol or message when the concentration of analyte is higher than a certain threshold. The proposed method detected the model analyte mouse IgG with a limit of detection of 0.3 μg mL–1, which was comparable to the limit of detection afforded by classical densitometry performed with a nonportable device. Whe...

Self-propelled particles are revolutionizing sensing applications thanks to a unique motion-based signal generation mechanism in which biorecognition reactions are detected as changes in the velocity of the colloids. Here a new family of self-propelled multifunctional Janus particles is introduced that enables detecting changes in particle motion colorimetrically. The particles consist of an iron oxide core that provides color and magnetism, and a Janus coating that provides biospecific recognition and locomotive properties. In this approach, biomolecular interactions trigger changes in particle motion that are detected as variations in color when spotted on a piece of paper. These variations in color are then read and quantified with a custom-made smartphone app. The high surface area and magnetism of the particles makes them ideal building blocks for developing biosensors because they allow for the rapid capture of a target molecule and the removal of non-specific interactions. Biosensors engineered with the proposed multifunctional particles were able to detect the sepsis biomarker procalcitonin at clinically relevant concentrations within 13 min in whole blood, which is faster than other approaches requiring hour-long incubation steps under controlled conditions to detect the same biomarker in purified serum. The short assay time along with the point-of-need design makes these biosensors suitable for stratifying patients according to their sepsis risk level during triage independently of resource constraints.

UV-ozone treatment is one of the most common ways to increase the work function of indium tin oxide (ITO), which is used as the transparent conducting anode in organic light-emitting diodes (OLEDs). However, the work function increase is time sensitive when the samples are left or processed in air, often returning to a similar value to that measured before UV-ozone treatment. We found that for OLEDs formed by solution processing and containing a poly(ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) hole injection layer that there was no advantage in terms of device efficiency of using UV-ozone treated ITO. However, if a triarylamine-based small molecule [N1,N3,N5-tris(4-n-butylphenyl)-N1,N3,N5-triphenylbenzene-1,3,5-triamine, 4-n-BTDAB] was introduced onto the UV-ozone treated ITO then the work function was stabilised. When 4-n-BTDAB was introduced between UV-ozone treated ITO and PEDOT:PSS, the resultant solution processed OLEDs were found to have a maximum external quantum efficiency ≈20% higher (corresponding to an absolute increase of ≈2% to around 12%) compared to devices with the same structure but without the triarylamine layer.

In this work solution-processed organic white-light emitting diodes comprising a blend of red and blue phosphorescent dendrimers are presented. In contrast to common small molecule blended-dye organic light emitting diodes (OLEDs), the bulky dendrons between the light emitting moieties increase the spacing and hamper the transfer of excitons between the dyes. The reduced transfer of the excitons from the blue dye to the red dye enables greater control over OLED color avoiding the issue in which small variations in the concentration of the red dye can dramatically change the emission color. Thus, the approach leads to enhanced manufacturing reproducibility. Transient electroluminescence measurements provide detailed insights into the charge carrier and exciton formation and transfer dynamics within the device.

A red-emissive poly(dendrimer) comprised of a norbornenyl-derived polymer backbone with a phosphorescent dendrimer side-chain has been prepared by ring-opening methathesis polymerization with a number average molecular weight of 164 kDa and a dispersity of 2.4. The dendrimer side-chain had a heteroleptic iridium(III) complex core containing two 2-phenylpyridyl ligands and one 2-(thiophen-2-yl)quinoline ligand. The 2-phenylpyridyl ligands had first generation fluorenylcarbazole dendrons with n-propyl surface groups attached and the 2-(thiophen-2-yl)quinoline ligand was linked to the polymer backbone. In spite of the presence of the two 2-phenylpyridine ligands that would normally give rise to green emission when complexed with iridium(III), the 2-(thiophen-2-yl)quinoline was responsible for the observed saturated red emission with CIE coordinates of (0.67, 0.33). The poly(dendrimer) had a high photoluminescence quantum yield (PLQY) for a red emissive species at 72 ± 7%, which was maintained when blended with 4,4′-bis(carbazol-9-yl)biphenyl (CBP) at a concentration of 10 wt % (PLQY = 74 ± 8%). Simple two-layer devices containing the blend emissive layer and an electron transporting hole blocking layer had a maximum external quantum efficiency of almost 11%.

Colorimetric detection with smartphones is ideal for point-of-care measurements because the signal reader is easily available. Densitometric detection schemes enable semiquantitative measurements but require a lightproof box to control photographic conditions and/or extensive data treatment to extract information. Approaches based on pattern recognition are not so sensitive to light artifacts but can only yield a yes/no type of answer when the signal is above or below a certain threshold. Here, we introduce a new method for detecting different concentrations of proteins as well as light artifacts with origami immunosensors and digital logic. The origami design consists of a folded piece of paper with three identical biorecognition sites so that one drop of sample generates three colorimetric signals simultaneously. The three colorimetric signals are then evaluated with an augmented reality app that generates a virtual semaphore that sequentially turns on its green, yellow, and red lights depending on the concentration of analyte. These three Boolean variables pass through "and" and "not" logic gates in a 3-to-8 decoder that enables the semiquantitative detection of proteins and adds a failsafe against erroneous results. The proposed method can detect the model analyte mouse IgG with a limit of detection and sensitivity comparable to densitometry performed under light-controlled conditions. It can also detect the sepsis biomarker procalcitonin at clinically relevant concentrations. With our approach, the detection is performed in real time, and signal processing is not required, which makes it suitable for rapid analyses by nonspecialists at the point of need.

Meeting policy requirements is essential for advancing molecular diagnostic devices from the laboratory to real-world applications and commercialization. Considering policy as a starting point in the design of new technology is a winning strategy. Rapid developments have put mobile biosensors at the frontier of molecular diagnostics, at times outpacing policymakers, and therefore offering new opportunities for breakthroughs in global health. In this Perspective we survey influential global health policies and recent developments in mobile biosensing in order to gain a new perspective for the future of the field. We summarize the main requirements for mobile diagnostics outlined by policy makers such as the World Health Organization (WHO), the World Bank, the European Union (EU), and the Food and Drug Administration (FDA). We then classify current mobile diagnostic technologies according to the manner in which the biosensor interfaces with a smartphone. We observe a trend in reducing hardware components and substituting instruments and laborious data processing steps for user-friendly apps. From this perspective we see software application developers as key collaborators for bridging the gap between policy and practice.