\r\n\tBoth diagnosis and clinical manipulation of the patient with vasospasm is a unique and challenging situation. Multi-clinical approach is extremely mandatory. The patient must be treated in a center, which requires a experienced team with both neurological surgeons, interventional radiologists, neurologists and neuroanesthesiologists. Moreover, a well-equiped, isolated neurointensive care is needed for all patients suffering form subarachnoid hemorraghe. \r\n\tIn their daily practice, both neurological surgeons, interventional radiologists, neurologists, neuroanesthesiologists, and even intensive care providers have to deal and challenge of vasospasm. Numerous studies relevant to pathophysiological mechanisms underlying vasospasm had been published, but we still know little about the exact mechanisms causing vasospasm. In the last decades of modern medical era, despite the technological developments concerning the neurological care of the patients with vasospasm, we still have no effective treatment and preventive care of this devastating entity. \r\n\tThe aim of this book project is to provide in detailed knowledge to both physicians and scientists dealing with cerebral vasospasm. This book will attract interest of both students, residents, specialists and academics of neurological sciences.
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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"62921",title:"Challenges for the Introduction and Evaluation of the Impact of Innovative Aedes aegypti Control Strategies",doi:"10.5772/intechopen.79862",slug:"challenges-for-the-introduction-and-evaluation-of-the-impact-of-innovative-aedes-aegypti-control-str",body:'\n
\n
1. Introduction
\n
The tools and strategies that have been implemented in recent decades to control the Aedes aegypti mosquito face an efficient vector of various viruses [dengue, chikungunya, Zika and yellow fever, which together are known as Aedes-borne diseases (ABD)] that has a great capacity for adaptation to human and urban habitats (domesticated).
\n
Improvements in the quantification and control of this mosquito in urban environments and the transmission of ABD require a reformulation of current control strategies, as well as a stronger focus on reducing vector abundance, preventing human-vector contact and finally, reducing virus transmission [1, 2]. Due to the multiplicity of co-circulating viruses transmitted by the Aedes mosquito and the absence of effective treatment or vaccines against these infections, the development of long-term strategies for managing the populations of the Aedes mosquito has become a public health priority.
\n
Traditional mosquito control strategies have consisted of nonintegrated vector management of the immature (larvae) mosquito stage and of the use of insecticides that have fairly low—and temporary—mortality rates in adult female mosquitoes. Effective and sustained control by these methods and intervention is impeded by a number of obstacles: effective coverage of all breeding sources, lack of personnel needed, the need of continuous insecticide re-application, the transitory nature of their effects, the false sense of security that they generate and the dependence fomented in both the affected communities and the mosquito management programs.
\n
On February 1, 2016, the World Health Organization (WHO) declared the Zika virus, along with microcephaly and the other associated neurological disorders, a public health emergency of international importance (public health emergency of international concern, PHEIC) [3]. The Zika outbreak rapidly reached across not only the Americas, but also 75 other countries and territories; its control continues to be a long-term challenge to public health even after the declaration of the end of the state of emergency by the WHO Emergency Committee in November of 2016.
\n
Due to this emergency, the scientific community; entrepreneurs and international, regional, and national governmental programs in areas endemic to Ae. aegypti and ABD are researching on innovative alternative methods of vector control. WHO has expressed its support for developing and upscaling three novel approaches to controlling the Ae. aegypti mosquito: the sterile insect technique (SIT), the release of insects carrying dominant lethal genes (RIDL) and the release of Wolbachia-infected mosquitoes.
\n
We find ourselves looking to the possible incorporation of various technological innovations whose application in the field of public health offers positive (theoretical) prospects of success along with new opportunities for enhancing the effectiveness of control programs; however, there are also technical and operational challenges that must be considered before incorporating these innovations into the inventory of mosquito management tools [4].
\n
\n
\n
2. Methods of intervention for Aedes aegypti control
\n
Vector control is a complex task. There are a number of options available for different stages (eggs, larvae, pupae and adult) of the mosquito populations; a variety of available tools (physical/mechanical, environmental, biological, chemical and behavioral preventive measures) and different goals for each strategy (covering containers to avoid egg-laying, eliminating breeding sites in order to diminish larval densities, spraying insecticides to kill and reduce adult mosquitoes or installing barriers that diminish vector-human contact). The ultimate goal of each strategy is diminishing transmission. However, experience has shown that there is no “magic bullet” that is effective, lasting, affordable and easy to implement.
\n
The purpose of vector control is to maintain populations at “acceptable” densities, to minimize vector-human contact (to prevent mosquito bites) and to reduce the longevity of female adult mosquitoes, in order to reduce the health problem to a manageable level that does not surpass the capacities of local health systems. The ambitious campaign (1947–1970) promoted by the Pan American Health Organization (PAHO) to eliminate Ae. aegypti from the continent was one of the great Latin American public health events due to the extent of its achievements throughout the continent. Eradication is not plausible for Ae. aegypti, elimination was a goal pursued in the past, but the desirable goal is now control.
\n
We are challenged by different stages of the vector’s life cycle which develop in different environments (air and water) and in different types of breeding sites (natural and artificial), made of a variety of materials (plastic, metal, cement, clay, glass, etc.) and have different productivity, different uses (some may be disposable and others able to be controlled) and can be either permanent or seasonal. This variability in type of vector breeding sites imposes diverse challenges for control—whether it can be sporadic (cleaning campaigns), continuous (use of larvicides or larvivorous fish), or permanent (physical elimination)—and it is not realistic to expect that these differences require a homogenous strategy. The characteristics of the different types of breeding sites require a variety of customized strategies so that the control may be effective and sustainable.
\n
The diversity of available vector control strategies and their implementation in each operation are related to the resources available, the cultural context in which the interventions are performed and the overall capacity for applying them appropriately and with sufficient coverage. These factors can and should be included in the integrated vector management (IVM) approach promoted by the WHO [5, 6]. IVM is based on a spectrum of intervention strategies, frequently utilized in synergy and applied simultaneously, that are selected based off of knowledge of local factors influencing the vector’s biology and the disease’s transmission and morbidity, with the goal of optimizing resources for vector control.
