Emerging technologies for next-generation point-of-care testing

Sandeep Kumar Vashist a*, Peter B. Luppa a, Leslie Y. Yeo b, Aydogan Ozcan c,d,e and John H.T.

Luong f*

a Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar der Technischen

Universität München, Ismaninger Str. 22, D-81675 Munich, Germany.

b Micro/Nanophysics Research Laboratory, RMIT University, Melbourne, VIC 3001, Australia.

c Electrical Engineering Department, University of California, Los Angeles, CA 90095, USA.

d Bioengineering Department, University of California, Los Angeles, CA 90095, USA.

e California NanoSystems Institute (CNSI), University of California, Los Angeles, CA 90095, USA.

f Innovative Chromatography Group, Irish Separation Science Cluster (ISSC), Department of Chemistry

and Analytical, Biological Chemistry Research Facility (ABCRF), University College Cork, Cork,

Ireland.

*Corresponding authors. (SKV) E-mail: sandeep.vashist@tum.de; Tel.: +49 89 41404071; Fax:

+49 89 41404875. (JHTL) E-mail: j.luong@ucc.ie

Supplementary Table S1. Cell phone-based point-of-care testing (CP-POCT).

Types Analyte(s) detected Characteristics Ref.Colorimetric detection

Peanut Detects 1-25 ppm of peanut within 20 min [1]

25-hydroxyvitamin D AuNP-based immunoassay (IA), linear detection range (LDR): 15-110 nM

[2]

Herpesvirus nucleic acid

DNA sequences [1 mM] from Kaposi’s sarcoma associated herpes virus (KSHV) using a nanoparticle (NP) assay in microfluidic chips

[3]

CRP CRP [0.035-0.182 µg mL-1] with limit of detection (LOD) of 0.026 µg mL-1

[4]

CRP Rapid sandwich IA for CRP [0.3-81 ng mL-1] with LOD of 0.4 ng mL-1 using a smartphone-based colorimetric reader

[5]

Cortisol Detects cortisol in 10 min with LDR of 0.01-10 ng mL-1 and LOD of 0.01 ng mL-1

[6]

Cholesterol Detects the total cholesterol level in blood [140-400 mg dL-1] within 1 min

[7]

Proteases A quantum dot (QD) based multiplex assay for the activity of trypsin, chymotrypsin and enterokinase [pM-nM]

[8]

Cocaine AuNP and aptamer-based assay for cocaine with LDR of 0.2-0.8 mg mL-1

[9]

HE4 Microchip ELISA for HE4 in urine with LDR of 19.5-1250 ng mL-1 and LOD of 19.5 ng mL-1

[10]

Hg2+ Plasmonic AuNP and aptamer-based assay for Hg2+ with LOD of ~3.5 ppb

[11]

Albumin Detects albumin in the LDR of 0-100 mg dL-1 with LOD of 6 mg dL-1

[12]

Glucose Detects glucose in the LDR of 0-300 mg dL-1 with LOD of 40 mg dL-1

[12]

Triplex detection of infectious diseases

Detects HIV antibody, treponemal specific antibody for syphilis, and non-treponemal antibody for active syphilis infection in 15 min

[13]

Mumps, measles and herpes simplex virus IgGs

CP-based hand-held micro-plate reader based ELISAs for mumps, measles and herpes simplex virus IgGs

[14]

Multi-analyte sensing arrays

An image processing algorithm for ascorbic acid, glucose, protein, ketones, urobilinogen, bilirubin and RBC using paper-based urine strips

[15]

Heavy metals (Cu2+, Ni2+, Cd2+ and Cr6+)

Detects Cu2+, Ni2+, Cd2+ and Cr6+ with LODs of 0.29, 0.33, 0.19 and 0.35 ppm, respectively

[16]

2,2ʹ,4,4ʹ-tetrabromodiphenyl ether (BDE-47)

Detects BDE-47 in the LDR of 10-3-104 ng mL-1 using CP-interfaced lab-on-a-chip device based ELISA

[17]

Fluorescent detection

M. tuberculosis M. tuberculosis bacilli in Auramine O-stained sputum smears. [18]

Salmonella typhimurium DNA

A fluorescent microscope and paper microfluidics-based assay for detecting S. typhimurium down to 104 CFU mL-1

[19]

DNA amplification Detects the DNA fragment of the Hepatitis B virus plasmid by convective polymerase chain reaction (cPCR)

[20]

Recombinant bovine somatotropin (rbST) Abs

Detects rbST Abs in milk extracts by an IA using magnetic polystyrene microspheres and QD-labelled detection Ab

[21]

Salmonella and E.coli O157

Lateral flow IA (LFIA) strips for Salmonella and E. coli O157 with LOD of 105 CFU mL-1

[22]

β-D-galactosidase A paper microfluidics-based IA for β-D-galactosidase, with LDR of 0.7-12 nM and LOD of 0.7 nM

[23]

Single NPs & viruses Fluorescent imaging of isolated 100 nM fluorescent NPs and human cytomegaloviruses

[24]

microRNA Fluorescent molecular beacon assay to detect microRNA with LOD of 10 pM.

