Person:

Hennek, Jonathan

Although simple and low-cost interventions for sickle cell disease (SCD) exist in many developing countries, child mortality associated with SCD remains high, in part, because of the lack of access to diagnostic tests for SCD. A density-based test using aqueous multiphase systems (SCD-AMPS) is a candidate for a low-cost, point-of-care diagnostic for SCD. In this paper, the field evaluation of SCD-AMPS in a large (n = 505) case-control study in Zambia is described. Of the two variations of the SCD-AMPS used, the best system (SCD-AMPS-2) demonstrated a sensitivity of 86% (82–90%) and a specificity of 60% (53–67%). Subsequent analysis identified potential sources of false positives that include clotting, variation between batches of SCD-AMPS, and shipping conditions. Importantly, SCD-AMPS-2 was 84% (62–94%) sensitive in detecting SCD in children between 6 months and 1 year old. In addition to an evaluation of performance, an assessment of end-user operability was done with health workers in rural clinics in Zambia. These health workers rated the SCD-AMPS tests to be as simple to use as lateral flow tests for malaria and HIV.

This paper describes the design and fabrication of a “pop-up” electrochemical paper-based analytical device (pop-up-EPAD) to measure beta-hydroxybutyrate (BHB)—a key biomarker for diabetic ketoacidosis—using a commercial glucometer. Pop-up-EPADs are inspired by pop-up greeting cards and children's books. They are made from a single sheet of paper folded into a three-dimensional (3D) device that changes shape, and fluidic and electrical connectivity, by simply folding and unfolding the structure. The reconfigurable 3D structure makes it possible to change the fluidic path and to control timing; it also provides mechanical support for the folded and unfolded structures that enables good registration and repeatability on folding. A pop-up-EPAD designed to detect BHB shows performance comparable to commercially available plastic test strips over the clinically relevant range of BHB in blood when used with a commercial glucometer that integrates the ability to measure glucose and BHB (combination BHB/glucometer). With simple modifications of the electrode and fluid path design, the pop-up-EPAD also detects BHB using a simple glucometer—a device that is much more available than combination BHB/glucometers. Strategies that use a “3D pop-up”—that is, large-scale changes a 3D structure and fluidic paths—by folding/unfolding add functionality (e.g., controlled timing, fluidic handling and path programming, control over complex sequences of steps, and alterations in electrical connectivity) to EPADs, and should enable the development of new classes of paper-based diagnostic de-vices.

Iron deficiency anemia (IDA) is a nutritional disorder that impacts over one billion people worldwide, it causes permanent cognitive impairment in children, fatigue in adults, and suboptimal outcomes in pregnancy. IDA can be diagnosed by detection of red blood cells (RBCs) that are characteristically small (microcytic) and deficient in hemoglobin (hypochromic), typically by examining the results of a complete blood count performed by a hematology analyzer. These instruments are expensive, not portable, and require trained personnel; they are therefore, unavailable in many low-resource settings. This paper describes a low-cost and rapid method to diagnose IDA using aqueous multiphase systems (AMPS)—thermodynamically stable mixtures of biocompatible polymers and salt that spontaneously form discrete layers having sharp steps in density. AMPS are preloaded into a microhematocrit tube and used with a drop of blood from a fingerstick. After only two minutes in a low-cost centrifuge, the tests (n = 152) were read by eye with a sensitivity of 84% (72-93%) and a specificity of 78% (68-86%), corresponding to an area under the curve (AUC) of 0.89. The AMPS test outperforms diagnosis by hemoglobin alone (AUC = 0.73) and is comparable to methods used in clinics like reticulocyte hemoglobin concentration (AUC = 0.91). Standard machine learning tools were used to analyze images of the resulting tests captured by a standard desktop scanner to 1) slightly improve diagnosis of IDA—sensitivity of 90% (83-96%) and a specificity of 77% (64-87%), and 2) predict several important red blood cell parameters, such as mean corpuscular hemoglobin concentration. These results suggest that the use of AMPS combined with machine learning provides an approach to developing point-of-care hematology.

Magnetic levitation (MagLev) enables rapid and non-destructive quality control of plastic parts. The feasibility of MagLev as a method to: i) rapidly assess injection-molded plastic parts for defects during process optimization, ii) monitor the degradation of plastics after exposure to harsh environmental conditions, and iii) detect counterfeit polymers by density is demonstrated.

Despite the growth of research in universities on point-of-care (POC) diagnostics for global health, most devices never leave the laboratory. The processes that move diagnostic technology from the laboratory to the field—the processes intended to evaluate operation and performance under realistic conditions—are more complicated than they might seem. Two case studies illustrate this process: the development of a paper-based device to measure liver function, and the development of a device to identify sickle cell disease based on aqueous multiphase systems (AMPS) and differences in the densities of normal and sickled cells. Details of developing these devices provide strategies for forming partnerships, prototyping devices, designing studies, and evaluating POC diagnostics. Technical and procedural lessons drawn from these experiences may be useful to those designing diagnostic tests for developing countries, and more generally, technologies for use in resource-limited environments.

This paper describes a method of isolating small, highly accurate density-standard beads and characterizing their densities using accurate and experimentally traceable techniques. Density standards have a variety of applications, including the characterization of density gradients, which are used to separate objects in a variety of fields. Glass density-standard beads can be very accurate (±0.0001 g cm–3) but are too large (3–7 mm in diameter) for many applications. When smaller density standards are needed, commercial polymer microspheres are often used. These microspheres have standard deviations in density ranging from 0.006 to 0.021 g cm–3; these distributions in density make these microspheres impractical for applications demanding small steps in density. In this paper, commercial microspheres are fractionated using aqueous multiphase systems (AMPS), aqueous mixture of polymers and salts that spontaneously separate into phases having molecularly sharp steps in density, to isolate microspheres having much narrower distributions in density (standard deviations from 0.0003 to 0.0008 g cm–3) than the original microspheres. By reducing the heterogeneity in densities, this method reduces the uncertainty in the density of any specific bead and, therefore, improves the accuracy within the limits of the calibration standards used to characterize the distributions in density.