\n
As dengue spread on the last decades, the idea of vector control replaced that of vector elimination, because the magnitude of the problem surpassed the capacity of institutional responses (vertical programs) and incorporated new approaches such as community participation; biological control of larvae (copepods, Bacillus thuringiensis (Bti) and fish); physical control (mosquito nets, curtains, clothing, etc., all impregnated with insecticide); chemical control (repellents, larvicides and novel insecticides); behavior change communication [7] (BCC) and communication for behavioral impact [8, 9] (COMBI); integrated management in the comprehensive control of vectors (EGI-Dengue, 2003) [10] and even the design of multidisciplinary approaches, such as an eco-bio-social emphasis [11]. The incorporation of so many different approaches is a clear sign of the complexity entailed in facing this mosquito.
\n
Despite new vector control strategies being introduced with the goal of diminishing transmission, entomological monitoring indicators were never adapted to the new demands of the programs, and the traditional indices designed to measure the presence and absence of larvae and containers, which were never linked to the risk of transmission, were maintained [12].
\n
The introduction of technological innovations—such as the use of Wolbachia, the genetic modification of mosquito (GMM) populations, and/or the use of irradiated mosquitoes—that promise better coverage, impact and sustainability propose to improve the effectiveness and durability of control interventions. Nevertheless, the innovations also present organizational and procedural challenges that must be attended before, during and after their introduction as control measures.
\n
\n
\n
3. Innovations to biological and genetic manipulation of mosquito vectors
\n
The strategies for genetic and biological control/manipulation with Wolbachia of mosquito vectors (GMM/BCMW) propose an attack on the mechanisms directly responsible for the proliferation of mosquito populations. Allowing the mosquitoes’ reproductive dynamics be the tool for spreading the intervention means that we will allow the modified populations to disperse naturally (through repeated releases) so that little by little the mosquitoes go about occupying the territory of wild populations to the point of reaching our objective by replacing them in their function as vectors or by suppressing them as a species.
\n
The mechanism of dispersion and coverage that is proposed is the male mosquito vector itself; these male mosquitoes will find their female counterparts and transmit the control measure before these females lay their eggs, undiscriminating as to preferred breeding site and location. The progeny (eggs, larvae and adults) will incorporate the intervention naturally and will maintain it in the population that emerges from their lineage (desirable). In essence, the dispersal and upkeep of the intervention will be a product of biological mechanisms rather than human intervention.
\n
Interventions consisting of biological manipulation and genetic control of vectors, furthermore, share many characteristics that again distinguish them from the traditional methods. Among these are as follows: (1) dependence on vertical (maternal) transmission of heritable elements (resistance genes and Wolbachia), (2) specificity in regard to affected species, (3) environmental friendliness, (4) harnessing of natural reproductive instincts, (5) noninvasiveness of domestic spaces and (6) large-scale application (indispensable). A common challenge of these innovations and of traditional measures of control is to achieve the coverage necessary to be effective and sustainable.
\n
In general, these innovations to vector manipulation are based on two strategies that can be organized according to the results obtained (population elimination vs. replacement) or to the implantation dynamics (self-sustainable or self-limiting).
\n
Population elimination/suppression: aimed to affect the demographics of the vector population with the goal of eliminating it from the area or reducing it to a low level that will not maintain transmission.
\n
Population substitution/replacement: This strategy seeks to replace wild populations with modified populations that are resistant to the viral infection. One of the most novel mechanisms that produce resistance to infection is transinfection with Wolbachia. Other mechanisms are effected through the incorporation of transgenes that—by way of impacting the vectors’ survival, physiology (flight, feeding) or susceptibility to the infection—indirectly reduce the mosquito’s vectorial competence (interference).
\n
Self-limiting: This strategy implicates the abundant and repeated release of mosquitoes in order to maintain the flux of the genetic change in the target population. It is reversible with the discontinuation of releases.
\n
Self-sustaining: This strategy proposes repeated releases of modified mosquito populations sufficient to establish themselves as the dominant population (replacement), to the end of their persisting in the population even while there may be unforeseen risks.
\n
\n
\n
4. Paradigm shift, focus and objective
\n
One of the most important changes upon incorporating GMM-BCMW into the Aedes and ABD control programs is a paradigm shift in passing from emphasis on the larval stages to the direct impact on adult populations. These innovations in Ae. aegypti control direct efforts to the reproductive capacity or its competence as a vector, rather than the breeding sites. The theoretical assumption is based on the key elements for vector control centered on adult mosquitoes (abundance, survival, incubation periods, biting rate, etc.) [13]. However, directing control toward adult mosquitoes requires information that is not currently produced in traditional control programs.
\n
Traditional programs of control direct their efforts toward larval stages, reducing breeding sites abundance and the density of larvae in houses and containers, while they attack adult mosquitoes with insecticides that have limited coverage, short duration and low mortality at the population level. The focus and objective of integrated vector management (IVM) are directed to the control of mosquito populations through multi-sector interventions with a multidisciplinary and/or eco-bio-social focus based on changes to community practices, achieved by way of educational interventions.
\n
GMM-BCMW are not technologies that can be used in case of emergency (outbreak control). Focus is directed to the reduction, suppression (elimination) or substitution of Ae. aegypti populations; but in all cases, they should be visualized within the IVM scheme as complimentary tools. Traditional vector control programs imposed a strong component of entomological surveillance (larval monitoring) not correlated to epidemiological surveillance (incidence of infection and disease); this favored control responses (reactive) before the increase of entomological indicators, without relating them to transmission risk (risk thresholds). This has resulted in reactive interventions based on detection of an increase in breeding sites or of the number of cases that frequently have late entomological effects but no epidemiological effect. With and IVM approach it is expected to use surveillance as a predictor of risk; the identification of priority areas for interventions and to promote actions before, during and after periods of epidemics. In the case of GMM-BCMW, surveillance should be improved so it can be a powerful (proactive) tool that permits entomological, epidemiological and viral surveillance.
