Many long-lasting insecticidal bed nets for protection against disease vectors consist of poly(ethylene) fibers in which insecticide is incorporated during manufacture. Insecticide molecules diffuse from within the supersaturated polymers to surfaces where they become bioavailable to insects and often crystallize, a process known as blooming. Recent studies revealed that contact insecticides can be highly polymorphic. Moreover, insecticidal activity is polymorph-dependent, with forms having a higher crystal free energy yielding faster insect knockdown and mortality. Consequently, the crystallographic characterization of insecticide crystals that form on fibers is critical to understanding net function and improving net performance. Structural characterization of insecticide crystals on bed net fiber surfaces, let alone their polymorphs, has been elusive owing to the minute size of the crystals, however. Using the highly polymorphous compound ROY (5-methyl-2-[(2-nitrophenyl)-amino]thiophene-3-carbonitrile) as a proxy for insecticide crystallization, we investigated blooming and crystal formation on the surface of extruded poly(ethylene) fibers containing ROY. The blooming rates, tracked from the time of extrusion, were determined by UV-vis spectroscopy after successive washes. Six crystalline polymorphs (of the 13 known) were observed on poly(ethylene) fiber surfaces, and they were identified and characterized by Raman microscopy, scanning electron microscopy, and 3D electron diffraction. These observations reveal that the crystallization and phase behavior of polymorphs forming on poly(ethylene) fibers is complex and dynamic. The characterization of blooming and microcrystals underscores the importance of bed net crystallography for the optimization of bed net performance.

Department of Chemistry and Molecular Design Institute New York University New York 29 Washington Place New York City New York 10003 United States

Department of Structure Analysis Institute of Physics Czech Academy of Sciences Na Slovance 2 1999 Prague 8 18221 Czech Republic

Zobrazit více v PubMed

Nouman M.; Saunier J.; Jubeli E.; Yagoubi N. Additive blooming in polymer materials: Consequences in the pharmaceutical and medical field. Polym. Degrad. Stab. 2017, 143, 239–252. 10.1016/j.polymdegradstab.2017.07.021. DOI

James B. J.; Smith B. G. Surface structure and composition of fresh and bloomed chocolate analysed using X-ray photoelectron spectroscopy, cryo-scanning electron microscopy and environmental scanning electron microscopy. LWT. 2009, 42 (5), 929–937. 10.1016/j.lwt.2008.12.003. DOI

Liu L.; Gong D.; Bratasz L.; Zhu Z.; Wang C. Degradation markers and plasticizer loss of cellulose acetate films during ageing. Polym. Degrad. Stab. 2019, 168, 10895210.1016/j.polymdegradstab.2019.108952. DOI

Bhunia K.; Sablani S. S.; Tang J.; Rasco B. Migration of chemical compounds from packaging polymers during microwave, conventional heat treatment, and storage. Comp. Rev. Food. Sci. Food. Safe. 2013, 12 (5), 523–545. 10.1111/1541-4337.12028. PubMed DOI

Begley T.; Castle L.; Feigenbaum A.; Franz R.; Hinrichs K.; Lickly T.; Mercea P.; Milana M.; O’Brien A.; Rebre S.; Rijk R.; Piringer O. Evaluation of migration models that might be used in support of regulations for food-contact plastics. Food Addit Contam. 2005, 22 (1), 73–90. 10.1080/02652030400028035. PubMed DOI

Till D.; Schwope A. D.; Ehntholt D. J.; Sidman K. R.; Whelan R. H.; Schwartz P. S.; Reid R. C.; Rainey M. L. Indirect food additive migration from polymeric food packaging materials. Crit. Rev. Toxicol. 1987, 18, 215–243. 10.3109/10408448709089862. PubMed DOI

Saunier J.; Mazel V.; Paris C.; Yagoubi N. Polymorphism of Irganox 1076®: discovery of new forms and direct characterization of the polymorphs on a medical device by Raman microspectroscopy. Eur. J. Pharm. Biopharm. 2010, 75 (3), 443–450. 10.1016/j.ejpb.2010.04.014. PubMed DOI

