Review of Microdevices for Hemozoin-Based Malaria Detection

Abstract

Despite being preventable and treatable, malaria still puts almost half of the world's population at risk. Thus, prompt, accurate and sensitive malaria diagnosis is crucial for disease control and elimination. Optical microscopy and immuno-rapid tests are the standard malaria diagnostic methods in the field. However, these are time-consuming and fail to detect low-level parasitemia. Biosensors and lab-on-a-chip devices, as reported to different applications, usually offer high sensitivity, specificity, and ease of use at the point of care. Thus, these can be explored as an alternative for malaria diagnosis. Alongside malaria infection inside the human red blood cells, parasites consume host hemoglobin generating the hemozoin crystal as a by-product. Hemozoin is produced in all parasite species either in symptomatic and asymptomatic individuals. Furthermore, hemozoin crystals are produced as the parasites invade the red blood cells and their content relates to disease progression. Hemozoin is, therefore, a unique indicator of infection, being used as a malaria biomarker. Herein, the so-far developed biosensors and lab-on-a-chip devices aiming for malaria detection by targeting hemozoin as a biomarker are reviewed and discussed to fulfil all the medical demands for malaria management towards elimination.

Keywords: biosensor; diagnosis; hemozoin; lab-on-a-chip; malaria; microdevices.

Figure 2

Example of sensors for malaria diagnosis based on hemozoin detection. (A) Schematic of a surface plasmon resonance sensor 1: (a) attachment of PAA to amine monolayer with EDC/NHS, (b) immobilization of Hemoglobin in PAA matrix, (c) removal of heme from hemoglobin and (d) injection of heme solution resulting in heme reconstitution 2: (a) attachment of PAA to amine SAM with EDC/NHS, (b) channel blocked off, (c) acid/acetone wash, and (d) injection of heme solution to determine nonspecific binding. (B) Schematic of the fabrication process of a SERS biosensor, where (a) Si substrate, (b) Si coated with PDDA, (c) M-AuNPs assembled on the PDDA-coated Si, (d) PDMS layer formed on the M-AuNP-assembled Si, (e) M-AuNP-embedded PDMS film, (f) Au film-coated Si, (g) hematin deposited on the Au film surface and (h) hematin-deposited Au film covered with M-AuNP-embedded PDMS SERS active substrate. Reprinted with permission: (A) [61] copyright © 2012 Elsevier B.V. All rights reserved, and (B) [75] copyright © 2021 American Chemical Society. Acronyms: Au, gold; EDC, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide; NHS, N-hydroxysuccinimide; NPs, Nanoparticles; PAA, Polyacrylic acid; PDDA, Poly(diallyl-dimethylammonium); PDMS, Polydimethylsiloxane; SAM, Self-assembled monolayer; SERS, Surface-enhanced Raman Spectroscopy; Si, Silicon.

Figure 1

(A) Tools that allow the detection of (a) acoustic, (b) optical, (c) magnetic and electrochemical properties of hemozoin (Hz). (B) Plasmodium-infected red blood cell (RBC) with Hz formation occurring in the digestive vacuole (DV) of the parasite. As parasite invade RBCs, hemoglobin (Hb) is degraded, releasing free heme (FH) that is polymerized into Hz.

Figure 3

Example lab-on-a-chip and microdevices for malaria diagnosis based on hemozoin detection. (A) Schematic of the microfluidic margination device (a) and the benchtop MRR system (b); (B) Schematics of a microfluidic device containing a ferromagnetic wire fixed on a glass slide (a and b) and photograph of the system (c); (C) Horizontal (a) and vertical (b) configurations of an on-chip magnetic system; and (D) Photographic image of Gazelle and schematic of magneto-optic detection of hemozoin (a) and testing procedure (b). Reprinted with permission: (A) [42] copyright © 2015 The Authors, reproduced under a Creative Commons Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND 4.0); (B) [90] copyright © 2013 American Chemical Society; (C) [91] copyright Licensee MDPI, Basel, Switzerland, under the Creative Commons Attribution License; and (D) [44] copyright © 2020 The Author(s). Published by Elsevier Ltd., under a Creative Commons Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND 4.0). MRR: Magnetic Resonance Relaxation.