\n
\n
\n
5. Challenges to entomological surveillance
\n
Entomological surveillance has been employed to (1) determine changes in the geographical distribution of Ae. aegypti, (2) obtain relative measurements of Ae. aegypti populations through time and identify areas of “high” infestation or periods of growth in vector populations and (3) evaluate the impact of anti-vector interventions. These indicators cannot be used straightforwardly to estimate the risk of virus transmission in the population at a certain time or location.
\n
Entomological indexes: There are various indicators (indexes) and methods to detect or monitor Aedes populations (egg, larval, pupal and adult stages) in relation to their location (containers, home or geographical area). The indicators were initially qualitative (negative/positive breeding sites or houses) and evolved toward being quantitative in order to identify the number of mosquitoes, though without specifying density, productivity or breeding site relevance (cryptic). The indices are not sufficiently exact to identify the risk of transmission [14].
\n
One element of the evolution of control programs has been the slow innovation of entomological monitoring indicators, an area dominated by the traditional Stegomyia indexes used in the campaign to eliminate Ae. aegypti in the fight against yellow fever: house (HI), container (CI) and Breteau (BI) indexes. These indices were useful in the extent to which they indicated the (qualitative) presence and absence of the vector in a campaign that sought its elimination and attempted to evaluate the endeavors toward physical elimination of breeding sites (positive breeding sites or houses). The focus now turned toward the reduction in density (rather than the elimination) of the vector, and these indicators have lost their usefulness [15, 16].
\n
The need for better indicators led to indices of pupae and oviposition, closer life stages to the ideal measure of adult (female) mosquito populations, which would allow for a better approximation of the estimated risk of transmitting dengue [17, 18]. These indicators of entomological risk did not reduce or eliminate the challenges to evaluate the interventions because the need to relate density and/or the threshold of the different vector stages to risk of transmission still persists [19, 20, 21].
\n
The use of “nonentomological” (though associated with infestation and facilitators of vector-human contact and epidemiological risk) indicators has also been proposed and ought to be considered in order to better understand the dynamics of dengue transmission—for example, density and distribution of human populations, socioeconomic conditions, living and public services, climate, etc. [22, 23, 24, 25, 26, 27].
\n
The selection of indicators and surveillance methods depends on the objective of surveillance (density reduction, risk detection and outbreak prevention), the levels of infestation and the capacity for implementation. Nevertheless, there is little evidence showing that the control programs employ systematic monitoring of vector populations—in particular, monitoring of adult females—in order to measure infestation and risk of dengue transmission [18, 28, 29]. In the best of cases, programs still employ indices of infested sites/breeding sites [29, 30] in order to establish “areas” of transmission risk without demonstrating the predictive capacity of these indices as indicators of dengue transmission risk in the last 50 years [31].
\n
The limitations of these methods for measuring mosquito populations are the absence of a “gold standard,” the fact that all measurements have a range of error (they are not precise) and that only a proportion of the total mosquito population (eggs, larvae or adults) is measured. Furthermore, it must be understood that the risk of transmission can occur in various locations and not necessarily where the measurement and/or intervention is performed and that in the selection of methods of measurement and entomological monitoring, precision is always sacrificed. This is to say that, despite being less precise, easier and cheaper methods are chosen over those (e.g., adult surveys) that require more resources and thus are more expensive [32].
\n
An additional challenge is the combination of strategies (not yet their integration) and the differentiated evaluation of their impact, since while one intervention can modify the physical availability of breeding sites, it does not necessarily result in a decrease of vector density nor control the most stable and productive breeding sites. On the other hand, there is insufficient evidence to support the idea that achieving a lower egg or larval density through a variety of available interventions has an impact on the rate of disease transmission. Nevertheless, the combined use of old strategies and/or the incorporation of new vector control tools imposes various challenges: (1) the use of indicators that measure more specifically the density of mosquitoes in all stages of development in order to more concretely evaluate all available modes of intervention, (2) the definition of risk thresholds and (3) that the programs demonstrate their capacity (in terms of human resources, equipment and finances) to be executed with the coverage and frequency necessary to make them valid [1, 2].
\n
\n
\n
6. Challenges to epidemiological surveillance
\n
The evaluation of interventions to control Ae. aegypti faces diverse challenges regarding the potential impact they may have on the risk of transmission not only of dengue but also of other arboviruses recently associated with the region’s epidemiological profile: Zika, chikungunya and yellow fever. The first challenge is estimating the impact derived from the disease that may be affected and the second in measuring the direct impact of the interventions on the vector populations in all of their stages and their relation to transmission risk (vectorial competence and capacity).
\n
Systems of epidemiological surveillance now have the task of measuring, in the most precise manner possible, three infections transmitted by Ae. aegypti. Now things are complicated because the syndrome of fever and exanthema may be indicative of dengue, Zika and chikungunya. The diseases are also associated with other signs, distinctive symptoms and highly specific clinical complications (hemorrhages with severe dengue, chronic arthralgia with the chikungunya virus and congenital syndromes and neurological complications with Zika).
\n
The estimate of the actual number of dengue cases, and now of Zika and chikungunya, is very difficult to calculate due to biological problems inherent to the infection, such as the number asymptomatic infections, or of unspecified fevers, which hinders the correct quantification of the impact of each of these illnesses. Clinical confusion regarding symptomatic fever/exanthema and discriminating diagnosis is reduced when complications are severe and chronic manifestations of each infection are observed. The operational problems are evidenced through the low demand of health services—especially during outbreaks—which results in under registration of cases when the person does not demand or lacks access to health services, medicates himself or opts for treatments of symptoms they already recognize through previous exposure to the problem.