Zhao W.; He J.; Yu P.; Jiang X.; Zhang L. Recent progress in the rubber antioxidants: A review. Polym. Degrad. Stab. 2023, 207, 11022310.1016/j.polymdegradstab.2022.110223. DOI

Pushpa S. A.; Goonetilleke P.; Billingham N. C. Diffusion of antioxidants in rubber. Rubber Chem. Technol. 1995, 68 (5), 705–716. 10.5254/1.3538767. DOI

Vahabi H.; Sonnier R.; Ferry L. Effects of ageing on the fire behaviour of flame-retarded polymers: A review. Polym. Int. 2015, 64, 313–328. 10.1002/pi.4841. DOI

Billingham N. C. Designing Polymer Additives to Minimise Loss. Makromnol. Chem. Macromol. Symp. 1989, 27 (1), 187–205. 10.1002/masy.19890270110. DOI

Skovmand O.; Dang D. M.; Tran T. Q.; Bossellman R.; Moore S. J. From the factory to the field: considerations of product characteristics for insecticide-treated net (ITN) bioefficacy testing. Malar. J. 2021, 20, 1–3. 10.1186/s12936-021-03897-7. PubMed DOI PMC

Lindsay S. W.; Gibson M. E. Bednets revisited: old idea, new angle. Parasitol Today. 1988, 4, 270–272. 10.1016/0169-4758(88)90017-8. PubMed DOI

Curtis C. F.; Lines J. D.; Carnevale P.; Robert V.; Boudin C.; Halna J. M.; Pazart L.; Gazin P.; Richard A.; Mouchet J.; Charlwood J. D.; Graves P. M.; Hossain M. I.; Kurihara T.; Ichimori K.; Li Z.; Lu B.; Majori G.; Sabatinelli G.; Coluzzi M.; Njunwa K. J.; Wiikes T. J.; Snow R. W.; Lindsay S. W.. Impregnated bednets and curtains against malaria mosquitoes. Appropriate technology in vector control. Taylor & Francis Group: Abingdon; 1990.

Jamet H. P. Insecticide treated bednets for malaria control. Outlooks Pest Manag. 2016, 27, 124–128. 10.1564/v27_jun_07. DOI

Okumu F. The fabric of life: what if mosquito nets were durable and widely available but insecticide-free?. Malar. J. 2020, 19, 260.10.1186/s12936-020-03321-6. PubMed DOI PMC

Gopalakrishnan R.; Sukumaran D.; Thakare V. B.; Garg P.; Singh R. A review on test methods for insecticidal fabrics and the need for standardisation. Parasitol. Res. 2018, 117, 3067–3080. 10.1007/s00436-018-6061-x. PubMed DOI

Bhatt S.; Weiss D. J.; Cameron E.; Bisanzio D.; Mappin B.; Dalrymple U.; Battle K.; Moyes C. L.; Henry A.; Eckhoff P. A.; Wenger E. A.; Briët O.; Penny M. A.; Smith T. A.; Bennett A.; Yukich J.; Eisele T. P.; Griffin J. T.; Fergus C. A.; Lynch M.; Lindgren F.; Cohen J. M.; Murray C. L. J.; Smith D. L.; Hay S. I.; Cibulskis R. E.; Gething P. W. The effect of malaria control on Plasmodium falciparum in Africa between 2000 and 2015. Nature 2015, 526, 207–211. 10.1038/nature15535. PubMed DOI PMC

World Malaria Report 2020. World Health Organization: Geneva, 2020.

Vogel G.Malaria-preventing bed nets save children’s lives–with impacts that can last for decades, Science, 2022, DOI:10.1126/science.ada0902 . DOI

Black W. C. IV.; Snell T. K.; Saavedra-Rodriguez K.; Kading R. C.; Campbell C. L. From global to local-new insights into features of pyrethroid detoxification in vector mosquitoes. Insects 2021, 12 (4), 276.10.3390/insects12040276. PubMed DOI PMC

Churcher T. S.; Lissenden N.; Griffin J. T.; Worrall E.; Ranson H. The impact of pyrethroid resistance on the efficacy and effectiveness of bednets for malaria control in Africa. Elife 2016, 5, 16090.10.7554/eLife.16090. PubMed DOI PMC

