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. 2026 Oct 5;6(5):988–999. doi: 10.1021/acsnanoscienceau.6c00109

QMini: A Portable Device for Infectious Disease Testing

Nafisa Mahbub †,‡,§, Matthew Osborne †,‡, Hongmin Chen †,‡, Ayokunle Lekuti †,‡,§, Warren C W Chan †,‡,∥,*
PMCID: PMC13693170  PMID: 42921413

Abstract

Widespread testing identifies infectious diseases early and reduces silent transmission. The large size of devices for testing limits their use in the field. We developed a portable device that miniaturizes nucleic acid testing: the QMini. The QMini simplified a fluidic module using direct connections between pumps and reaction chambers. It shielded an optical module from ambient light with a 3D-printed enclosure. We applied the QMini to detect synthetic nucleic acid sequences of respiratory syncytial virus B, SARS-CoV-2, and influenza A with a bead-based assay using quantum dot barcodes. The QMini detected 500 copies of respiratory syncytial virus B, 500 copies of SARS-CoV-2, and 1,000 copies of influenza A. We observed limited cross-reactivity in the QMini with six nontarget viral nucleic acid sequences. The QMini advances the portability of nucleic acid testing using quantum dot barcodes through device miniaturization.

Keywords: diagnostics, devices, portability, miniaturization, quantum dots

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Introduction

Infectious diseases are a major cause of illness worldwide. They account for 28% of the global disease burden. Resource-limited countries bear a disproportionate share of this burden. In these settings, infectious diseases comprise at least four of the top ten leading causes of death. Early diagnosis is critical for effective treatment and containment. Outbreaks can quickly overwhelm strained healthcare systems.

Diagnostic technologies help manage the spread of infectious diseases. They identify pathogens, guide treatment, and drive public health responses. Timely testing improves patient care and population-level outcomes. For example, delayed diagnosis of human immunodeficiency virus increased the risk of death. Countries with greater testing coverage experienced lower mortality during the COVID-19 pandemic. Traditional diagnostic workflows rely on centralized laboratories. Only 19% of people in resource-limited countries have access to basic diagnostic testing from primary care facilities.

Point-of-care diagnostic tools detect infectious diseases at or near the site of care. This proximity reduces reliance on laboratories. It shortens the time to treatment and supports faster outbreak response. In tuberculosis-endemic settings, point-of-care testing reduced the median time to treatment from 56 to 5 days. Testing at triage centers supported early isolation of suspected cases and facilitated contact tracing during the West African Ebola outbreak. , Point-of-care diagnostic tools can therefore improve patient outcomes and disease containment.

Antigen tests are diagnostic tools used widely at the point of care. They detect the presence of pathogen-specific proteins using antibodies. Antigen tests do not require complex instrumentation and can be adapted to compact formats. Rapid antigen tests expanded access to decentralized testing during the COVID-19 pandemic. However, these tests have lower sensitivity than molecular tests. This limitation increases the risk of false negatives.

Molecular tests are commonly used in laboratory settings. , They detect pathogen-specific nucleic acid sequences with high sensitivity. These systems require complex instrumentation and have large device footprints. For example, Cepheid’s one-module GeneXpert instrument is 9,270 cm3, excluding the external computer. The QBox developed by Osborne et al. is 11,000 cm3. Their large size limits portability and deployment to point-of-care settings.

Decentralized molecular testing brings accurate nucleic acid detection closer to the site of care. This approach is critical for infections caused by pathogens with recurrent outbreak potential. For example, respiratory syncytial virus, SARS-CoV-2, and influenza virus cocirculate seasonally and produce overlapping clinical presentations. In 2022, the United States faced a triple epidemic from these three respiratory pathogens. Their similar profiles made it difficult to distinguish each infection using symptoms alone. Molecular testing at the point of care would help differentiate pathogens that present similarly in patients.

Miniaturizing molecular tests is challenging because they require the integration of multiple functions in a small footprint. , Molecular tests need to extract nucleic acids from biological samples. This extraction step requires fluidic components to move sample and lysis reagents between reaction chambers. Molecular tests next amplify target nucleic acid sequences. Amplification requires thermal control to maintain the reaction temperature. The amplified target sequences are detected using readout methods such as fluorescence microscopy. Fluorescence microscopy requires excitation sources, emission filters, lenses, and cameras. This technique often employs organic fluorophores to detect target sequences. These fluorophores can increase device complexity. Different fluorophores may need separate excitation sources or emission filters for detection. The workflow itself necessitates power supplies and electronic controls to operate pumps, heaters, light sources, and imaging components. Molecular testing in a miniaturized platform requires maintaining these functions while reducing the size of the system. ,

Our group developed the QBox to automate molecular testing using the quantum dot barcode assay. This assay detects multiple nucleic acid target sequences simultaneously. − It identifies each target via colocalization of fluorescence signals from a quantum dot barcode with target-specific reporter probes. Fournier-Bidoz et al. generated a library of more than 100 spectrally distinct quantum dot barcodes. This library highlights the potential of these barcodes to support scalable detection of multiple pathogens. The broad excitation and narrow emission spectra of quantum dot barcodes reduce the number of optical components required to distinguish them from each other. A single excitation source and emission filter can detect multiple barcodes. Scalable detection differentiates infectious diseases with similar presentations efficiently. The QBox detected up to five molecular targets. A portable QBox could extend molecular testing of multiple pathogens to point-of-care settings.

The World Health Organization introduced the ASSURED criteria to guide the design of point-of-care diagnostic tools. Land and colleagues later expanded these criteria into the REASSURED framework. The framework recommends hand-held formats to maximize portability. Hand-held use is constrained by human ergonomics. McConville et al. reported an average adult hand size of 19.3 by 8.9 cm. Objects of 3,300 cm3 can comfortably be carried in one hand. Existing devices for molecular testing exceed this volume. Miniaturizing molecular tests to hand-held formats will support deployment to point-of-care settings.