\n
Only patients with severe symptoms go to the doctor, and these are the best detected by the surveillance system. An additional operational problem is the lack of sensibility to clinical diagnoses of fever and the limited collection of samples in order to confirm diagnosis—even during an epidemic—now that normative processes restrict the collection of samples to only severe cases or those at the onset of an outbreak. Only those cases confirmed by diagnostic methods available in regional labs (serology and viral isolation) are recorded [33].
\n
These circumstances impact the opportunity for vector control interventions (operational problem) since the presence of asymptomatic cases and unspecified or febrile patients are not registered early, and it is not until the accumulation of many cases that an increase in transmission is detected; it is at this point that control actions are initiated [34]. Among the cultural problems, or problems of perception, we find the familiarity with the sickness and its management given prior experience; fever is not considered an important risk to one’s health and does not merit a visit to a doctor unless accompanied by more serious symptoms.
\n
The necessity of improving detection, diagnosis and notification: Epidemiological surveillance of arboviruses faces two importance problems that occur in two different spaces: the community and health services. Given the clinical characteristics, an important number of cases do not demand health services due to their asymptomatic status or the unspecified fever that does not merit a visit to a doctor. Even many clinical cases do not consult medical services due to the patient having recognized and identified the case and knowing how to treat it. Due to this situation, we underestimate the number of cases and the detection of the illness and detection for those affected should be improved [35, 36].
\n
In the health services sector, diagnosis and documentation related to cases should be improved by strengthening the capacities of health personnel and local laboratories. To accomplish this, the following are indispensable: (1) counting on clinical guidelines that facilitate the health personnel in the identification and treatment of clinical cases under surveillance (dengue, Zika and chikungunya) and that reduce the identification of false negatives, (2) establishing criteria for the collection of samples and having the supplies necessary for serological and/or viral confirmation of suspected cases, (3) improving the reporting of cases unconfirmed in the laboratory (probable/suspected) following the algorithms of differential diagnosis for the three illnesses, (4) encouraging the reporting of cases by epidemiological association in the case of an outbreak and (5) seeking mechanisms for notification of cases identified by private medical services [37].
\n
\n
\n
7. Operational changes to the programs of control with Wolbachia and GMM
\n
Evidence indicates that technological innovations should be viewed as tools complementary to vector control programs—tools whose introduction would be performed in carefully selected sites until the detection of evidence of the sustained impact and the reduction of potential risks of evolution in the manipulated species and introduced genetic or biological marker. It is believed that innovations would be used in places where traditional measures of control have little to no effect and where they may have an important epidemiological impact on transmission dynamics. However, as with any intervention—and especially with innovative interventions—there are some operational changes that will need to be considered for the programs of control with Wolbachia and GMM.
\n
Integration of interventions by level of application: A central element is the organization of interventions by level of application. We must keep on with simple practices, such as domestic hygiene (personal level); routine broad procedures such as breeding sites elimination campaigns; technically elaborated entomological sampling and larvicide application (community level); and even specialized, high-cost actions that require equipped, professional personnel, such as insecticide sprays (town level) or programs of medical attention for the correct handling of severe cases (national level). On the other hand, interventions aimed at urban infrastructure (access to potable water, garbage collection and a recycling system) ought to be incorporated bearing in mind that require high-level political commitment and substantial investments (municipal level).
\n
An additional challenge is the integration of abovementioned interventions in order to perform them in a combined and sequential manner and differential intensity in accordance with the epidemiology of each area vulnerable to transmission. Although the available human and financial resources will generally define this, we must pursue on the objective to direct efforts to high-risk areas. The selection of localities in which to introduce these innovations for control should take into account the degree of risk in that area as well as the impact produced by the illnesses.
\n
Program structure: The organization of the control programs has evolved from a vertical centralized structure (“Top-down”)—independent of health services and with a “militarized” organization—to a more horizontal and decentralized structure, more tightly linked to services of surveillance and medical care and more participatory (“Bottom-up”). The advances toward a horizontal organization are variable, and in many programs, there exists a combination of both structures, in which the coordination is centralized. The need of coordinating all these processes—including the application of GMM/BCMW-based strategies—implies that programs that adopt these innovations ought to incorporate a centralized perspective, although the host communities ought to participate in the operational unfolding of the new technologies.
\n
Implementation: The traditional control programs have an established procedural routine repeated each year, in the same season, with the same resources (human resources as well as physical, chemical and biological); however, the areas of control must be expanded and the actions intensified due to the increase in at-risk zones. In the case of IVM, it has been proposed that actions implemented should be differential in frequency and intensity in accordance with epidemiological risk.
\n
Human resources and operational infrastructure: The vertical focus of traditional control programs developed a whole line of training for technical vector control personnel totally apart from promotional, preventative and educational health activities. This operational personnel was integrated in brigades separated from other health activities that were not exclusively linked to vector control. This resulted in an independent organization with equipment, vehicles, machinery and supplies (insecticides) that has been growing hand-in-hand with the problem. With IVM, a more rational use of resources is proposed, starting with the multi-sector and multidisciplinary nature (social participation) of the approach, where the social communication component is incorporated as a substantial element of this strategy.
\n
The incorporation of GMM-BCMW into the vector control programs involves the components proposed for IVM, but also requires adaptation of the technology to the local conditions, as well as the development of an infrastructure of basic technology (insectariums and laboratories) to permit mass, sustained production, implementation and appropriate evaluation of the interventions. In this case, a specialized multidisciplinary group—in addition to technical personnel—is needed to achieve the introduction, monitoring and evaluation of new interventional strategies.
\n
Coverage: A problem inherent to the traditional programs of control in urban and suburban areas in countries where ABD are endemic is their limited coverage; not all breeding sites can be protected or removed, and their productive potential cannot be eliminated with biological, chemical or physical agents. It is not possible to protect or control the totality of the most productive and stable breeding sites in urban centers due to their number, seasonal productivity, location and access (“cryptic” breeding sites).
