Featuring a Review from the Rice Optical Spectroscopy and As featured in: Imaging Laboratory, Dr. Rebecca Richards-Kortum, Rice University, Texas, USA. Point-of-care diagnostics to improve maternal and neonatal health in low-resource settings We review technologies to diagnose the leading causes of maternal and neonatal mortality, with a focus on identifying key gaps in development where new technology could improve health outcomes at the point of care. Image reproduced by permission of Brandon Martin. See Rebecca Richards-Kortum et al., Lab Chip, 2017, 17, 3351. rsc.li/loc Registered charity number: 207890 Lab on a Chip View Article Online CRITICAL REVIEW View Journal | View Issue Published on 10 August 2017. Downloaded by Rice University 12/06/2018 17:39:38. View Article Online Critical review Lab on a Chip of these facilities lack sophisticated laboratory infrastructure ase chain reaction, a standard method for diagnosing HIV in and do not have the resources to transport clinical specimens neonates, requires the use of expensive thermocycling equip- to central laboratories. Where available, point-of-care (POC) ment and highly trained technicians. Additionally, reagents diagnostics can provide a solution to this challenge. However, used in many diagnostic tests have special storage or trans- as shown in Tables 1 and 2, only a limited number of POC di- portation requirements, such as cold transportation of anti- agnostic tools are available for use at health centers and bodies used in ELISA testing to detect biomarkers of many health posts to detect the conditions that account for the ma- diseases. Consumables, such as test strips or specialized car- jority of maternal and neonatal deaths.6,7 For many of these tridges, can be difficult to supply and lead to higher per-test conditions, early detection and rapid initiation of treatment costs. Instrumentation cost and associated maintenance is key to reducing morbidity and mortality and achieving costs also prevent some diagnostic technologies from being SDG three.8,9 implemented in low-resource settings. The time-to-result as- Currently available diagnostic tools often face barriers to sociated with some tests limits their utility in both low- and implementation at the POC. Many diagnostic techniques can high-resource settings. For example, bacterial culture is the only be performed in laboratory facilities with access to con- gold standard to diagnosis sepsis, but the technique requires stant power, water, and trained staff. For example, polymer- 24 to 48 hours to complete,10 preventing diagnosis-directed treatment during the effective treatment window.11 Finally, insufficient human resources can limit the efficacy of diag- nostics for some conditions that require continuous monitor- Mary Natoli received her bache- ing, such as neonatal hypothermia. While low-cost thermom- lor's degree in Bioengineering eters exist to measure a neonate's temperature, the human from the University of Maryland, resources required for constant monitoring present a barrier. College Park. She is currently a All of these barriers must be considered when developing a third year graduate student at useful POC test for low-resource settings that can be appro- Rice University, pursuing a Ph.D. priately implemented. in Bioengineering. Her current To address the shortcomings of existing diagnostics for research focuses on low-cost low-resource settings, the WHO introduced a list of criteria methods of detecting HIV drug for the ideal point-of-care test, known as ASSURED (afford- resistance. able, sensitive, specific, user-friendly, robust & rapid, equip- ment-free, and deliverable).12 Diagnostic tests targeted for use at the POC in low-resource settings should be designed Mary Natoli with these criteria in mind to minimize barriers for success- ful implementation. However, there has been some criticism of the ASSURED criteria as being subjective and not Published on 10 August 2017. Downloaded by Rice University 12/06/2018 17:39:38. Kathryn Kundrod received her B. Dr. Rebecca Richards-Kortum is S. in Bioengineering from Lehigh the Malcom Gillis University University in 2015. She is cur- Professor, Professor of Bioengi- rently working toward her Ph.D. neering and ECE at Rice Univer- in Bioengineering with Dr. sity, director of Rice360°: Insti- Rebecca Richards-Kortum at Rice tute for Global Health University. Her research focuses Technologies, and founder of the on developing point-of-care diag- Rice Beyond Traditional Borders nostic tools for early infant HIV initiative. Her research focuses and high-risk HPV detection. An on developing low-cost, high- area of emphasis within her re- performance technologies for search is the development of low-resource settings. Currently, Kathryn Kundrod sample preparation techniques Rebecca Richards-Kortum she is leading a multi- for nucleic acid amplification institutional team to develop a testing. package of 17 life-saving neonatal technologies designed for low- resource settings. She received a B.S. in Physics and Mathematics from the University of Nebraska, a M.S. in Physics from the Mas- sachusetts Institute of Technology, and a Ph.D. in Medical Physics from the Massachusetts Institute of Technology. 