We did not develop the QBox with an intended maximum volume of 3,300 cm3. This lack of an initial size constraint introduced difficulties during miniaturization. The QBox used a 12-port rotary valve, midsized pumps, and long tubing paths to move fluids between reaction chambers and reagent reservoirs. These components supported automated fluid handling but occupied substantial volume. The QBox housed its optical module in a large box configuration. This configuration shielded the imaging system from ambient light but introduced unused space into the device. Miniaturizing the QBox required redesigning fluidic and optical modules. The fluidic module needed to shorten the distance between pumps, reaction chambers, and reagent reservoirs. The optical module had to eliminate dead space. Reducing the QBox from 11,000 cm3 to 3,300 cm3 demanded significant changes to the device architecture.

Here, we miniaturized the QBox into a portable 3,300 cm3 device: the QMini. We engineered (1) a fluidic module to minimize the distance between pumps and reaction chambers and (2) an enclosure to reduce the penetration of ambient light into the optical module. We characterized the fluidic and optical modules of the QMini to assess their functionality. We evaluated the QMini using the quantum dot barcode assay. The QMini detected nucleic acid sequences from respiratory syncytial virus B, SARS-CoV-2, and influenza A. It demonstrated limited cross-reactivity with nontarget viral nucleic acid sequences. The QMini supports the translation of molecular tests to point-of-care settings through miniaturization.

Results

The QMini Miniaturized the QBox to 3,300 cm3

We wanted to miniaturize the QBox from 11,000 cm3 to 3,300 cm3 (Figure A). A device of this volume is suitable for portable use in point-of-care settings based on recommendations by the World Health Organization. , We retained the two-unit design of the QBox. The two-unit design included a reusable base and a disposable cartridge (Figure B). The base processed the sample in the cartridge using fluidic, optical, and electronics modules (Figure C). These modules facilitated precise control over reaction conditions applied to the cartridge. The cartridge contained the components required for testing a single sample. Cartridges can be swapped to test different pathogens. The two-unit design reduced the risk of cross-contamination between samples. We modified the modules of the base and the components of the cartridge to miniaturize the QBox.

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The QMini device is 3,300 cm3. (A) The QMini scales down the size of the QBox by 3-fold. (B) It consists of a reusable base and a disposable cartridge. (C) The fluidic, optical, and electronics modules of the base process a sample in the cartridge. (D) The fluidic module uses four peristaltic pumps to drive fluid flow in the cartridge via a connector block. (E) The optical module is shielded from ambient light by a 3D printed enclosure. It operates an imaging system and a translation stage to visualize fluorescence signals emitted by quantum dot barcodes and reporter probes to detect target sequences in the sample. (F) The electronics module powers and controls electrical components in the QMini using a Raspberry Pi, voltage step-down converters, protoboard, and battery or power supply.

The QMini workflow began with sample loading into the extraction chamber of the disposable cartridge. FastAmp Viral and Cell Lysis Solution was dispensed into this chamber to release nucleic acids into solution. The extracted sample was then moved to the amplification chamber. It underwent recombinase polymerase amplification to produce multiple copies of target nucleic acid sequences. The amplified products were transferred to the detection chamber. They mixed with quantum dot barcodes and target-specific reporter probes. Target binding produces colocalized fluorescence signals from quantum dot barcodes and reporter probes. The processed sample was loaded onto a microfluidic slide beneath the optical module. The optical module captured images of the fluorescence signals from the quantum dot barcodes and reporter probes. The images were analyzed to identify positive or negative signals for each target sequence.

The QMini reconfigured the fluidic module of the QBox to drive sample processing in the cartridge (Figure D). The module consisted of four miniature peristaltic pumps. These pumps reduced contamination by restricting fluid flow to the tubing only. The tubing of the pumps terminated at connectors on a 3D-printed block in the base. The proximity of the pumps to the block shortened the fluid path and enabled greater miniaturization of the fluidic module. The fluidic module processed the cartridge once the cartridge was attached to the connectors on the block.

We enclosed the optical module that imaged fluorescence signals from quantum dot barcodes and fluorophore-labeled reporter probes (Figure E). The imaging system was adapted from the QBox (Supplementary Figure S1A). A light-emitting diode excited quantum dot barcodes of different fluorescence signatures assigned to target nucleic acid sequences. A laser diode excited reporter probes. Quantum dot barcodes and reporter probes produced overlapping fluorescence signals when bound to target nucleic acid sequences. An infinity-corrected imaging system collected and focused these signals onto a 2-megapixel color camera (Supplementary Figure S1B). Emission filters selected signals from the quantum dot barcodes or reporter probes. A compact 3D-printed enclosure prevented interference from ambient light (Figure E). A vertical translation stage moved the cartridge to the focal point of the imaging system (Supplementary Figure S1C). This enclosure eliminated dead space present in the optical module of the QBox.

We reduced the size of the electronics module that operated electrical components in the fluidic and optical modules (Figure F). A 14 V, 5 Ah lithium-ion battery powered the device. Lithium-ion batteries have high energy density. They can act as a compact power supply. A voltage step-down converter reduced 14 V from the battery to 5 and 3 V on a protoboard power rail. Permanent soldered connections on a protoboard provided strong electrical contact and long-term circuit reliability. The protoboard distributed power to components including a Raspberry Pi. The Raspberry Pi executed programs to control electrical components in the device. Electrical components requiring higher voltages were connected directly to the battery in a parallel circuit (Supplementary Figure S2).

We redesigned the cartridge. The cartridge was self-contained and required only sample loading by the user (Supplementary Figure S3A). Self-containment eliminated additional preparation and handling steps. The cartridge consisted of reaction chambers, a reagent pack, and a cartridge connector frame (Supplementary Figure S3B–D). Spin columns were adapted as reaction chambers because their negatively charged walls prevented nucleic acid adsorption. Each reaction chamber contained lyophilized reagents for extraction, amplification, and detection. The processed sample was loaded onto a microfluidic slide beneath the optical module for imaging. A reagent pack of 3D-printed bottles stored buffers and collected waste. Bottle dimensions were chosen to minimize dead space. The bottles were 3D-printed using polypropylene for watertightness. The reagent pack removed the need for users to add buffers or dispose of waste during testing.