\n
The coverage of a vector control program functions at the level of the individual, the household, the block or neighborhood, but rarely at the town level. With the IVM programs, the target for intensive application of control efforts will be the neighborhood and towns at greatest risk; there are no claims that all affected areas, neighborhoods or towns will be covered. Coverage in the case of GMM-BCMW can include areas, towns, or medium-sized urban centers, since the mass release of treated mosquitoes cannot limit itself to blocks or a neighborhood. Thus, monitoring and maintenance in such broad areas is complicated by the necessity of technical and (specially trained) human resources and not presently contemplated by surveillance programs.
\n
Scale: One of the most important challenges for any vector control intervention is reaching a level of sufficient coverage (breeding sites, houses, people or communities) in order to effectively limit transmission. These technological innovations are proposed as intervention at a scale larger than that established by traditional vector control strategies. However, all of the processes of production, introduction and maintenance must be initially evaluated at an intermediate scale before considering their application at the regional or national level.
\n
Their application for control of mosquitoes that transmit disease is today only viewed within the context of the strategy of integrated vector management (IVM). This implies necessary adaptations in control programs as regard production of biological materials as well as in relation to the operation, which should be designed in accordance with the technical specifications of the modified organisms.
\n
Efficiency in large-scale production: In order to obtain the desired results, it is necessary to release a large quantity of mosquitoes (sterile, genetically manipulated or infected) into the environment in a reasonably short period of time that will allow for reduction and substitution of wild mosquito populations. Production, handling (separation), distribution and release may affect the capacity and competence of freed vectors. Production is easy to evaluate, but the same may not be said for the competence of the generated mosquitoes.
\n
Quality: The performance, or fitness, of the vector should be evaluated, and there is not much experience with this sort of evaluation. Some factors to be evaluated are physical distinctions (pupa and/or adult size), survival rate, dispersal, mating capabilities, sperm quality, competition with wild or native species, and so on. Training of technical personnel and a specialized multidisciplinary group is needed.
\n
Social participation: Social and community participation are essential to the acceptance, monitoring and evaluation of GMM strategies. Given the nature of the new GMM methods, communication with the communities is necessary in order to introduce these methods, which are conceptually very different from traditional methods of control.
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Sustainability: The re-introduction of an eliminated species is possible if control interventions cease or diminish in intensity and frequency. Invasion or re-introduction from other nontreated areas requires a containment plan with geographical barriers to inhibit vector migration. The concerns are more environmental than health-related. The emptied niche may promote the invasion of a more dangerous, competent and effective species.
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Costs: Cost-effectiveness studies of traditional control methods begin to be an important strategy in evaluating their potential and their degree of incorporation, and in defining the conditions that create for their maximum usefulness. The success of an intervention in terms of costs is subject to the context of where it is applied, the scale of implementation, the availability of personnel and appropriate equipment and the scale of the problem (endemic, epidemic, hyperendemic and introduction of new agents). Traditional control programs require resources in response to the growing magnitude and breadth of the problem. The investments associated with IVM increase costs because of the community and multi-sector participation and the necessary social communication, which touch on other relevant community issues. The incorporation of GMM-MBW needs to be accompanied by an important investment in infrastructure, personnel training, equipment and supplies, along with a strong social communication component that ought to be considered within the comprehensive cost of the program.
\n
\n
\n
8. Final considerations
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During the last decade, the WHO has been promoting IVM but has been using only those intervention methods traditionally available. Several innovative methods are being developed to complement the current control of Ae. aegypti populations and affect the transmission of ABD. Some show great potential, such as the use of GMM-BCMW, but are not yet available as part of institutional prevention and control programs. In addition to the challenges exposed earlier, other limitations include a lack of scientific and technological infrastructure of the quality and capacity necessary for the implementation of novel methods of mosquito control. This extends to laboratories, systems for the mass rearing of mosquitoes and processes such as quality control, transportation, field release, monitoring and evaluation of effectiveness. Both WHO and the Pan American Health Organization (PAHO) are offering their technical cooperation to support pilot studies using innovative methods. The technical advisory group on entomology in public health and vector control explicitly recommended to PAHO “Promoting rapid, robust and accelerated evaluation of new tools complementary to the control of Aedes, with particular attention to the use of mosquitoes infected with the bacteria Wolbachia and sterile and genetically modified insects.”
\n
Vector control programs do not use “single” methods. Innovations should be considered complementary tools to control programs, not substitutes. Traditional and/or new interventions of greater complexity can be implemented proactively using a risk stratification approach calling for different intensity and greater coverage in priority areas. However, we can anticipate complications on monitoring and evaluation, since there is little evidence and experience of multiple or combined interventions with intersectoral participation and IVM.
\n
Traditional vector control has demonstrated limited impacts and transitory decreases in larval and adult mosquito populations. Monitoring of these traditional control programs is performed on an irregular basis throughout the year, without taking into account that there are important seasonal effects on vector populations. Furthermore, these evaluations are unstructured and usually not conduced at the time intervals necessary in order to estimate the magnitude and longevity of the effects on vector populations. In the case of GMM-BCMW, in addition to performing entomological monitoring to estimate the effects of suppression on target populations, in the case of substitution or population replacement strategies, it is necessary to include measurements of the reproductive and biological performance of the introduced populations.
\n
Estimates of the effect of traditional actions (larval density) do not imply impacts on disease transmission (incidence). The IVM strategies share these limitations, although they diversify the indicators due to the multidisciplinary nature of their interventions. In the case of GMM-BCMW, the evaluations ought to incorporate continuous monitoring of adult mosquito populations (wild and introduced): their survival, performance (or fitness), competence as vectors or capacity to transmit the infectious agents, reproductive capacities, flight range, dispersal, and so on. The indicators should purvey information relevant to measuring the effects on reproductive capacity; reduction in infection and other entomological, epidemiological and even ecological parameters that describe the dynamics of adaptation of introduced populations.