Ranson H.; Lissenden N. Insecticide resistance in African Anopheles mosquitoes: a worsening situation that needs urgent action to maintain malaria control. Trends Parasitol. 2016, 32, 187–196. 10.1016/j.pt.2015.11.010. PubMed DOI

Grossman M. K.; Oliver S. V.; Brooke B. D.; Thomas M. B. Use of alternative bioassays to explore the impact of pyrethroid resistance on LLIN efficacy. Parasites Vectors 2020, 13, 179.10.1186/s13071-020-04055-9. PubMed DOI PMC

Carrasco D.; Lefèvre T.; Moiroux N.; Pennetier C.; Chandre F.; Cohuet A. Behavioural adaptations of mosquito vectors to insecticide control. Curr. Opin. Insect Sci. 2019, 34, 48–54. 10.1016/j.cois.2019.03.005. PubMed DOI

Gutman J. R.; Lucchi N. W.; Cantey P. T.; Steinhardt L. C.; Samuels A. M.; Kamb M. L.; Kapella B. K.; McElroy P. D.; Udhayakumar V.; Lindblade K. A. Malaria and parasitic neglected tropical diseases: potential syndemics with COVID-19?. Am. J. Trop. Med. Hyg. 2020, 103, 572–577. 10.4269/ajtmh.20-0516. PubMed DOI PMC

Chiodini J. COVID-19 and the impact on malaria. Travel. Med. Infect. Dis. 2020, 35, 10175810.1016/j.tmaid.2020.101758. PubMed DOI PMC

Rogerson S. J.; Beeson J. G.; Laman M.; Poespoprodjo J. R.; William T.; Simpson J. A.; Price R. N.; Anstey N.; Fowkes F.; McCarthy J.; McCaw J.; Mueller I.; Gething P. Identifying and combating the impacts of COVID-19 on malaria. BMC Med. 2020, 18 (1), 239.10.1186/s12916-020-01710-x. PubMed DOI PMC

Jones R. T.; Ant T. H.; Cameron M. M.; Logan J. G. Novel control strategies for mosquito-borne diseases. Philos. Trans. R. Soc. London B. Biol. Sci. 2021, 376, 2019080210.1098/rstb.2019.0802. PubMed DOI PMC

Datoo M. S.; Natama M. H.; Somé A.; Traoré O.; Rouamba T.; Bellamy D.; Yameogo P.; Valia D.; Tegneri M.; Ouedraogo F.; Soma R.; Sawadogo S.; Sorgho F.; Derra K.; Rouamba E.; Orindi B.; Ramos L. F.; Flaxman A.; Cappuccini F.; Kailath R.; Elias S.; Mukhopadhyay E.; Noe A.; Cairns M.; Lawrie A.; Roberts R.; Valéa I.; Sorgho H.; Williams N.; Glenn G.; Fries L.; Reimer J.; Ewer K. J.; Shaligram U.; Hill A. V. S.; Tinto H. Efficacy of a low-dose candidate malaria vaccine, R21 in adjuvant Matrix-M, with seasonal administration to children in Burkina Faso: a randomised controlled trial. Lancet 2021, 397, 1809–1818. 10.1016/S0140-6736(21)00943-0. PubMed DOI PMC

Macias V. M.; Ohm J. R.; Rasgon J. L. Gene drive for mosquito control: Where did it come from and where are we headed?. Int. J. Environ. Res. Public Health. 2017, 14, 1006.10.3390/ijerph14091006. PubMed DOI PMC

Carballar-Lejarazú R.; Ogaugwu C.; Tushar T.; Kelsey A.; Pham T. B.; Murphy J.; Schmidt H.; Lee Y.; Lanzaro G. C.; James A. A. Next-generation gene drive for population modification of the malaria vector mosquito, Anopheles gambiae. Proc. Natl. Acad. Sci. U. S. A. 2020, 117 (37), 22805–22814. 10.1073/pnas.2010214117. PubMed DOI PMC

Skovmand O. Insecticidal bednets for the fight against malaria–present time and near future. Open Biol. J. 2010, 3, 92–96. 10.2174/18741967010030100092. DOI

Mapossa A. B.; Sibanda M. M.; Moyo D.; Kruger T.; Focke W. W.; Androsch R.; Boldt R.; Wesley-Smith J. Blooming of insecticides from polyethylene mesh and film. Trans. R. Soc. South Africa. 2021, 76, 127–136. 10.1080/0035919X.2021.1900950. DOI

Chan M.Ten Years in Public Health, 2007–2017; World Health Organization: Geneva: 2017.