We miniaturized the 11,000 cm3 QBox to the 3,300 cm3 QMini (Figure A). The QMini weighed 1.5 kg and had a volume of 3,300 cm3. Its physical properties were comparable to a single-slice toaster. The device could be easily carried in one adult hand and required minimal table space. The reduced size and weight of the QMini position it as a hand-held, portable nucleic acid testing device suitable for point-of-care use.

Fluid Path Shortening Reduced the Need for Bulky Components

We wanted to shorten the fluid path between the reaction chambers and reagent bottles. A shortened fluid path lowers the device’s physical footprint by reducing the number of bulky components. The QMini eliminated the 12-port rotary valve and midsized pumps in the QBox (500 cm3). Instead, it routed fluids through a connector-to-connector apparatus using four miniature pumps (250 cm3) (Figure A). The apparatus consisted of two 3D-printed blocks fitted with straight connectors. We attached each block to either the reusable base or disposable cartridge. The pumps connected to the block in the base. Tubing from the reaction chambers and reagent bottles terminated at the block in the cartridge. When the user slid the cartridge into the base, the connectors on each of the blocks created a slip fit (Figure B). The slip fit produced a physical link held together by friction. Pumps in the base controlled fluid movement in the cartridge through this connector-to-connector apparatus.

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The fluidic module minimized the path between cartridge components. (A) The base consists of four pumps that terminate at connectors adhered to a 3D-printed block. Tubing attached to the reaction chambers and reagent pack ends at connectors glued onto a secondary 3D-printed block in the cartridge. The physical link between the two 3D-printed blocks completes the flow path. (B) The connector-to-connector apparatus is held together by a 0.41 mm slip fit. (C) The connector-to-connector apparatus demonstrates significant leak-tightness with a liquid loss of only 1.7%. Simple linear regression demonstrated R 2 > 0.99. (D) The flow rates of the QMini and QBox pumps are directly proportional to the duty cycle applied. The QMini pumps (blue, circle) demonstrate a greater flow-rate range than the QBox pumps (green, square). (E) The QMini pumps and connector-to-connector apparatus can maintain steady and consistent flow rates for various duty cycles and viscosities. Viscosity values included 1 mPa·sec (blue, circle), 2 mPa·sec (green, star), 3 mPa·sec (gold, hexagon), 4 mPa·sec (taupe, diamond), 5 mPa·sec (purple, triangle), and 6 mPa·sec (pink, square).

We evaluated leak-tightness, pump performance, and viscosity robustness to assess the function and reliability of the apparatus. Comparisons of input and output volumes across the apparatus established leak-tightness. We compared the performance of the QBox and QMini pumps by measuring flow rates at varying duty cycle percentages. The highest duty cycle applied was 100%, corresponding to the 5 V, as in the QBox. We determined viscosity robustness by quantifying flow rates of fluids with viscosities ranging from 1 to 6 mPa·sec. This range occurs in sample matrices like nasal swabs in viral transport media, urine, and saliva. , The apparatus demonstrated a liquid loss of 1.7 ± 1.2% between the input and output volumes (Figure C). This minimal liquid loss indicated reliable sealing at the interface of the connectors on each block. The QMini pumps produced a range of flow rates between 4.18 μL/sec and 71.51 μL/sec (Figure D). The QBox pumps could not operate below 50% duty cycle and generated flow rates between 0.85 μL/sec and 12.78 μL/sec (Figure D). The wide operating range of the QMini pumps within 100% duty cycle makes them ideal for a portable device. It allows flexible control of fluid flow without adding extra bulky components. The flow rates for the QMini pumps did not change across the range of viscosities (Figure E). This consistency demonstrates versatile liquid handling with the QMini pumps in the apparatus. The fluidic module of the QMini provided leak-tight, efficient, and controllable fluid transport suitable for decentralized testing.

The Enclosed Optical Module Eliminated Unused Volume without Reducing Performance

We wanted to reduce unused volume in the QBox to improve space efficiency. The QBox had a large box configuration that housed its optical module. This box configuration accounted for 1,680 cm3. Empty space comprised 70% of the box configuration’s total volume. We miniaturized the optical module by enclosing it in a compact 3D printed housing. The 3D printed housing consisted of three major components: an L-shaped block, a rectangular tower, and a square cover (Supplementary Figure S4). The L-shaped block covered the objective lens and emission filter slide. The rectangular tower shielded the tube lens. The square cover encased the camera. This enclosure configuration in the QMini replaced the box configuration in the QBox. It reduced the system volume from 1,680 cm3 (QBox) to 445 cm3 (QMini) (Figure A). This reduction eliminated approximately 74% of the QBox optical module’s original volume.

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An enclosed optical module reduced unused volume in the QBox. (A) Two configurations of the optical system as box and enclosure. The box configuration in the QBox covers the entire system and includes dead space. The enclosure configuration in the QMini consists of compact housing that envelops the imaging system. (B) The negative (pink) and positive (orange) conditions demonstrate a significant difference (p < 0.001) in each configuration. The negative condition is nuclease-free water. The positive condition is consisted of a 50-nucleotide single-stranded DNA control (Table S1). Statistical significance was determined using a two-way ANOVA. (C) The limit of detection for the box (square, pink) and enclosure (orange, circle) configuration was 5 × 1011 DNA copies. We generated each curve using varying DNA copies of a target sequence in SARS-CoV-2 (Table S1). (B-C) Three independent samples were run per condition.