\n
Despite intense research on Ae. aegypti, we still do not have entomological parameters linking vector density to risk of transmission. It is also still difficult to define the transmission risk’s direct impact on human populations and its duration (days, weeks and months) in mosquito populations—and even more difficult to count on indicators that allow for efficient evaluation of the effects of different vector control interventions on the impact of the illness within the community (infection, severity of clinical cases, mortality, etc.). These limitations are the same for GMM-BCMW, and we still need indicators that will correlate efficacy in terms of entomological parameters (reduction or substitution of mosquito populations) to effects on transmission of the illness.
\n
Entomological surveillance is indispensable in order to monitor vector populations and to count on the basic parameters that allow for evaluation of direct impact on affected populations. Larval densities are not sufficient for evaluating the effects expected with the inclusion of these innovations, since the introduced populations are competing adults; as a result, it is necessary to evaluate adult density (males and females) as well as vector survival, mating habits, reproductive capacities (fecundity) and so on.
\n
Last but not least, the success of any control intervention should be measured ultimately in terms of resultant decrease in infection transmission and in the impact of the illness on the community. This process entails decreased herd immunity in human populations and would introduce the risk of greater epidemics if the intervention measures lost intensity or effectiveness or were no longer applied. Decreased immunity augments the population’s susceptibility, which results in lower vector density thresholds for transmission or risk of transmission.
\n
Here, we have exposed some of the major challenges for the introduction, implementation and evaluation of innovative Aedes aegypti control strategies based on GMM/BCMW. Nowadays, they are still being evaluated to gauge their entomological impact; and evidence of epidemiological impact is desirable in the near future.
\n
Other basic requirements for the adoption of technological innovations include a regulatory and legislative framework for their use in public health (Environmental, Biosecurity and Bioethics); following a set of Protocols & Portfolio having to do with safety, quality control, efficacy, and so on; and necessary integration with local vector control programs including agreement/acceptance by institutions and communities. In terms of administrative and financial requirements, we still need to resolve whether these technological innovations can be acquired under the current budget structure (as a product or service). In order to more quickly implement these new technologies, we need to develop a medium to long-term implementation and financing plan; production, distribution, monitoring and evaluation logistics and private-public partnerships.
\n
\n
Acknowledgments
\n
To the Canadian Institutes of Health Research (CIHR) and IDRC (Preventing Zika disease with novel vector control approaches Project 108412) and Fondo Mixto CONACYT–Gobierno del Estado De Yucatán (Project YUC-2017-03-01-556). Abdiel Martin-Park is supported by the Cátedras–CONACYT program. Special thanks to Ana García-Moreno Malcolm for grammar corrections.
\n
\n',keywords:"dengue, chikungunya, Zika, Wolbachia, SIT, RIDL, entomological surveillance, epidemiology",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/62921.pdf",chapterXML:"https://mts.intechopen.com/source/xml/62921.xml",downloadPdfUrl:"/chapter/pdf-download/62921",previewPdfUrl:"/chapter/pdf-preview/62921",totalDownloads:411,totalViews:169,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,dateSubmitted:"March 28th 2018",dateReviewed:"July 1st 2018",datePrePublished:"November 5th 2018",datePublished:"January 30th 2019",dateFinished:null,readingETA:"0",abstract:"Innovative control tools for the dengue, chikungunya and Zika vector Aedes aegypti, such as genetically modified mosquitoes and biological control and manipulation with the bacteria Wolbachia, are now becoming available and their incorporation into institutional vector control programs is imminent. The objective of this chapter is to examine the technical and organizational mechanisms together with the necessary processes for their introduction and implementation, as well as the indispensable indicators to measure their entomological effect on vector populations and their epidemiological impact in the short, medium and long term as part of an integrated vector management approach.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/62921",risUrl:"/chapter/ris/62921",book:{slug:"dengue-fever-a-resilient-threat-in-the-face-of-innovation"},signatures:"Héctor Gómez-Dantés, Norma Pavía-Ruz, Fabián Correa-Morales,\nAbdiel Martín-Park, Gonzalo Vázquez-Prokopec and Pablo\nManrique-Saide",authors:[{id:"195817",title:"Prof.",name:"Pablo",middleName:null,surname:"Manrique-Saide",fullName:"Pablo Manrique-Saide",slug:"pablo-manrique-saide",email:"pablo_manrique2000@hotmail.com",position:null,institution:null},{id:"204740",title:"Dr.",name:"Abdiel",middleName:null,surname:"Martin-Park",fullName:"Abdiel Martin-Park",slug:"abdiel-martin-park",email:"ampark27@gmail.com",position:null,institution:null},{id:"204744",title:"Dr.",name:"Norma",middleName:null,surname:"Pavia-Ruz",fullName:"Norma Pavia-Ruz",slug:"norma-pavia-ruz",email:"pruz@correo.uady.mx",position:null,institution:null},{id:"204747",title:"Dr.",name:"Gonzalo",middleName:null,surname:"Vazquez-Prokopec",fullName:"Gonzalo