Transdermal Diagnosis of Malaria Using Vapor Nanobubbles - Volume 21, Number 7—July 2015 - Emerging Infectious Disease journal - CDC
Volume 21, Number 7—July 2015
Transdermal Diagnosis of Malaria Using Vapor Nanobubbles
Malaria control and elimination would benefit greatly from an efficient and universal diagnostic tool that is fast (provides results in seconds), noninvasive and safe (uses no blood sampling or reagents), simple to use (can be operated by nonmedical personnel), sensitive and specific (detects low-level asymptomatic infections), and inexpensive and that detects malarial infection in humans and in mosquitoes (1–21). We recently proposed a transdermal blood- and reagent-free approach based on hemozoin-generated vapor nanobubbles (H-VNBs) (22) in which malaria parasite–specific endogenous nanocrystals of hemozoin are optically excited in vivo with a safe and short laser pulse (delivered to blood vessels through the skin). The light is converted into nonstationary localized heat that evaporates the adjacent nanovolume of liquid and thus generates an expanding and collapsing vapor nanobubble inside the parasite. The nanosize and high optical absorbance of hemozoin provide higher malaria infection specificity of these H-VNBs than does any normal blood and tissue components (23–26). Their transient expansion and collapse result in a noninvasive pressure pulse that is easily detected through the skin with an ultrasound sensor. In our preliminary studies (22), H-VNBs detected parasitemia as low as 0.0001% in vitro (human blood), and 0.00034% in vivo (transdermal detection in animals), with no false-positive signals. Therefore, H-VNB might be able to detect extremely low parasite densities provided the method can be applied to humans or mosquitoes simply and inexpensively.
To determine the technical and medical feasibility of H-VNBs for malaria diagnosis and screening, we prototyped a diagnostic device and evaluated it in a patient with confirmed malaria and in noninfected persons as controls. We also evaluated the device in Plasmodium falciparum–infected mosquitoes.
Dr. Lukianova-Hleb is a research scientist at Rice University. Her research interests include nanophotonics and nanomedicine with the focus on cancer and infectious diseases.
We thank K. Keene, A. Garbino, P. Hotez, S. Hoxhaj, K. Mattox, J. Braam, and J. Olson for their support and assistance with the study.
Studies in the laboratory of N.K. are supported by National Institutes of Health grants (AI47089 and AI101427). The patent application for the method described has been filed by Rice University.
The authors have the following competing financial interests: M.B. for Standa UAB; A.K. for X Instruments LLC; T.K. and A.H. for Precision Acoustics Ltd.
- Sturrock HJ, Hsiang MS, Cohen JM, Smith DL, Greenhouse B, Bousema T, Targeting asymptomatic malaria infection: active surveillance in control and elimination. PLoS Med. 2013;10:e1001467.
- The malERA Consultative Group on Diagnoses and Diagnostics. A research agenda for malaria eradication: diagnoses and diagnostics. PLoS Med.2011;8:e1000396.
- World Health Organization. World malaria report 2014 [cited 2014 Dec 19].http://www.who.int/malaria/publications/world_malaria_report_2014/report/en/
- McMorrow ML, Aidoo M, Kachur SP. Malaria rapid diagnostic tests in elimination settings—can they find the last parasite? Clin Microbiol Infect.2011;17:1624–31.
- Oriero EC, Jacobs J, Van Geertruyden J, Nwakanma D, D’Alessandro U. Molecular-based isothermal tests for field diagnosis of malaria and their potential contribution to malaria elimination. J Antimicrob Chemother. 2015;70:2–13.
- Wongsrichanalai C, Barcus M, Muth S, Sutamihardja A, Wernsdorfer W. A review of malaria diagnostic tools: microscopy and rapid diagnostic test (RDT). Am J Trop Med Hyg. 2007;77:119–27 .
- Ochola LB, Vounatsou P, Smith T, Mabaso ML, Newton CR. The reliability of diagnostic techniques in the diagnosis and management of malaria in the absence of a gold standard. Lancet Infect Dis. 2006;6:582–8.
- Horning MP, Delahunt CB, Singh SR, Garing SH, Nichols KP. A paper microfluidic cartridge for automated staining of malaria parasites with an optically transparent microscopy window. Lab Chip. 2014;14:2040–6.
- Newman DM, Heptinstall J, Matelon RJ, Savage L, Wears ML, Beddow J, A magneto-optic route toward the in vivo diagnosis of malaria: preliminary results and preclinical trial data. Biophys J. 2008;95:994–1000.
- Demirev PA, Feldman AB, Kongkasuriyachai D, Scholl P, Sullivan D Jr, Kumar N. Detection of malaria parasites in blood by laser desorption mass spectrometry. Anal Chem. 2002;74:3262–6.
- Wood BR, Hermelink A, Lasch P, Bambery KR, Webster GT, Khiavi MA, Resonance Raman microscopy in combination with partial dark-field microscopy lights up a new path in malaria diagnostics. Analyst (Lond). 2009;134:1119–25.