We compared the configurations for negative–positive discrimination and limit of detection. We performed the quantum dot barcode assay on nuclease-free water and 1 × 1013 DNA copies of a single-stranded 50-nucleotide sequence (Table S1). We chose this copy number because it is representative of the copy numbers produced after recombinase polymerase amplification. The 50-nucleotide sequence served as a positive control for the assay. If the quantum dot barcode assigned to this sequence did not produce a positive fluorescence signal, we considered the reaction unsuccessful. We selected a 50-nucleotide length because it supported efficient sandwich hybridization and preserved sequence specificity. Fluorescence signals from these samples were measured using the box and enclosure configurations to characterize negative–positive discrimination. We conducted the quantum dot barcode assay on varying numbers of DNA copies of a single-stranded sequence of SARS-CoV-2. The copy numbers were varied from 1 × 1010 to 1 × 1013 (Table S1). We used the SARS-CoV-2 DNA sequence to represent the amplicon product generated after recombinase polymerase -amplification. This copy number range reflects postamplification numbers detectable using fluorescence microscopy. We quantified fluorescence signals from the samples using each configuration to determine their limits of detection. These comparisons established whether enclosing the optical module reduced fluorescence signal readout performance. Each configuration demonstrated strong negative–positive discrimination with significant differences in fluorescence signals for negative and positive samples (Figure B). The limit of detection for both systems was 5 × 1011 DNA copies of SARS-CoV-2 (Figure C). These results indicated that the enclosure configuration reduced unused volume in the box configuration without compromising fluorescence detection performance.

The QMini Cartridge Executed the Extraction, Amplification, and Detection Steps Independently

We wanted to validate whether the cartridge could independently perform extraction, amplification, and detection. Stepwise validation confirms that each step works reliably before integration into a single workflow.

The extraction step released nucleic acids from intact biological samples into solution (Figure A). We selected FastAmp Viral and Cell Lysis Solution for extraction. FastAmp did not require additional purification steps or centrifugation. The QBox used the same reagent to lyse SARS-CoV-2 virions from nasopharyngeal samples in prior work. Qian et al. and Arizti-Sanz et al. have also leveraged FastAmp to support SARS-CoV-2 virion lysis. , In this study, we chose human glioblastoma cells (U87) and mouse brain endothelial cells (bEnd.3) as model biological samples with abundant nucleic acid content. We did not use these cells as direct proxies for respiratory virions. We evaluated whether the QMini cartridge could perform the fluid handling and incubation steps required for extraction in this experiment. We loaded the human glioblastoma cells (U87) and mouse brain endothelial cells (bEnd.3) into the extraction chamber. A pump dispensed FastAmp into the extraction chamber. We quantified the amount of nucleic acids released into solution after 5 min. The extraction step established a positive linear relationship between the number of cells and fluorescence intensity of nucleic acids in solution (Figure B). Incubation with FastAmp in the QMini cartridge lysed the cells.

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The QMini cartridge executed three steps: extraction, amplification, and detection. The QMini performs extraction, amplification, and detection steps for nucleic acid testing. (A) The QMini releases nucleic acids, amplifies target nucleic acid sequences, and detects those target sequences using quantum dot barcodes and reporter probes. (B) The extraction step in the QMini demonstrates a positive linear relationship between the number of cells in the sample and the amount of nucleic acids released into solution (R 2 > 0.90). The human U87 glioblastoma cells (blue, square) and the bEnD.3 cells (pink, circle) were used as intact biological samples to evaluate the extraction step. (C) The QMini amplified target sequences from respiratory syncytial virus B (in blue), SARS-CoV-2 (in green), and influenza A (in pink). The negative and positive conditions for each pathogen included its specific primer set. Nuclease-free water was the negative condition and 1 × 105 copies of a pathogen’s target sequence comprised the positive condition. A two-way ANOVA showed a significant difference (p ≤ 0.0001) between each condition for all target nucleic acid sequences. (D) The detection step in the QMini presents with a limit of detection of 5 × 1011 for respiratory syncytial virus B (blue, circle), SARS-CoV-2 (green, square), and influenza A (pink, triangle). (B-D) Three independent samples were run per condition.

The amplification step produced multiple copies of target sequences corresponding to each pathogen of interest (Figure A). We used recombinase polymerase amplification because it required a single temperature of 40 °C for 15 min. This isothermality reduced the complexity of the heating mechanism and the power consumption of the device. We loaded either nuclease-free water or 1 × 105 copies of target double-stranded DNA sequences from respiratory syncytial virus B, SARS-CoV-2, or influenza A into the extraction chamber. We selected 1 × 105 copies of the target sequence to functionally evaluate amplification in the QMini. This copy number is below the limit of detection for the quantum dot barcode assay using fluorescence microscopy. Successful amplification increases the copy number enough to produce colocalized fluorescence signals from the quantum dot barcodes and reporter probes. A pump drew the samples into the amplification chamber. The samples mixed with lyophilized reagents at 40 °C for 15 min. We measured fluorescence signals from the amplified samples. The amplification step demonstrated a significant difference in fluorescence intensity between nuclease-free water negative controls and samples containing the target sequence (Figure C). The QMini cartridge amplified target sequences from respiratory syncytial virus B, SARS-CoV-2, and influenza A.

The detection step confirmed the presence of each target sequence (Figure A). Quantum dot barcode assays can detect multiple pathogens simultaneously without increasing device size. We loaded varying copy numbers of target sequences from respiratory syncytial virus B, SARS-CoV-2, or influenza A into the extraction chamber. The copy numbers varied from 1 × 1010 to 1 × 1013 to simulate a postamplification range. A pump drew the samples into the amplification chamber. The amplification chamber was heated to 95 °C for 5 min to denature the target sequences in the sample. The samples were drawn into the detection chamber and mixed with lyophilized reagents for 20 min. We quantified the fluorescence signals from the samples at each copy number. Analysis of the detection step determined a limit of detection of 5 × 1011 copies for all three target nucleic acid sequences in the QMini cartridge (Figure D). This limit of detection is comparable to that of the QBox for SARS-CoV-2. These findings confirmed that the QMini cartridge can perform the fluid handling and incubation steps required for extraction, as well as the amplification and detection of target nucleic acid sequences.