Vazquez-Prokopec",slug:"gonzalo-vazquez-prokopec",email:"gmvazqu@emory.edu",position:null,institution:null},{id:"205179",title:"Dr.",name:"Hector",middleName:null,surname:"Gomez-Dantés",fullName:"Hector Gomez-Dantés",slug:"hector-gomez-dantes",email:"hector.gomez@insp.mx",position:null,institution:null},{id:"205180",title:"MSc.",name:"Fabian",middleName:null,surname:"Correa-Morales",fullName:"Fabian Correa-Morales",slug:"fabian-correa-morales",email:"fabiancorrea@msn.com",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Methods of intervention for Aedes aegypti control",level:"1"},{id:"sec_3",title:"3. Innovations to biological and genetic manipulation of mosquito vectors",level:"1"},{id:"sec_4",title:"4. Paradigm shift, focus and objective",level:"1"},{id:"sec_5",title:"5. Challenges to entomological surveillance",level:"1"},{id:"sec_6",title:"6. Challenges to epidemiological surveillance",level:"1"},{id:"sec_7",title:"7. Operational changes to the programs of control with Wolbachia and GMM",level:"1"},{id:"sec_8",title:"8. Final considerations",level:"1"},{id:"sec_9",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Achee NL, Gould F, Perkins TA, Reiner RC Jr, Morrison AC, Ritchie SA, Gubler DJ, Teyssou R, Scott TW. A critical assessment of vector control for dengue prevention. PLoS Neglected Tropical Diseases. 2015;9(5):e0003655. 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Dengue: Guidelines for Diagnosis, Treatment, Prevention and Control. Geneva, Switzerland: WHO; 2009. http://whqlibdoc.who.int/publications/2009/9789241547871_eng.pdf [Accessed: March 07, 2015]\n'},{id:"B35",body:'Undurraga EA, Halasa YA, Shepard DS. Use of expansion factors to estimate the burden of dengue in Southeast Asia: A systematic analysis. PLoS Neglected Tropical Diseases. 2013;7(2):e2056. DOI: 10.1371/journal.pntd.0002056\n'},{id:"B36",body:'Horstick O, Morrison AC. Dengue disease surveillance: Improving data for dengue control. PLoS Neglected Tropical Diseases. 2014;8(11):e3311. DOI: 10.1371/journal. pntd.0003311\n'},{id:"B37",body:'Pan American Health Organization (PAHO). Dengue and Dengue Hemorrhagic Fever in the Americas: Guidelines for Prevention and Control. Washington, D.C: PAHO; 1994\n'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Héctor Gómez-Dantés",address:null,affiliation:'
Unidad Colaborativa para Bioensayos Entomológicos (UCBE), Campus Ciencias Biológicas y Agropecuarias, Universidad Autónoma de Yucatán, México
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Christophides",authors:[{id:"154007",title:"Dr.",name:"Mathilde",middleName:null,surname:"Gendrin",fullName:"Mathilde Gendrin",slug:"mathilde-gendrin"},{id:"154008",title:"Prof.",name:"George",middleName:"K",surname:"Christophides",fullName:"George Christophides",slug:"george-christophides"}]},{id:"43829",title:"Bacterial Biodiversity in Midguts of Anopheles Mosquitoes, Malaria Vectors in Southeast Asia",slug:"bacterial-biodiversity-in-midguts-of-anopheles-mosquitoes-malaria-vectors-in-southeast-asia",signatures:"Sylvie Manguin, Chung Thuy Ngo, Krajana Tainchum, Waraporn\nJuntarajumnong, Theeraphap Chareonviriyaphap, Anne-Laure\nMichon and Estelle Jumas-Bilak",authors:[{id:"50017",title:"Prof.",name:"Sylvie",middleName:null,surname:"Manguin",fullName:"Sylvie Manguin",slug:"sylvie-manguin"},{id:"75315",title:"Prof.",name:"Theeraphap",middleName:null,surname:"Chareonviriyaphap",fullName:"Theeraphap Chareonviriyaphap",slug:"theeraphap-chareonviriyaphap"},{id:"88985",title:"Prof.",name:"Anne-Laure",middleName:null,surname:"Michon",fullName:"Anne-Laure Michon",slug:"anne-laure-michon"},{id:"88986",title:"Prof.",name:"Estelle",middleName:null,surname:"Jumas-Bilak",fullName:"Estelle Jumas-Bilak",slug:"estelle-jumas-bilak"},{id:"156016",title:"MSc.",name:"Chung Thuy",middleName:null,surname:"Ngo",fullName:"Chung Thuy Ngo",slug:"chung-thuy-ngo"},{id:"156018",title:"MSc.",name:"Krajana",middleName:null,surname:"Tainchum",fullName:"Krajana Tainchum",slug:"krajana-tainchum"},{id:"156019",title:"Dr.",name:"Waraporn",middleName:null,surname:"Juntarajumnong",fullName:"Waraporn Juntarajumnong",slug:"waraporn-juntarajumnong"}]},{id:"43899",title:"Distribution, Mechanisms, Impact and Management of Insecticide Resistance in Malaria Vectors: A Pragmatic Review",slug:"distribution-mechanisms-impact-and-management-of-insecticide-resistance-in-malaria-vectors-a-pragmat",signatures:"Vincent Corbel and Raphael N’Guessan",authors:[{id:"152666",title:"Dr.",name:"Vincent",middleName:null,surname:"Corbel",fullName:"Vincent Corbel",slug:"vincent-corbel"},{id:"169017",title:"Dr.",name:"Raphael",middleName:null,surname:"N'Guessan",fullName:"Raphael N'Guessan",slug:"raphael-n'guessan"}]},{id:"43851",title:"Perspectives on Barriers to Control of Anopheles Mosquitoes and Malaria",slug:"perspectives-on-barriers-to-control-of-anopheles-mosquitoes-and-malaria",signatures:"Donald R. Roberts, Richard Tren and Kimberly Hess",authors:[{id:"151439",title:"Prof.",name:"Donald",middleName:null,surname:"R. Roberts",fullName:"Donald R. Roberts",slug:"donald-r.