- Wilson BK, Behrend MR, Horning MP, Hegg MC. Detection of malarial byproduct hemozoin utilizing its unique scattering properties. Opt Express.2011;19:12190–6.
- Webster GT, de Villiers KA, Egan TJ, Deed S, Tilley L, Tobin MJ, Discriminating the intraerythrocytic lifecycle stages of the malaria parasite using synchrotron FT-IR microspectroscopy and an artificial neural network. Anal Chem. 2009;81:2516–24.
- Butykai A, Orbán A, Kocsis V, Szaller D, Bordács S, Tátrai-Szekeres E, Malaria pigment crystals as magnetic micro-rotors: key for high-sensitivity diagnosis. Sci Rep. 2013;3:1431.
- Orbán A, Butykai Á, Molnár A, Pröhle Z, Fülöp G, Zelles T, Evaluation of a novel magneto-optical method for the detection of malaria parasites. PLoS ONE. 2014;9:e96981.
- Peng WK, Kong TF, Ng CS, Chen L, Huang Y, Bhagat AA, Micromagnetic resonance relaxometry for rapid label-free malaria diagnosis. Nat Med.2014;20:1069–73.
- Delahunt C, Horning M, Wilson B, Proctor J, Hegg M. Limitations of haemozoin-based diagnosis of Plasmodium falciparum using dark-field microscopy. Malar J. 2014;13:147.
- Balasubramanian D, Mohan Rao C, Panijpan B. The malaria parasite monitored by photoacoustic spectroscopy. Science. 1984;223:828–30.
- Custer J, Kariuki M, Beerntsen B, Viator J. Photoacoustic detection of hemozoin in human mononuclear cells as an early indicator of malaria infection. Proc SPIE. 2010;7564:75641F.
- Samson EB, Goldschmidt BS, Whiteside PJ, Sudduth AS, Custer JR, Beerntsen B, Photoacoustic sepctroscopy of β-hematin. J Opt. 2012;14:065302.
- Beier JC, Perkins PV, Koros JK, Onyango FK, Gargan TP, Wirtz RA, Malaria sporozoite detection by dissection and ELISA to assess infectivity of afrotropical Anopheles (Diptera: Culicidae). J Med Entomol. 1990;27:377–84.
- Lukianova-Hleb EY, Campbell KM, Constantinou PE, Braam J, Olson JS, Ware RE, Hemozoin-generated vapor nanobubbles for transdermal reagent and needle-free detection of malaria. Proc Natl Acad Sci U S A. 2014;111:900–5.
- Lee J, Clarke ML, Tokumasu F, Lesoine JF, Allen DW, Chang R, Absorption-based hyperspectral imaging and analysis of single erythrocytes. IEEE J Sel Top Quantum Electron. 2012;18:1130–9.
- Zonios G, Bykowski J, Kollias N. Skin melanin, hemoglobin, and light scattering properties can be quantitatively assessed in vivo using diffuse reflectance spectroscopy. J Invest Dermatol. 2001;117:1452–7.
- Sullivan DJ Jr, Gluzman IY, Goldberg DE. Plasmodium hemozoin formation mediated by histidine-rich proteins. Science. 1996;271:219–22.
- Egan TJ. Recent advances in understanding the mechanism of hemozoin (malaria pigment) formation. J Inorg Biochem. 2008;102:1288–99.
- Lukianova-Hleb EY, Lapotko DO. Experimental techniques for imaging and measuring transient vapor nanobubbles. Appl Phys Lett.2012;101:264102.
- Lapotko D. Optical excitation and detection of vapor bubbles around plasmonic nanoparticles. Opt Express. 2009;17:2538–56 and.
- Anderson RR, Parrish JA. Selective photothermolysis: precise microsurgery by selective absorption of pulsed radiation. Science. 1983;220:524–7.
- Wang LV, Hu S. Photoacoustic tomography: in vivo imaging from organelles to organs. Science. 2012;335:1458–62 and.
- Laser Institute of America. American national standard for safe use of lasers (ANSI Z136.1–2007) (approved March 16, 2007). Orlando (FL): American Standards Institute, Inc.; 2007.
- Sullivan D. Hemozoin: a biocrystal synthesized during the degradation of heloglobin. Biopolym Online. 2005;9 [cited 2014 Dec 19].
- Nagaraj VA, Sundaram B, Varadarajan NM, Subramani PA, Kalappa DM, Ghosh SK, Malaria parasite-synthesized heme is essential in the mosquito and liver stages and complements host heme in the blood stages of infection. PLoS Pathog. 2013;9:e1003522.
Suggested citation for this article: Lukianova-Hleb E, Bezek S, Szigeti R, Khodarev A, Kelley T, Hurrell A, et al. Transdermal diagnosis of malaria using vapor nanobubbles. Emerg Infect Dis. 2015 Jul [date cited]. http://dx.doi.org/10.3201/eid2107.150089