The QMini Detected Low Copy Numbers of Viral Target Nucleic Acid Sequences

We wanted to characterize the QMini’s analytical sensitivity. Analytical sensitivity determines the limit of detection of the device. The limit of detection is the lowest copy number of a target sequence that produces a positive signal compared to the signal from a negative control. This metric allows for comparisons of the QMini with existing systems. We loaded nuclease-free water or low copy numbers of target sequences from respiratory syncytial virus B, SARS-CoV-2, or influenza A into the extraction chamber. We varied the copy numbers of each sequence from 1 × 101 to 1 × 105. The QMini cartridge executed the amplification and detection steps. We quantified the fluorescence intensities produced by the samples using the optical module in the QMini. We calculated the limit of detection to be 500, 500, and 1,000 copies for respiratory syncytial virus B, SARS-CoV-2, and influenza A (Figure A). Clinically relevant copy numbers vary across pathogens, sample types, and stages of infection. For example, the World Health Organization target product profile for acute SARS-CoV-2 point-of-care testing defines an acceptable limit of detection as 1 × 106 copies/mL. The QMini detected each target nucleic acid sequence at low absolute copy numbers.

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Analytical validation of the QMini. (A) The limit of detection for the QMini’s entire workflow is 500, 500, and 1,000 copies for target nucleic acid sequences of respiratory syncytial virus B (blue, circle), SARS-CoV-2 (green, square), and influenza A (pink, triangle). (B) The QMini showed limited cross-reactivity with nontarget viral nucleic acid sequences from respiratory syncytial virus B (RSV B), influenza A, Middle East respiratory syndrome coronavirus (MERS), Lassa virus, Marburg virus, and Rift Valley fever virus. Nuclease-free water served as the negative control; SARS-CoV-2 target nucleic acid sequence was the positive control. An ordinary one-way ANOVA demonstrated statistical significance (p < 0.0001) only between the negative and positive controls. All other comparisons to the negative control were not significant (p > 0.05). (A-B) Three independent samples were run per condition.

The QMini Demonstrated Limited Cross-Reactivity with Six Nontarget Viral Nucleic Acid Sequences

We wanted to evaluate the QMini’s analytical specificity. Analytical specificity is characterized by using a cross-reactivity test. Cross-reactivity tests determine if the device produces positive signals for nontarget sequences. Minimal cross-reactivity reduces the likelihood of false positives. We selected the cross-reactivity panel to evaluate the SARS-CoV-2 assay against respiratory-relevant and diverse nontarget viral sequences. We included sequences derived from respiratory syncytial virus B, influenza A, and Middle East respiratory syndrome coronavirus because these viruses have clinical relevance to SARS-CoV-2 testing. We added sequences from Lassa virus, Marburg virus, and Rift Valley fever virus to test whether diverse nontarget sequences produced nonspecific amplification or positive reporter signals in the quantum dot barcode assay. We loaded our samples into the extraction chamber. Each sample consisted of nuclease-free water or 1 × 105 copies of a target sequence from SARS-CoV-2 or 1 × 105 copies of a nontarget sequence. The QMini cartridge carried out the amplification and detection steps. We used the QMini’s optical module to quantify the fluorescence intensities of each sample. Only the target sequence from SARS-CoV-2 produced fluorescence signals significantly different from the fluorescence signals of the negative control (Figure B). The QMini exhibited limited cross-reactivity with nontarget viral nucleic acid sequences.

Discussion

Infectious diseases remain a major global health challenge. Resource-limited countries are particularly vulnerable due to reduced access to centralized laboratory testing. Point-of-care testing supports fast treatment decisions and early disease containment. Antigen tests are portable but have lower sensitivity compared to molecular tests. , Nucleic acid tests offer higher sensitivity at the cost of larger device footprints. Miniaturizing nucleic acid tests would expand access to sensitive diagnostics.

Industry and academic researchers have driven the development of point-of-care molecular diagnostics. Cepheid’s GeneXpert, BioFire’s Spotfire, and Becton Dickinson’s MAX devices demonstrated high sensitivity. They are all approximately 10,000 cm3 or greater. ,, Academic laboratories have designed small devices using microfluidics. , These microfluidic devices are often operated by large external instrumentation. For example, researchers built a 14,000 cm3 unit to operate a cartridge. These devices are well-suited for laboratory testing. They are difficult to deploy in settings such as primary care clinics or community centers due to their size.

We previously reported the QBox. The QBox automated the quantum dot barcode assay. Quantum dot barcodes can detect multiple molecular targets with high sensitivity and specificity. − However, the QBox remained too large for portable use at 11,000 cm3. We built the QMini to retain the quantum dot barcode assay workflow of the QBox in a hand-held format. The QMini adapted the fluidic, optical, and electronic modules of the QBox into a hand-held 3,300 cm3 device. The connector-to-connector apparatus in the fluidic module facilitated leak-tight and efficient fluid transport. The compact enclosure of the optical module minimized physical dead space and retained imaging performance. Analytical validation demonstrated that the QMini detected nucleic acid sequences from respiratory syncytial virus B, SARS-CoV-2, and influenza A. We quantified the limit of detection for each target nucleic acid sequence at or below 1,000 copies. Limited cross-reactivity with six nontarget viral nucleic acid sequences supports the future use of the QMini in the detection of multiple pathogens simultaneously. The QMini will be validated for clinical sensitivity and specificity using patient samples in future work to confirm its accuracy.

The QMini’s modular two-unit design allows for greater operational flexibility. The disposable cartridge reduces contamination risk between samples and allows for testing of different pathogen panels without modifying the reusable base. The quantum dot barcode assay can detect different pathogens via reagent changes only. In this study, the QMini detected target nucleic acid sequences of respiratory syncytial virus B, SARS-CoV-2, and influenza A just by swapping cartridges. This modularity will support expansion into testing different pathogen panels. Future optimization of assay kinetics, reagent lyophilization, and sample preparation steps will reduce total assay time and extend shelf life.