3352 | Lab Chip,2017,17, 3351–3387 This journal is © The Royal Society of Chemistry 2017 View Article Online Lab on a Chip Critical review Table 1 Causes of maternal mortality globally with commercially available diagnostic tools. Global mortality column represents annual mortality rates. Level of health system indicates the level at which commercially available diagnostics can be deployed, taking into account the need for electrical power, refrigeration, consumable reagents, device and consumable costs, and necessary human resources for use.375 * Available at health posts but limited by a lack of affordable consumables. ** Technology exists for measuring blood loss but not for predicting those at risk. *** Available at health posts but limited by a lack of human resources. **** Available at health posts but limited by a lack of sensitivity. Table 2 Causes of neonatal mortality globally with commercially available diagnostic tools. Global mortality column represents annual mortality rates. Level of health system indicates the level at which commercially available diagnostics can be deployed, taking into account the need for electrical power, refrigeration, consumable reagents, device and consumable costs, and necessary human resources for use.375 Published on 10 August 2017. Downloaded by Rice University 12/06/2018 17:39:38. * Available at health posts but limited by a lack of affordable consumables. ** Available at health posts but limited by a lack of human resources. sufficiently comprehensive for new technologies. Addition- shortcomings, the ASSURED criteria are frequently used in ally, meeting all of the ASSURED criteria does not necessarily discussing the ability of a newly developed technology to be mean that a technology is appropriate for use at the POC. As deployed at the POC. Pai et al. stated in 2012, “… the technology as such does not When coupled with effective treatment strategies, low-cost define a POC test nor determine its use at the POC. Rather, it POC diagnostics that can be administered in low-resource is the successful use at the POC that defines a diagnostic pro- settings have the potential to reduce both neonatal and ma- cess as POC testing,”13 underscoring the importance of test- ternal mortality. Tables 3 and 4 summarize representative di- ing technologies at the POC and performing rigorous usabil- agnostic technologies that are commercially available to meet ity studies in the field. It is important to consider the final maternal and neonatal health needs, respectively, highlight- context in which a technology will be used during the design ing a need to develop further commercialized technologies process and to determine how this context will affect the defi- that reduce per-test cost, improve accuracy, and move away nitions used for and the relative importance of each of the from reliance on power and benchtop analyzers. ASSURED criteria. For example, the use of smartphones in Here, we review key innovations in POC diagnostic tools POC diagnostics, which has previously been reviewed,14 has to detect the leading causes of maternal and neonatal death allowed for implementation of detection methods that previ- in low-resource settings. We review both commercially avail- ously required inaccessible equipment, changing our under- able technologies and technologies that are currently in de- standing of the criterion “equipment-free”. Despite these velopment. We begin by reviewing diagnostic formats, This journal is © The Royal Society of Chemistry 2017 Lab Chip,2017,17, 3351–3387 | 3353 View Article Online 3354 Critical review Table 3 Representative commercially available technologies available to diagnose the leading causes of maternal mortality. Notably, many of the listed technologies are lacking robust usability, scal- ability, and field performance studies | Lab Chip Health Representative Core Input Diagnostic system a ,2017, Condition technology Analyte measured technology sample performance Cost Power use level Advantages Limitations Image HIV Alere Determine HIV-1/2 antibodies Lateral flow Whole Sensitivity: $18.22 None Heatlh Results in 20 Unsuitable for 17 diagnosis HIV-1/2 Ag/Ab and free HIV-1 p24 blood 99.9% post minutes; approved acute infection 376,377 , 3351 Combo antigen Specificity: for fingerstick use; and treatment 98.3–99.9%b376