Lorenz L. M.; Bradley J.; Yukich J.; Massue D. J.; Mageni Mboma Z.; Pigeon O.; Moore J.; Kilian A.; Lines J.; Kisinza W.; Overgaard H. J.; Moore S. J.; Ashley E. A. Comparative functional survival and equivalent annual cost of 3 long-lasting insecticidal net (LLIN) products in Tanzania: A randomised trial with 3-year follow up. PLoS Med. 2020, 17 (9), e100324810.1371/journal.pmed.1003248. PubMed DOI PMC

Innovation to Impact. December 2021 Convening – Raising the floor on nets. https://innovationtoimpact.org/raising-the-floor-on-nets/.

World Health Organization . ITN Product review report: Insecticide treated nets formulated with pyrethroid+PBO and pyrethroid+2nd active; PQT/VCP Public Report. https://extranet.who.int/prequal/vector-control-products/itn-product-review-report.

Innovation to Impact. Summary of Raising the Floor on Nets Convening on ITN Quality and Performance, May 2022. https://innovationtoimpact.org/resources/summary-of-raising-the-floor-on-nets-convening-on-itn-quality-and-performance-may-2022/.

Mapossa A. B.; Moyo D.; Wesley-Smith J.; Focke W. W.; Androsch R. Blooming of chlorfenapyr from polyethylene films. AIP Conf. Proc. 2020, 2289, 02003610.1063/5.0028438. DOI

Gesta E.; Skovmand O.; Espuche E.; Fulchiron R. Migration of additive molecules in a polymer filament obtained by melt spinning: Influence of the fiber processing steps. AIP Conf. Proc. 2015, 1695, 02001210.1063/1.4937290. DOI

Yang J.; Erriah B.; Hu C. T.; Reiter E.; Zhu X.; López-Mejías V.; Carmona-Sepúlveda I. P.; Ward M. D.; Kahr B. A deltamethrin crystal polymorph for more effective malaria control. Proc. Natl. Acad. Sci. U. S. A. 2020, 117, 26633–26638. 10.1073/pnas.2013390117. PubMed DOI PMC

Zhu X.; Hu C. T.; Erriah B.; Vogt-Maranto L.; Yang J.; Yang Y.; Qiu M.; Fellah N.; Tuckerman M. E.; Ward M. D.; Kahr B. Imidacloprid crystal polymorphs for disease vector control and pollinator protection. J. Am. Chem. Soc. 2021, 143, 17144–17152. 10.1021/jacs.1c07610. PubMed DOI

Yang J.; Hu C. T.; Zhu X.; Zhu Q.; Ward M. D.; Kahr B. DDT Polymorphism and the lethality of crystal forms. Angew. Chem., Int. Ed. 2017, 56, 10165–10169. 10.1002/anie.201703028. PubMed DOI

Yang J.; Zhu X.; Hu C. T.; Qiu M.; Zhu Q.; Ward M. D.; Kahr B. Inverse correlation between lethality and thermodynamic stability of contact insecticide polymorphs. Cryst. Growth Des. 2019, 19, 1839–1844. 10.1021/acs.cgd.8b01800. DOI

Zhu X.; Hu C. T.; Yang J.; Joyce L. A.; Qiu M.; Ward M. D.; Kahr B. Manipulating solid forms of contact insecticides for infectious disease prevention. J. Am. Chem. Soc. 2019, 141, 16858–16864. 10.1021/jacs.9b08125. PubMed DOI

Yu L.; Stephenson G. A.; Mitchell C. A.; Bunnell C. A.; Snorek S. V.; Bowyer J. J.; Borchardt T. B.; Stowell J. G.; Byrn S. R. Thermochemistry and conformational polymorphism of a hexamorphic crystal system. J. Am. Chem. Soc. 2000, 122, 585–591. 10.1021/ja9930622. DOI