Further iterations of the QMini can engage in real-time result interpretation and wireless data transmission using the onboard Raspberry Pi. Python scripts can analyze the quantum dot barcode and reporter probe images to provide a positive or negative result for each pathogen of interest. SQL databases can store the results of each sample. These data can be wirelessly transmitted and stored for remote monitoring and epidemiological data aggregation. Researchers have developed databasing applications to track infections in the community. These further developments will position the QMini as a portable platform for nucleic acid testing in decentralized settings. We envision the use of a future iteration of the QMini in point-of-care settings such as community centers, primary care clinics, and urgent care centers.

The QMini’s physical footprint and volume represent a 3-fold reduction compared to established diagnostic systems such as the GeneXpert and QBox. This downsizing aligns with the “equipment-minimal” criterion of the REASSURED framework. This criterion recommends a hand-held size for diagnostic tools in the field to ensure portability. At 3,300 cm3 and 1.5 kg, the QMini is a hand-held platform. The QMini is a working prototype. Other criteria in the framework require future evaluation. For example, the “affordability” criterion cannot be addressed without manufacturing cost analysis. We employed the framework to motivate the design of the QMini. This approach positions the QMini as a miniaturized platform for nucleic acid testing using quantum dot barcodes.

Conclusion

A hand-held device for molecular testing would decentralize diagnostics. Many molecular devices have large device footprints that limit deployment to the point of care. Complex instrumentation facilitates the processes required to achieve high analytical performance. Miniaturizing the QBox called for coordinating the fluidic, optical, and electronic modules within a confined space. In the QMini, we redesigned each QBox module while retaining the base-cartridge architecture. We validated each module separately before integrating them together into the 3,300 cm3 space of our device. The QMini demonstrated low limits of detection and little cross-reactivity for nucleic acid sequences from three respiratory pathogens. We envision the continued development of the QMini with clinical validation and integration of automated image analysis and wireless reporting. The QMini could help expand access to quantum dot barcode-based molecular testing in point-of-care settings.

Methods

Build of the QMini

We 3D printed the housing and most components of the QMini using an Ultimaker S3 and polylactic acid filament (3D Printing Canada). Waterproof components were printed with polypropylene (Ultimaker), and heat-resistant components were printed with acrylonitrile butadiene styrene (3D Printing Canada). The fluidic module consists of four 1.5 mm-diameter 3 V peristaltic pumps (Clark Solutions), a 3D-printed polylactic acid block, 1/16” polypropylene straight and tee connectors (McMaster-Carr), and 1/16” silicone rubber tubing (McMaster-Carr). The optical module was adapted from Osborne et al. We 3D printed three components using black polylactic acid to enclose the optical module. The L-shaped block enclosed the excitation sources, objective lens, emission filters, and iris. It consisted of two orthogonal rectangular prisms. Prism A had dimensions 104.8 × 34.6 × 2.5 mm, and Prism B had dimensions of 104.8 × 31.2 × 2.5 mm. Prism A included slits for the insertion of the rectangular tower. The rectangular tower shielded the tube lens and the camera. It had dimensions of 54.0 × 49.0 × 105.0 mm. The square cover slid onto the rectangular frame. The square cover was 57.0 × 62.0 × 32.0 mm. These three components comprised the enclosure for the optical module in the QMini. The electronics module in the QMini includes a Raspberry Pi 4 Model B (CanaKit), 7” HDMI LCD touchscreen (SunFounder), 5 V 2A buck converter, 3 V 2A buck converter (Creatron Inc.), TIP120 Darlington transistors (Creatron Inc.), a DC and Stepper Motor HAT (Adafruit), and a Gold-Plated Protoboard (Gikfun). These boards were powered using a 14 V 5 Ah lithium-ion battery pack (Aegis). We adapted the heating system and modified the cartridge design from Osborne et al. The cartridge included a 3D-printed polylactic acid block with nine adhered 1/16” polypropylene straight connectors (McMaster-Carr) and a reagent pack. This pack included a 3D-printed polylactic acid holder and three polypropylene reagent/waste bottles closed with 3D-printed polylactic acid caps.

3D Printing of Reagent and Waste Bottles

We fabricated custom reagent and waste bottles using fused deposition modeling 3D printing. Each bottle had an internal volume capacity of 4.25 mL. We constructed the bottles in an Ultimater 2+ (3D printer with polypropylene filament. Prints were prepared using the Ultimaker Cura slicing software. We set the layer height to 0.2 mm, wall thickness to 0.8 mm, infill density to 100%, infill pattern to quarter cubic, print speed to 20 mm/sec, and fan speed to 20%. During printing, the nozzle temperature was 240 °C and the build plate temperature was 105 °C. Nine reagent and waste bottles were printed per run.

Characterization of the Connector-to-Connector Apparatus

The connector-to-connector apparatus was 3D-printed using an Ultimaker S3 and polylactic acid filament (3D Printing Canada) in two units. The first unit modeled the base 3D-printed block and was mounted on a stage. The second unit replicated the cartridge 3D-printed block. Both units had nine 1/16” polypropylene straight connectors (McMaster-Carr) (Supplementary Figure S3D). The two units were pressed together until the connectors formed a physical link. We attached 1/16” silicone rubber tubing (McMaster-Carr) to the other side of the connectors to complete the fluidic network (Figure B). A 1.5 mm diameter 3 V peristaltic pump (Clark Solutions) flowed a liquid out of an input reservoir, through the connector-to-connector apparatus, and into a waste reservoir. We characterized leak-tightness by flowing double-distilled water of known volumes through the apparatus. 1.6 mm diameter 6 V peristaltic pumps (APT Instruments) from the QBox were compared to 1.5 mm diameter 3 V peristaltic pumps from the QMini. We flowed double-distilled water through the apparatus while changing the voltage applied to the pumps. Liquid handling of the apparatus was assessed by flowing liquids of different viscosities through it. We varied viscosity by mixing double-distilled water with ultrapure glycerol (Invitrogen).

