Point-of-care diagnostics to improve maternal and neonatal health in low-resource settings

Abstract

Each day, approximately 830 women and 7400 newborns die from complications during pregnancy and childbirth. Improving maternal and neonatal health will require bringing rapid diagnosis and treatment to the point of care in low-resource settings. However, to date there are few diagnostic tools available that can be used at the point of care to detect the leading causes of maternal and neonatal mortality in low-resource settings. Here we review both commercially available diagnostics and technologies that are currently in development to detect the leading causes of maternal and neonatal mortality, highlighting key gaps in development where innovative design could increase access to technology and enable rapid diagnosis at the bedside.

Figure 1

Some examples of lateral flow tests to diagnose neonatal and maternal conditions. (a) Generalized depiction of a lateral flow device with a sample pad, conjugate pad, nitrocellulose membrane, and wicking pad. Figure reproduced from Reference with the permission of The Royal Society of Chemistry. (b) The ChemBio DPP HIV-Syphilis Assay detects antibodies for both syphilis (first “S” line) and HIV (second “H” line) from a drop of whole blood. The patented Dual Path Platform enables separate delivery of sample and detection reagents and improves sensitivity. Figure from Chembio Diagnostic Systems, Inc. All rights reserved.

Figure 2

Photo (a) and optical diagram (b) emphasizing the ease of use of HemoSpec, a portable device that optically measures hemoglobin concentration from blood spotted onto chromatography paper. The form, user interface, and included optical components are shown, but sample loading is not depicted. © 2014 IEEE. Reprinted, with permission, from M. Bond, J. Mvula, E. Molyneux and R. Richards-Kortum, presented in part at 2014 IEEE Healthcare Innovation Conference (HIC), 2014.

Figure 3

Schematic of paper-based bacterial culture device. This work illustrates a novel, low-cost platform for performing bacterial culture at the POC. (a) Devices are fabricated out of wax patterned paper, tape, PDMS, and a dialysis membrane. (b) When the device is folded shut, the lysogeny broth (LB) medium reservoir is brought into contact with the bacterial growth zone for bacterial culture. Because of the dialysis membrane and oxygen flow through the PDMS (c), bacteria are able to grow within the device. (d) When the device is impregnated with viability dye resazurin (PrestoBlue^™), a visual color change occurs during incubation, allowing quantification of bacterial load within the sample. Reproduced from Reference with permission of the Royal Society of Chemistry. (e) Antibiotics can be added to the paper disks to allow for antibiotic susceptibility testing, in which growth will be stunted surrounding the antibiotic areas in susceptible bacterial strains, whereas it will not be in antibiotic resistant strains. Reproduced from Reference with permission of the Royal Society of Chemistry. The images presented here depict the platform components, assay overview, and selected results, but does not provide information on workflow and use of the platform.

Figure 4

Technologies in development for performing a WBC count. All-plastic microscope (Top left) used with disposable slides (Top right: A, B) for complete blood count measurements. Sample diagnostic images obtained of lymphocytes and granulocytes are shown (Top right: C). The chosen images depict the size of the microscope, the relatively small number of components required to build the system and slides, and a representative image produced by the system. However, the figure does not illustrate the workflow, including sample loading. (Bottom) Method of imaging and analyzing blood count diagnostics using sub-microliter volumes of blood. The images presented here show the workflow and representative images produced by the system, but do not provide information on the size or form of the microscope. Figure Permissions: (Top left) Figure reprinted from Reference with permission from the Optical Society of America; (Top right) © 2014 IEEE. Reprinted, with permission, from C. E. Majors, M. E. Pawlowski, T. Tkaczyk and R. R. Richards-Kortum, presented in part at 2014 IEEE Healthcare Innovation Conference (HIC), Seattle, WA, 2014. Figure reproduced from Reference with permission from the Royal Society of Chemistry.

Figure 5

The complete workflow of the Liat Analyzer. The Liat Analyzer is an example of an automated sample-to-answer NAT platform that performs nucleic acid extraction, purification, reverse transcription, PCR amplification and real-time detection. A sample such as whole blood (shown) or plasma, is collected directly into a Liat Tube (a and b). After the tube is capped, the analyzer scans the tube barcode (c), and the tube is inserted into the analyzer (d). Then, the analyzer automatically performs all the nucleic acid testing steps and reports results in 1 hour (e). The mechanism for measurement and assay components are not depicted here. Reproduced from S. Tanriverdi, L. Chen and S. Chen, “A Rapid and Automated Sample-to-Result HIV Load Test for Near-Patient Application.” J. Infect. Dis., 2010, 201(s1), S52–S58, by permission of Oxford University Press.

Figure 6

Counting beads used by various international organizations. (a) Bead strands used by Save the Children, which employs two age-specific, color-coded strands that can be distinguished by bead size and colors. (b) Bead strands used by the Malaria Consortium and the International Rescue Committee, which also employs two age-specific, color-coded strands that are distinguished by colored beads that match the age specific amoxicillin packaging. (b) Bead strand used by UNICEF that is non-specific for ages 0–5 years and each color is made up of 10 beads for ease of counting. Reprinted from Reference under the terms of Creative Commons Attribution License.

Figure 7

MAD NAAT is a fully integrated sample-to-answer nucleic acid testing platform. The sample processing, amplification, and detection schemes are depicted. Reagent delivery is timed by melting wax barriers (valves). The components shown here are housed in a reusable plastic cassette with heaters included, which are not depicted here, but can be seen in the original source along with figures showing user workflow and timing. The representative image shown here shows the novel integration of multiple sample preparation steps for nucleic acid testing through the MAD NAAT’s reagent delivery scheme. Figure reproduced from Reference with permission from the Royal Society of Chemistry.

Figure 8

A novel detection technique for Zika virus that incorporates toe-hold switches and CRISPR-Cas9 technology capable of detecting single-nucleotide differences in RNA strands. (Top) Sensors for specific RNA strands are developed using a novel detection technique known as toe-hold. In short, these toe-hold switches (shown as the RNA hairpin complex) only unfold in the presence of the target RNA strand, revealing a ribosome binding site; this, in combination with a cell-free system dried into paper discs, results in the translation of proteins that cause a visual color change. (Bottom left) The toe-hold switches are combined with an isothermal RNA amplification technique to detect this color change in samples with clinically relevant RNA levels. (Bottom right) CRISPR-Cas9 is used to detect strain mutations; in the American ZIKV strain, the target RNA contains a PAM site (protospacer adjacent motif) generated by the strain mutation at which CRISPR-Cas9 binds and cleaves the target RNA, preventing the downstream translation of color-change proteins. As such, color change will only occur in the African ZIKV strain. This figure provides an overview of the molecular detection components of the system, but does not show the size of the system, required equipment, or workflow to perform the assay. Figure reprinted from Cell, 165, K. Pardee, A. A. Green, M. K. Takahashi, D. Braff, G. Lambert, J. W. Lee, T. Ferrante, D. Ma, N. Donghia, M. Fan, N. M. Daringer, I. Bosch, D. M. Dudley, D. H. O’Connor, L. Gehrke and J. J. Collins, “Rapid, Low-Cost Detection of Zika Virus Using Programmable Biomolecular Components,” 1255–1266, Copyright (2016), with permission from Elsevier.