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Biosensors and Bioelectronics Multifunctional Motion-To-Color Janus Transducers for the Rapid Detection of Sepsis Biomarkers In

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Biosensors and Bioelectronics Multifunctional Motion-To-Color Janus Transducers for the Rapid Detection of Sepsis Biomarkers In Biosensors and Bioelectronics 140 (2019) 111346 Contents lists available at ScienceDirect Biosensors and Bioelectronics journal homepage: www.elsevier.com/locate/bios Multifunctional motion-to-color janus transducers for the rapid detection of sepsis biomarkers in whole blood T ∗ Steven M. Russella,b, Alejandra Alba-Patiñoa,b, Marcio Borgesa, Roberto de la Ricaa,b, a Multidisciplinary Sepsis Group, Balearic Islands Health Research Institute (IdISBa), Son Espases University Hospital, S Building, Carretera de Valldemossa 79, 07120, Palma de Mallorca, Spain b Department of Chemistry, University of the Balearic Islands, Carretera de Valldemossa km 7.5, 07021, Palma de Mallorca, Spain ARTICLE INFO ABSTRACT Keywords: Self-propelled particles are revolutionizing sensing applications thanks to a unique motion-based signal gen- Magnetic eration mechanism in which biorecognition reactions are detected as changes in the velocity of the colloids. Here Self-propelled a new family of self-propelled multifunctional Janus particles is introduced that enables detecting changes in Biosensor particle motion colorimetrically. The particles consist of an iron oxide core that provides color and magnetism, Smartphone and a Janus coating that provides biospecific recognition and locomotive properties. In this approach, biomo- Colorimetric lecular interactions trigger changes in particle motion that are detected as variations in color when spotted on a Procalcitonin 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. 1. Introduction Schattling et al., 2015). Multifunctional self-propelled particles have been shown to perform complex tasks autonomously, as evidenced by Multifunctional particles are versatile building blocks of hybrid magnetic self-propelled particles with chemical handles reported to materials that have novel biotechnological applications. For example, capture and transport cells (Villa et al., 2018). In sensing, it has been multifunctional particles have the potential to simultaneously diagnose demonstrated that self-propulsion can expedite biorecognition reac- and treat diseases, and to imbue biosensors with additional properties tions (Yu et al., 2014). Moreover, the motion of self-propelled bio- to improve their analytical performance (Agusil et al., 2017; Koren sensors offers a new way to detect biorecognition reactions when the et al., 2010; F. Li et al., 2018; Lu et al., 2015; Periyasami et al., 2017; ligand-receptor interactions change the velocity of the particles. Such Rosal et al., 2018). The various functions of these particles are made changes can be transduced into quantifiable signals by imaging the possible by the use of materials with specific physicochemical proper- individual trajectories of a collection of particles and measuring their ties, or by the incorporation of biomolecules, which can endow them average velocity. This approach has been successful for the detection of with biomolecular recognition and catalytic functions (Pourrahimi and a wide range of targets including pollutants (Orozco et al., 2013; Rojas Pumera, 2018). New functions also arise according to the spatial or- et al., 2016), disease biomarkers (Yu et al., 2014), viruses (Draz et al., ganization of the components in the particles. It is well established that 2018b), oligonucleotides (Van Nguyen and Minteer, 2015) and varia- Janus particles with an asymmetric coating of catalysts have locomo- tions in pH (Su et al., 2016). Recently it has been demonstrated that the tive properties mainly due to a bubble thrust (Jurado-Sánchez et al., trajectories of self-propelled microparticles in a microfluidic chip can 2017; Wang et al., 2016; Wu et al., 2015), or a diffusio- or electro- be imaged with the camera of a mobile device, therefore paving the phoretic mechanism (Ma et al., 2015; Pourrahimi and Pumera, 2018; way to implement this approach in decentralized analyses performed at ∗ Corresponding author. Multidisciplinary sepsis group, Balearic Islands Health Research Institute (IdISBa), Son Espases University Hospital, S Building, Carretera de Valldemossa 79, 07120, Palma de Mallorca, Spain. E-mail address: [email protected] (R. de la Rica). https://doi.org/10.1016/j.bios.2019.111346 Received 