Yu L. Polymorphism in molecular solids: an extraordinary system of red, orange, and yellow crystals. Acc. Chem. Res. 2010, 43, 1257–1266. 10.1021/ar100040r. PubMed DOI

Li X.; Ou X.; Rong H.; Huang S.; Nyman J.; Yu L.; Lu M. The twelfth solved structure of ROY: single crystals of Y04 grown from melt microdroplets. Cryst. Growth. Des. 2020, 20, 7093–7097. 10.1021/acs.cgd.0c01017. DOI

Hilden J. L.; Reyes C. E.; Kelm M. J.; Tan J. S.; Stowell J. G.; Morris K. R. Capillary precipitation of a highly polymorphic organic compound. Cryst. Growth. Des. 2003, 3, 921–926. 10.1021/cg034061v. DOI

Harty E. L.; Ha A. R.; Warren M. R.; Thompson A. L.; Allan D. R.; Goodwin A. L.; Funnell N. P. Reversible piezochromism in a molecular wine-rack. Chem. Commun. 2015, 51, 10608–10611. 10.1039/C5CC02916C. PubMed DOI

Ziemecka I.; Gokalp S.; Stroobants S.; Brau F.; Maes D.; De Wit A. Polymorph selection of ROY by flow-driven crystallization. Crystals 2019, 9 (7), 351.10.3390/cryst9070351. DOI

Tang S.; Yusov A.; Li Y.; Tan M.; Hao Y.; Li Z.; Chen Y.-S.; Hu C. T.; Kahr B.; Ward M. D. ROY confined in hydrogen-bonded frameworks: Coercing conformation of a chromophore. Mater. Chem. Front. 2020, 4, 2378–2383. 10.1039/D0QM00200C. DOI

Van Nerom M.; Gelin P.; Hashemiesfahan M.; De Malsche W.; Lutsko J. F.; Maes D.; Galand Q. The effect of controlled mixing on ROY polymorphism. Crystals 2022, 12 (5), 577.10.3390/cryst12050577. DOI

Tyler A. R.; Ragbirsingh R.; McMonagle C. J.; Waddell P. G.; Heaps S. E.; Steed J. W.; Thaw P.; Hall M. J.; Probert M. R. Encapsulated nanodroplet crystallization of organic-soluble small molecules. Chem. 2020, 6 (7), 1755–1765. 10.1016/j.chempr.2020.04.009. PubMed DOI PMC

Jones C. G.; Martynowycz M. W.; Hattne J.; Fulton T. J.; Stoltz B. M.; Rodriguez J. A.; Nelson H. M.; Gonen T. The cryoEM method microED as a powerful tool for small molecule structure determination. ACS Cent. Sci. 2018, 4 (11), 1587–1592. 10.1021/acscentsci.8b00760. PubMed DOI PMC

Gemmi M.; Mugnaioli E.; Gorelik T. E.; Kolb U.; Palatinus L.; Boullay P.; Hovmöller S.; Abrahams J. P. 3D electron diffraction: The nanocrystallography revolution. ACS Cent. Sci. 2019, 5 (8), 1315–1329. 10.1021/acscentsci.9b00394. PubMed DOI PMC

Broadhurst E. T.; Xu H.; Clabbers M. T.; Lightowler M.; Nudelman F.; Zou X.; Parsons S. Polymorph evolution during crystal growth studied by 3D electron diffraction. IUCrJ. 2020, 7, 5–9. 10.1107/S2052252519016105. PubMed DOI PMC

Gruene T.; Mugnaioli E. 3D electron diffraction for chemical analysis: Instrumentation developments and innovative applications. Chem. Rev. 2021, 121 (19), 11823–11834. 10.1021/acs.chemrev.1c00207. PubMed DOI PMC

Gruene T.; Holstein J. J.; Clever G. H.; Keppler B. Establishing electron diffraction in chemical crystallography. Nat. Rev. Chem. 2021, 5, 660–668. 10.1038/s41570-021-00302-4. PubMed DOI

Saha A.; Nia S. S.; Rodriguez J. A. Electron diffraction of 3D molecular crystals. Chem. Rev. 2022, 122 (17), 13883–13914. 10.1021/acs.chemrev.1c00879. PubMed DOI PMC

