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Mosquito‐Repellent Controlled‐Release Formulations for Fighting Mapossa et al. Malar J (2021) 20:165 https://doi.org/10.1186/s12936-021-03681-7 Malaria Journal REVIEW Open Access Mosquito‐repellent controlled‐release formulations for fghting infectious diseases António B. Mapossa1,2*, Walter W. Focke1,2, Robert K. Tewo3, René Androsch4 and Taneshka Kruger2 Abstract Malaria is a principal cause of illness and death in countries where the disease is endemic. Personal protection against mosquitoes using repellents could be a useful method that can reduce and/or prevent transmission of mosquito- borne diseases. The available repellent products, such as creams, roll-ons, and sprays for personal protection against mosquitoes, lack adequate long-term efcacy. In most cases, they need to be re-applied or replaced frequently. The encapsulation and release of the repellents from several matrices has risen as an alternative process for the develop- ment of invention of repellent based systems. The present work reviews various studies about the development and use of repellent controlled-release formulations such as polymer microcapsules, polymer microporous formulations, polymer micelles, nanoemulsions, solid-lipid nanoparticles, liposomes and cyclodextrins as new tools for mosquito- borne malaria control in the outdoor environment. Furthermore, investigation on the mathematical modelling used for the release rate of repellents is discussed in depth by exploring the Higuchi, Korsmeyer-Peppas, Weibull models, as well as the recently developed Mapossa model. Therefore, the studies searched suggest that the fnal repellents based-product should not only be efective against mosquito vectors of malaria parasites, but also reduce the biting frequency of other mosquitoes transmitting diseases, such as dengue fever, chikungunya, yellow fever and Zika virus. In this way, they will contribute to the improvement in overall public health and social well-being. Keywords: Malaria, Vector control, Mosquito repellent, controlled‐release formulations, Kinetic model Background considered most prone to malaria. During that year, Mosquitoes are vectors of numerous diseases, including the WHO reported that around 67 % (272,000) out of malaria, chikungunya, Zika virus, or yellow fever. Among the total number of deaths were the deaths of children them, malaria is a principal cause of illness and death [2]. Te United Nations’ Sustainable Development Goal in countries where the disease is endemic. According 3 (health and wellbeing for all), specifcally target 3.3, to the World Health Organization (WHO) [1], in 2018, contains the bold commitment to end the epidemic of around 228 million malaria cases were reported with malaria by the year 2030. Tis may be achieved by pre- an estimated number of 405,000 fatalities [2]. Most of venting or reducing the incidence of infective mosquito the reported cases occurred in sub-Saharan Africa, with bites that can also cause secondary infections, pain, dis- children younger than fve years and pregnant women comfort and allergic reactions in sensitive individuals and *Correspondence: [email protected] 2 UP Institute for Sustainable Malaria Control & MRC Collaborating Centre for Malaria Research, School of Health Systems and Public Health, University of Pretoria, Private Bag X20, Hatfeld, 0028 Pretoria, South Africa Full list of author information is available at the end of the article © The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://crea- tivecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdo- main/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Mapossa et al. Malar J (2021) 20:165 Page 2 of 33 systemic reactions, such as urticaria and angioedema of the biting of An. arabiensis, lasting for up to four hours. the skin [3–5]. Te blend also caused the mortality of the mosquitoes Over the years, malaria control has been increasingly used in the study. N’Guessan et al. [11] reported an excel- aimed at eliminating or reducing mosquito populations. lent activity of repellency and mortality of nets treated Several methods are available for controlling the malaria with repellent N,N-diethyl-3-methylbenzamide (DEET) vectors. Among them, long-lasting insecticidal nets against Aedes aegypti for 6 months. Akhtar [12] devel- (LLINs) and indoor residual spraying (IRS) are the most oped a natural mosquito repellent-based polymer matrix important control strategies recommended by the WHO. and evaluated the repellent release from the polymer However, these methods are not efective in an outdoor matrix. Sibanda et al. [13] reported on the slow release environment, where people spend time during the day of DEET from polymer fbres. Teir results provided and early evening. efectiveness against An. arabiensis for up to 20 weeks. In Braack et al. [6] reported on the biting behaviour of addition, Mapossa et al. [14] investigated repellents, such African malaria vectors to identify where they tend to as DEET and Icaridin, incoporated in microporous poly- bite on the human body. Te vectors used in the study olefns strands against An. arabiensis. It was found that were Anopheles arabiensis from Malahlapanga in South the strands with 20 % and 30 % of repellents provided a Africa, and Anopheles gambiae and Anopheles funestus good repellency activity against An. arabiensis for up to from northern Uganda. Te results showed that more twelve weeks. Te results obtained suggest the develop- than 93 % of mosquito bites occur on the ankles and feet ment of an alternative tool such as repellent-based prod- of people seated or standing outdoors. Additionally, the ucts (example bracelets/anklets containing repellent) for study reported that mosquitoes are attracted to the smell long protection duration against mosquitoes. According of the feet and ankles. However, if the feet and ankles are to these studies, polymer systems hold the most prom- protected or covered, the mosquitoes will not bite above ise for the controlled release of repellents. A polymer is the ankle but seek alternative hosts with non-covered a substance made up of macromolecules composed of ankles and feet. Additionally, Reddy et al. [7] studied the many repeating subunits. behaviour of An. gambiae and Anopheles melas outdoors In this paper, a review of formulations for controlled- on Bioko Island, Equatorial Guinea. Te study showed release of repellents is provided in terms of: (i) basic prin- that high levels of outdoor biting by mosquitoes occurred ciples of preparation of the repellent-based formulations; at night and during the early evening and morning. Tese (ii) mechanism of repellent release from formulations, fndings highlight the need for further studies about the and (iii) the efectiveness against mosquitoes. Further- importance and urgency of developing new methods more, mathematical models for release of repellents and to control mosquito-borne diseases when humans are their use are also presented and discussed. outdoors. Personal protection against mosquitoes by the appli- Wearable device’s based on mosquitoes repellents cation of repellents has become a useful practice that available on the markert can reduce and/or prevent transmission of many insect- Previous studies have showed an association between borne diseases. Mosquito repellents are known as vola- the application of personal protection products and a tile chemicals which, when applied on human skin, repel reduction in mosquito bites and disease incidence [15]. mosquitoes in the opposite direction from its source, For example, Schreck and Kline [16] reported that the thus discouraging contact and bites [8]. Numerous repel- repellents-treated military clothing demonstrated to be lent-based products, such as creams, roll-ons and sprays, efective in signifcantly reducing mosquito bites in the are available on the market for outdoor protection. How- covered regions. Repellent such as DEET-based on soaps ever, most of these applications have a very short period has been demonstrated to successfully reduce malaria of protection of a few hours only [9]. Tis also includes infections [17, 18]. Furthermore, the efcacy of diferent topical skin applications, requiring frequent application spray-on repellents on various species of mosquitoes has due to environmental efects such as excessive sweating, been reported in several studies [19]. humidity and insect activity. Due to the use of repellent Additionally, a study conducted by Rodriguez et al. products requiring frequent application, their use would [20, 21] evaluated the efcacy of various commercial not be afordable to poorer communities. Longer periods controlled release devices based on repellents against of protection from mosquito bites
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