[25]

Red blood cells (RBCs)White blood cells (WBCs)Haemoglobin (Hb)

Imaging cytometry platform for Hb concentration and the density of RBCs and WBCs

[26]

E. coli Detects E.coli O157 by QD-based sandwich IA in glass capillaries with LOD of ~5-10 CFU mL-1

[27]

WBCsGiardia lamblia cysts

Imaging labelled WBCs in whole blood and water-borne pathogenic Giardia lamblia cysts [resolution of 10 µm and FOV of 81 mm2]

[28]

Trypanosoma cruzi T. cruzi genomic DNA [0.1 to100 fg µL-1] with LOD of 9.6 ag [29]Collagenase and Trypsin

Detects collagenase and trypsin with LODs of 3.75 µg mL-1

and 930 pg, respectively, using a simple CP and tablet-based fluorescence detection system

[30]

Luminescent detection

Bile acid An lateral flow assay (LFA) minicartridge format for total bile acid in serum and oral fluid with LDR and LOD of 0.5-100 µM and 0.5 µM

[31]

Cholesterol LFA minicartridge format for total cholesterol in serum with LDR and LOD of 20-386 mg dL-1 and 20 mg dL-1

[31]

Salivary cortisol LFIA for salivary cortisol [0.3-60 ng mL-1] with LOD of 0.3 ng mL-1

[32]

Spectrophotometric detection

microRNA CP fluorimeter system to detect specific microRNA sequence with LOD of 10 pM using molecular beacon FRET assay

[33]

Additives in beverages and food

CP-based spectroscopic analysis using CP’s screen for illumination and front camera for imaging.

[34]

SPR detection β2 microglobulin (β2M)

Angle-resolved SPR detection system for β2M with LOD of 0.1 µg mL-1

[35]

Glycerol Fiber optic SPR sensor to detect glycerol concentrations of 0-20%

[36]

IgG Fiber optic SPR sensor to detect various concentrations of IgG binding to protein A-bound sensing element

[37]

Electrochemical detection

Plasmodium falciparum histidine-rich protein 2 (PfHRP2) biomarker for malaria,

Detects PfHRP2 in 15 min with LOD of 16 ng mL-1 using a compact embedded circuit, disposable microfluidic chip and capillary flow

[38]

blood glucose and trace heavy metals (Pb2+, Cd2+, Zn2+) in water, Na+ in urine, and PfHRP2

Universal low-cost CP-based electrochemical detector for the detection of blood glucose and heavy metals in water, Na+ in urine, and PfHRP2 biomarker

[39]

2,4,6-trinitrotoluene (TNT)

A CP-based electrochemical biosensor, using screen-printed electrodes modified with TNT-specific peptides, to detect TNT with LOD of 1 µM

[40]

iHealth Wireless Smart Gluco-Monitoring System

Detects pathophysiological blood glucose concentrations using a miniaturized glucometer interfaced with SP via a smart application

[41]

iHealth Align Detects pathophysiological blood glucose concentrations using the smallest Food and Drug Administration (FDA) approved blood glucose meter

[42]

Escherichia coli CP-based electrochemical biosensor pre-concentrates E.coli and detects it with a LDR and LOD of 10-100 cells mL -1 and 10 cells mL-1, respectively

[43]

Nitrate Audio jack-based electrochemical sensor that detects nitrate concentration in water with LOD of 0.2 ppm and LDR of 1.4-70 ppm within 1 min

[44]

Cytometry Optofluidic fluorescent imaging-based flow cytometer

Compact, light-weight and cost-effective CP-based flow cytometer with fluorescent resolution of ~2 µm and capability to analyze samples >0.1 mL

[45]

RBCs, WBCs and Hb Determines the density of RBCs, WBCs and Hb in blood from a 10 µL sample

[26]

Other detection techniques

Microscopy and spectroscopy

Stained and unstained blood smears, and transmission and fluorescence spectroscopy of diffuse tissue

[46]

Unlabelled DNA Monitoring the electrochemical dissolution of chromium electrode array in a microfluidic system

[47]

Malaria, TB, HIV CP-based integrated reader for malaria, TB and HIV [48]RBCs & WBCs A glass-based tapered fiber-optic array and multi-frame

imaging for RBCs and WBCs in transmission mode[49]

Salmonella and E.coli A paper microfluidic device and a Mie scattering-based IA for Salmonella and E. coli (102-105 CFU mL-1)

[50]

P. falciparum-infected and sickle RBCs

CP-based microscope for the bright field imaging of P. falciparum-infected and sickle RBCs in blood smears

[18]

Thyroid stimulating hormone (TSH)

CP-based Mie scatter optimized LFA for TSH with LOD of 0.4 mIU L-1

[51]

Aflatoxin B1 (AFB1) Reader and LFIA using a competitive binding format for AFB1 with linearity of 5-1000 µg kg-1 and LOD of 5 µg kg-1

[52]

Single molecules CP-based system using plasmonic substrates to detect surface enhanced Raman signals from solids and liquids

[53]

Hepatitis B and Human Immunodeficiency Virus (HIV)

Detection of biomarkers for Hepatitis B and HIV in nM range using a CP camera and an optomechanical cradle that monitors the intensity of light reflected by the surface using the CP’s LED for illumination

[54]

Supplementary Figure S1. (A) Schematic of a CP-based device for the colorimetric detection of

Hg2+ [11]. Reprinted with permission from the American Chemical Society. (B) vitaAID

accessory on an iPhone for the colorimetric detection of vitamin D [2]. Reprinted with

permission from the Royal Society of Chemistry. (C) CP attachment and minicartridge for

biochemiluminescent detection of cholesterol [31]. Reprinted with permission from the

American Chemical Society. (D) A CP-based colorimetric reader using screen-based bottom

illumination provided by gadgets [5]. Reprinted with permission from the Elsevier B.V. (E) CP

attachment for wide-field fluorescent and dark field imaging along with its schematic [28].

Reprinted with permission from the Royal Society of Chemistry. (F) Schematic of a CP-based

fluorescence microscope and its ray-tracing diagram [24]. Reprinted with permission from the

American Chemical Society (G) A CP-based contact microscopy platform and a schematic of the

CP attachment [49]. Reprinted with permission from the Royal Society of Chemistry.

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