19 March 2019; Received in revised form 8 May 2019; Accepted 21 May 2019 Available online 25 May 2019 0956-5663/ © 2019 Elsevier B.V. All rights reserved. S.M. Russell, et al. Biosensors and Bioelectronics 140 (2019) 111346 Fig. 1. Schematic representation of the multi- functional Janus particles; The iron oxide core pro- vides magnetic and colorimetric properties, whereas the Janus coating contains anti-PCT antibodies that endow the particles with biorecognition functions. An immunoassay renders the particles covered with catalase, which triggers colloid motion in the pre- sence of H2O2. the point of need (Draz et al., 2018b, 2018a). Expanding this approach an early stage before multi-organ dysfunction becomes irreversible. for use with nanoparticles, however, faces limitations in terms of ima- Procalcitonin (PCT) is one of the most trustworthy biomarkers for ra- ging and measuring individual trajectories of nanometric objects with pidly identifying sepsis. This protein is found at undetectable levels only a mobile phone. Another limitation is that the presence of bubbles (< 0.05 ng⋅mL-1) in the serum of healthy individuals, but its con- or dust particles in the microfluidic device may result in spurious re- centration steadily increases to values higher than 2 ng⋅mL-1 during sults. Finally, mobile phone attachments and microfluidic chips, al- sepsis (Meynaar et al., 2011). Although current laboratory tests can though inexpensive, are additional pieces of hardware that require detect PCT in about 30 min, PCT tests are generally not performed until transportation and training for use, which impacts their suitability in a patient arrives to the intensive care unit (ICU), which delays diagnosis decentralized settings. and results in a poorer prognosis. A rapid test that could detect PCT in a Here we introduce a new family of multifunctional particles that drop of blood within 10-15 min could help prioritize patients during have been designed not only to excel in biosensing, but also to exploit a triage so that they receive life-saving treatments as soon as possible novel motion-to-color signal generation mechanism for in-field ana- (Reddy et al., 2018). The multifunctional particles reported here are lyses. The particle design is shown in Fig. 1. The particles have a especially engineered to meet this challenge. With our design, the magnetic iron oxide core that enables fast and efficient washing steps in capture of PCT is accelerated by increasing the concentration of parti- order to remove non-specific interactions in biosensing applications. cles in contact with the sample, while potential non-specific interac- The characteristic brown color of this material also makes the particles tions present in the blood matrix are rapidly removed through magnetic amenable for colorimetry, and the colloidal nature of the biosensor washings. The motion-to-color transduction mechanism generates sig- ensures a high surface area for expediting the capture of a target mo- nals within seconds that are read in real time. The whole assay takes lecule. The iron oxide core is coated with antibodies through avidin- place in a record time of 13 min, therefore making it useful for detecting biotin interactions following a Janus design. The antibodies in the PCT rapidly at the point of need. Recently biosensors have been pro- Janus coating capture the target molecule by means of a competitive posed for detecting PCT with very low limits of detection. However, immunoassay (Fig. 2A). This results in the binding of the enzyme cat- they require hour-long incubation steps under controlled temperature o alase to the particles, which generates O2 bubbles and induces their conditions (37 C), and therefore they are not suitable for the rapid motion (Keller et al., 2018). Since particle velocity is directly related to diagnosis of sepsis. Furthermore, they were only tested in serum, which the number of enzymes bound to the colloids through biospecific in- requires an additional purification step from blood that delays the de- teractions, this approach enables quantifying the concentration of the tection of PCT even more (Chen et al., 2018; C. Li et al., 2018; Sui et al., target molecule by measuring the average velocity of the particles. In 2018). Finally, it should be noted that the proposed multifunctional our design, the combination of color and self-propulsion in the same particles could be easily adapted for detecting other blood biomarkers particle gives rise to a new method for evaluating changes
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