Characterization of the Box and Enclosure Configurations

The box and enclosure configurations were 3D-printed using an Ultimaker 2+ and polylactic acid filament (3D Printing Canada). We performed the quantum dot barcode assays using 2 μL of quantum dot barcodes (575 nm at 10,000 barcodes/μL), 8 μL of reporter probes (10 μM), 40 μL of hybridization buffer (10× SSC, 0.1% SDS), and 40 μL of Milli-Q water. For positive–negative discrimination, we used our positive control sequence (Table S1). We detected the SARS-CoV-2 sequence to determine the limit of detection (Table S1).

Synthesis of Quantum Dot Barcodes

We synthesized quantum dot barcodes using the concentration-controlled flow-focusing method. , We prepared a 4% w/v solution of poly­(styrene-co-maleic anhydride) in chloroform (Sigma-Aldrich) and filtered it through a 0.2 μm PTFE syringe filter (Nalgene). We mixed 1 mL of the polymer solution with 180 μL of FeO nanoparticles (5 mg/mL) and 100 μL of CdSe/ZnS quantum dots (5 mg/mL) (NN Laboratories). Quantum dots emitting 520, 575, and 600 nm wavelengths were used during synthesis. We loaded this mixture into a glass syringe. A syringe pump injected the mixture into a customized flow-focusing nozzle at a rate of 0.9 mL/h. The focusing fluid (double-distilled water) flowed through the nozzle at a rate of 180 mL/h. The quantum dot barcodes were synthesized into a glass beaker with a starting volume of 250 mL of double-distilled water. The synthesized quantum dot barcodes were hardened overnight by constant stirring at room temperature. We collected and pelleted the quantum dot barcodes in Falcon tubes with centrifugation at 3000 × g for 10 min. We consolidated the quantum dot barcodes into Eppendorf tubes and characterized size, concentration, and emission spectra.

Conjugation of Capture Probes on the Surface of Quantum Dot Barcodes

We adapted the procedure for conjugation from our previous work. We conjugated DNA capture probes onto each quantum dot barcode using 1-ethyl-3-(3-(dimethylamino)­propyl) carbodiimide (EDC) cross-linker chemistry. We combined 1 million quantum dot barcodes with 9 μL of DNA capture probes (10 pmol/μL) and 65 μL of 2-(N-morpholino)­ethanesulfonic acid (MES) buffer (pH 5.5, 100 mM). We added 32 μL of EDC dissolved in MES (3.1 M) to the mixture. This mixture was rotated overnight at room temperature. We removed unbound capture probes by washing the conjugated quantum dot barcodes with 0.05% Tween-20 three times.

Image Analysis in the QMini

The fourth peristaltic pump drew completed quantum dot barcode assays from the detection chamber into a single-channel microfluidic slide. A rare-earth magnet (McMaster-Carr) positioned beneath the slide immobilized the barcodes to the floor in 20 sec. The third peristaltic pump continuously added a wash buffer (0.5× SSC, 0.1% SDS) to the detection chamber. The fourth peristaltic pump flowed the wash buffer out of the detection chamber, through the slide, and into a waste bottle in the cartridge. This flushed unbound reporter probes from the slide. The QMini’s optical module imaged each slide for the quantum dot barcodes and reporter probes. A 405 nm LED excited the quantum dot barcodes. We positioned the emission filter slider to the 425 nm longpass filter and captured the image of the quantum dot barcodes. A 642 nm diode laser excited the reporter probes. We changed the emission filter slide position to the 676 nm bandpass filter and captured the image of the reporter probes. We used FLIR SpinView software to capture the images. We processed the colocalized fluorescence signals of five quantum dot barcodes per slide and reporter probes using ImageJ.

Reagent Lyophilization

We lyophilized reagents for recombinase polymerase amplification and quantum dot barcode assay. We freeze-dried 4.8 μL of forward and reverse primers (10 μM) with 5 μL of magnesium acetate from TwistDx’s RPA kits and 35.4 μL of 15% w/v trehalose in nuclease-free water for recombinase polymerase amplification. We lyophilized 4 μL of quantum dot barcodes (520, 575, and 600 nm at 10,000 barcodes/μL) with 16 μL of reporter probes (10 μM), 40 μL of hybridization buffer (10× SSC, 0.1% SDS), and 40 μL of 15% w/v trehalose in nuclease-free water. Freeze-dried reagents were sealed in the cartridge’s amplification and detection chambers, respectively.

Extraction of Nucleic Acids in the QMini

We assembled cartridges with the extraction chamber and FastAmp reagent bottle. The extraction chamber connected to the FastAmp reagent bottle through the connector frames and first peristaltic pump. We suspended 1,000 to 100,000 human U87 glioblastoma cells or bEnD.3 cells in 50 μL of nuclease-free water. Each suspension was loaded into the extraction chamber in the cartridge. The first peristaltic pump drew 50 μL of FastAmp from a reagent bottle into the extraction chamber. The QMini incubated the cell suspension with FastAmp for 5 min. We quantified the amount of nucleic acids in the solution using SYBR Gold and a microplate reader.

Amplification of Target Sequences of Respiratory Syncytial Virus B, SARS-CoV-2, and Influenza A in the QMini

The cartridges were assembled with the extraction chamber and amplification chamber. We sealed lyophilized primer-magnesium pellets, along with two enzyme pellets from the RPA kits, into the amplification chamber. The second peristaltic pump connected the cap of the amplification chamber to a tubing reservoir. It directed fluid movement between the two chambers.

We loaded samples into the extraction chamber. Each sample consisted of 90 μL of rehydration buffer from TwistDx’s RPA kit, 20 μL of FastAmp, 38 μL of nuclease-free water, and 2 μL of nuclease-free water or double-stranded target sequences from respiratory syncytial virus B, SARS-CoV-2, or influenza A. The concentrations of the target sequences were 1 × 105 copies/2 μL.

We executed the Python code for amplification. The amplification chamber was heated to 40 °C. The second peristaltic pump drew the samples from the extraction chamber into the amplification chamber. The samples were gently mixed with the lyophilized primer-magnesium pellets and the two enzyme pellets for 15 min. We removed the amplified samples from the QMini.