Palatinus L.; Brázda P.; Jelínek M.; Hrdá J.; Steciuk G.; Klementová M. Specifics of the data processing of precession electron diffraction tomography data and their implementation in the program PETS2.0. Acta. Cryst. B 2019, 75 (4), 512–522. 10.1107/S2052520619007534. PubMed DOI

Brázda P.; Klementová M.; Krysiak Y.; Palatinus L. Accurate lattice parameters from 3d electron diffraction data. I. Optical distortions. IUCrJ. 2022, 9 (6), 735–755. 10.1107/S2052252522007904. PubMed DOI PMC

Calvert P. D.; Billingham N. C. Loss of additives from polymers: A theoretical model. J. Appl. Polym. Sci. 1979, 24, 357–370. 10.1002/app.1979.070240205. DOI

Crank J.The Mathematics of Diffusion; Oxford University Press: Oxford, 1975.

Yu L. Surface mobility of molecular glasses and its importance in physical stability. Adv. Drug Delivery Rev. 2016, 100, 3–9. 10.1016/j.addr.2016.01.005. PubMed DOI

Chen Y.; Zhang W.; Yu L. Hydrogen bonding slows down surface diffusion of molecular glasses. J. Phys. Chem. B 2016, 120 (32), 8007–8015. 10.1021/acs.jpcb.6b05658. PubMed DOI

Moisan J. Y. Diffusion des additifs du polyethylened – I: Influence de la nature du diffusant. Eur. Polym. J. 1980, 16, 979–987. 10.1016/0014-3057(80)90180-9. DOI

Wakabayashi M.; Kohno T.; Kimura T.; Tamura S.; Endoh M.; Ohnishi S.; Nishioka T.; Tanaka Y.; Kanai T. New bleeding model of additives in a polypropylene film under atmospheric pressure. J. Appl. Polym. Sci. 2007, 104 (6), 3751–3757. 10.1002/app.25922. DOI

Beran G. J. O.; Sugden I. J.; Greenwell C.; Bowskill D. H.; Pantelides C. C.; Adjiman C. S. How many more polymorphs of ROY remain undiscovered. Chem. Sci. 2022, 13 (5), 1288–1297. 10.1039/D1SC06074K. PubMed DOI PMC

Kaminsky W. WinXMorph: a computer program to draw crystal morphology, growth sectors and cross sections with export files in VRML V2. 0 utf8-virtual reality format. Journal of applied crystallography. 2005, 38, 566–7. 10.1107/S0021889805012148. DOI

Mitchell C. A.; Yu L.; Ward M. D. Selective Nucleation and Discovery of Organic Polymorphs through Epitaxy with Single Crystal Substrates. J. Am. Chem. Soc. 2001, 123 (44), 10830–10839. 10.1021/ja004085f. PubMed DOI

Ostwald W. Studien Über Die Bildung Und Umwandlung Fester Körper: 1. Abhandlung: Übersättigung Und Überkaltung. Z. Phys. Chem. 1897, 22U (1), 289–330. 10.1515/zpch-1897-2233. DOI

Földes E. Physical aspects of polymer stabilization. Polym. Degrad. Stab. 1995, 49 (1), 57–63. 10.1016/0141-3910(95)00038-N. DOI

Takano M.; Sasaki T.; Insect repellent net. JP20091969522008, https://patents.google.com/patent/JP2009196952A/en?oq=2009196952.

Ejiri S.; Nagamatsu T.. Resin composition for filament, filament and process for producing the filament. WO20080019272008. https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2008001927.

Brown A. X-ray diffraction studies of the stretching and relaxing of polyethylene. J. Appl. Phys. 1949, 20 (6), 552–558. 10.1063/1.1698424. DOI

Stephenson G. A.; Borchardt T. B.; Byrn S. R.; Bowyer J.; Bunnell C. A.; Snorek S. V.; Yu L. Conformational and color polymorphism of 5-methyl-2-[(4-methyl-2-ntrophenyl)amino]-3-thi- ophenecarbonitrile. J. Pharm. Sci. 1995, 84 (11), 1385–1386. 10.1002/jps.2600841122. PubMed DOI