We quantified the fluorescence signals from the amplified samples using the quantum dot barcode assay. They were first denatured at 95 °C for 5 min. We incubated the denatured samples with 2.5 μL of quantum dot barcodes (10,000 barcodes/μL), 8 μL of reporter probes (10 μM), and 40 μL of hybridization buffer (10× SSC, 0.1% SDS) for 20 min at 37 °C. The resulting solutions were loaded into the microfluidic slide and imaged using an Olympus IX51 microscope. We captured images of the quantum dot barcodes with the DAPI channel and the reporter probes with the Cy5 channel. We used ImageJ to analyze the images for colocalized fluorescence signals from the quantum dot barcodes and reporter probes.

Detection of Target Sequences of Respiratory Syncytial Virus B, SARS-CoV-2, and Influenza A in the QMini

We assembled cartridges with the extraction, amplification, and detection chambers. Lyophilized reagents for the quantum dot barcode assay were sealed in the detection chamber. The second peristaltic pump drove fluid movement between the extraction, amplification, and detection chambers. The third peristaltic pump continuously added a wash buffer (0.5× SSC, 0.1% SDS) to the detection chamber. The fourth perisaltic pump flowed the wash buffer from the detection chamber through the microfluidic slide and into a waste bottle in the cartridge.

We loaded samples into the extraction chamber. Each sample consisted of 10 μL of double-stranded target sequences from influenza A, respiratory syncytial virus B, and SARS-CoV-2 in 90 μL of rehydration buffer supplied by TwistDx’s RPA kit, 20 μL of FastAmp, and 30 μL of nuclease-free water. The concentrations of the target sequences were 1 × 109, 1 × 1010, 1 × 1011, and 1 × 1012 copies/μL.

We executed the Python code for detection. The amplification chamber was heated to 95 °C. The second peristaltic pump drew the samples from the extraction chamber to the amplification chamber. The samples were heated to 95 °C for 5 min. Then, the second peristaltic pump pushed the samples from the amplification chamber into the detection chamber. The samples were gently mixed with the lyophilized reagents for the quantum dot barcode assay for 20 min. The third peristaltic pump added 50 μL of wash buffer to the detection chamber. The fourth peristaltic pump drew the sample and wash buffer mixture into the center of the microfluidic slide. A rare-earth magnet attracted the quantum dot barcodes to the floor of the slide. The third peristaltic pump continuously added 4 mL of wash buffer to the detection chamber as the fourth peristaltic pump flowed the wash buffer through the microfluidic slide and into a waste bottle. We removed the microfluidic slide from the QMini.

We quantified the fluorescence signals of the quantum dot barcodes and reporter probes loaded onto the microfluidic slide. We used an Olympus IX51 microscope to capture images of the quantum dot barcodes with the DAPI channel and the reporter probes with the Cy5 channel. We used ImageJ to analyze the images for colocalized fluorescence signals from the quantum dot barcodes and reporter probes.

Limit of Detection in the QMini

Cartridges were assembled with extraction, amplification, and detection chambers, along with the microfluidic slide and reagent pack. The amplification chamber contained a primer-magnesium pellet and two enzyme pellets from the RPA kits. The detection chamber consisted of lyophilized reagents for the quantum dot barcode assay. We prepared samples with 90 μL of RPA rehydration buffer, 20 μL of FastAmp, 38 μL of nuclease-free water. Each sample consisted of either 2 μL of double-stranded target sequences from respiratory syncytial virus B, SARS-CoV-2, or influenza A, or nuclease-free water. Target concentrations were 1 × 101, 1 × 102, 5 × 102, 1 × 103, 1 × 104, and 1 × 105 copies/2 μL. Following amplification and detection steps, the microfluidic slide in the cartridge was imaged using the QMini imaging module. We quantified fluorescence intensity using ImageJ. The limit of detection was defined as the lowest input DNA copy number producing a mean reporter fluorescence exceeding the mean blank signal by three standard deviations.

Cross-Reactivity in the QMini

We assembled cartridges with all of their reaction chambers, the microfluidic slide, and the reagent pack. A primer-magnesium pellet and two enzyme pellets from the RPA kits were sealed in the amplification chamber. Lyophilized reagents for the quantum dot barcode assay were placed in the detection chamber. Contrived samples included 90 μL of RPA rehydration buffer, 20 μL of FastAmp, and 38 μL of nuclease-free water. We added 2 μL of nuclease-free water, or 105 copies of double-stranded nontarget sequences, or 105 copies of a target sequence of SARS-CoV-2. We imaged the microfluidic slide using the QMini imaging module after the amplification and detection steps were executed. We quantified fluorescence intensity using ImageJ and compared each sample to the nuclease-free water negative control.

Supplementary Material

ng6c00109_si_001.pdf (658.7KB, pdf)

Acknowledgments

The authors would like to thank Natural Sciences and Engineering Research Council of Canada, Canadian Research Chairs Program, and the Emerging and Pandemic Infections Consortium at the University of Toronto, the Government of Ontario (N.M.), the Natural Sciences and Engineering Research Council of Canada (M.O., H.C., A.L.), the Jennifer Dorrington Award (M.O.), the University of Toronto’s Centre for Global Engineering (M.O.), the Wildcat Graduate Scholarship (H.C.), and the Barbara and Frank Milligan Graduate Fellowship (A.L.) for student fellowships and scholarships.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsnanoscienceau.6c00109.

  • Additional materials and methods, including detailed schematics of device modules and nucleic acid sequences used for quantum dot barcode assays (PDF)

N.M. and W.C.W.C. conceptualized the study, developed the experimental framework, and wrote the paper. M.O. and H.C. provided experimental support and computer-aided design files from the QBox. A.L. designed the primers and probes for respiratory syncytial virus B and influenza A.

The authors declare no competing financial interest.

Published as part of ACS Nanoscience Au special issue “Colloidal Nanoparticles for Emerging Applications”.

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