-roberts"},{id:"151656",title:"Mr.",name:"Richard",middleName:null,surname:"Tren",fullName:"Richard Tren",slug:"richard-tren"},{id:"154152",title:"Ms.",name:"Kimberly",middleName:null,surname:"Hess",fullName:"Kimberly Hess",slug:"kimberly-hess"}]},{id:"43874",title:"Residual Transmission of Malaria: An Old Issue for New Approaches",slug:"residual-transmission-of-malaria-an-old-issue-for-new-approaches",signatures:"Lies Durnez and Marc Coosemans",authors:[{id:"152754",title:"Prof.",name:"Marc",middleName:null,surname:"Coosemans",fullName:"Marc Coosemans",slug:"marc-coosemans"},{id:"169018",title:"Dr.",name:"Lies",middleName:null,surname:"Durnez",fullName:"Lies Durnez",slug:"lies-durnez"}]},{id:"44330",title:"Vector Control: Some New Paradigms and Approaches",slug:"vector-control-some-new-paradigms-and-approaches",signatures:"Claire Duchet, Richard Allan and Pierre Carnevale",authors:[{id:"151662",title:"Dr.",name:"Pierre",middleName:null,surname:"Carnevale",fullName:"Pierre Carnevale",slug:"pierre-carnevale"},{id:"169000",title:"Dr.",name:"Richard",middleName:null,surname:"Allan",fullName:"Richard Allan",slug:"richard-allan"},{id:"169008",title:"Dr.",name:"Claire",middleName:null,surname:"Duchet",fullName:"Claire Duchet",slug:"claire-duchet"}]},{id:"43870",title:"New Salivary Biomarkers of Human Exposure to Malaria Vector Bites",slug:"new-salivary-biomarkers-of-human-exposure-to-malaria-vector-bites",signatures:"Papa M. Drame, Anne Poinsignon, Alexandra Marie, Herbert\nNoukpo, Souleymane Doucoure, Sylvie Cornelie and Franck\nRemoue",authors:[{id:"151515",title:"Dr.",name:"Papa Makhtar",middleName:null,surname:"Drame",fullName:"Papa Makhtar Drame",slug:"papa-makhtar-drame"},{id:"151648",title:"Dr.",name:"Franck",middleName:null,surname:"Remoué",fullName:"Franck Remoué",slug:"franck-remoue"},{id:"154034",title:"Dr.",name:"Anne",middleName:null,surname:"Poinsignon",fullName:"Anne Poinsignon",slug:"anne-poinsignon"},{id:"154035",title:"MSc.",name:"Alexandra",middleName:null,surname:"Marie",fullName:"Alexandra Marie",slug:"alexandra-marie"},{id:"154037",title:"Dr.",name:"Souleymane",middleName:null,surname:"Doucoure",fullName:"Souleymane Doucoure",slug:"souleymane-doucoure"},{id:"154038",title:"MSc.",name:"Herbert",middleName:null,surname:"Noukpo",fullName:"Herbert Noukpo",slug:"herbert-noukpo"},{id:"154039",title:"Dr.",name:"Sylvie",middleName:null,surname:"Cornélie",fullName:"Sylvie Cornélie",slug:"sylvie-cornelie"}]},{id:"44149",title:"Transgenic Mosquitoes for Malaria Control: From the Bench to the Public Opinion Survey",slug:"transgenic-mosquitoes-for-malaria-control-from-the-bench-to-the-public-opinion-survey",signatures:"Christophe Boëte and Uli Beisel",authors:[{id:"98400",title:"Dr.",name:"Christophe",middleName:null,surname:"Boëte",fullName:"Christophe Boëte",slug:"christophe-boete"},{id:"167749",title:"Dr.",name:"Uli",middleName:null,surname:"Beisel",fullName:"Uli Beisel",slug:"uli-beisel"}]}]}]},onlineFirst:{chapter:{type:"chapter",id:"74378",title:"Microfluidics for Time-Resolved Small-Angle X-Ray Scattering",doi:"10.5772/intechopen.95059",slug:"microfluidics-for-time-resolved-small-angle-x-ray-scattering",body:'\n
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1. Introduction
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Microfluidics is a multidisciplinary field dealing with the manipulation and behaviour of liquids and gases in dimensions below 1000 micron. The origin of microfluidics can be traced back to the 1970s, when miniaturisation became more and more developed. Applications in various fields, such as analytics, biology, chemistry, medicine and technology, became much more apparent with the development of rapid prototyping. Rapid prototyping describes a combination of photolithography, soft lithography and commercial printing, which makes the fast and efficient fabrication of custom designed microfluidic devices possible. Microfluidic devices for analysing aqueous samples were first introduced by Manz [1, 2], Harrison [3], Ramsey [4] and Mathies [5].
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The most important benefit of microfluidic devices is their ability to perform quantitative and qualitative analysis with high sensitivity and resolution, while being a low cost method for fast, highly efficient analysis [6]. These factors make it especially useful for time resolved measurements, and coupling to small angle X-ray scattering (SAXS) measurements for the analysis of the average particle size and shape, and the evolution thereof under various in situ conditions. These approaches, in particular the coupling of microfluidics to SAXS, finds application in various areas, including biological materials, polymers, colloids, chemistry, nanocomposites, metals, minerals, food, pharmaceuticals and quality control [7].
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Here we aim to detail background information important for the design of microfluidic devices for time resolved measurements, and the applications of these devices in time-resolved SAXS nanoparticle and self-assembly experiments.
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1.1 Microfluidic principles
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Fundamentally, the fluid dynamics in micro-dimensions are different from macroscopic systems. Fluid flows in these tiny systems are characterised by non-chaotic, smooth flow, where the fluid travels in parallel layers and the only interaction between those layers of flow is diffusion. By adapting reactions to microfluidic environments, the time axis of a reaction is converted into a distance axis along the outlet channel of the microfluidic device. This is key to enabling time-resolved studies in situ in a microfluidic channel.
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The Navier–Stokes equation describes the motion of fluids mathematically, and is derived from Newton’s second law of motion (F = ma), resulting in a set of two partial differential equations. For an incompressible Newtonian fluid, the Navier–Stokes equation is defined as:
where ρ is the density and η the viscosity of the fluid, p is the pressure, u the vector of the fluid flow, \n\n∇\n\n is the Nabla-Operator and F stands for any additional forces, that are directed at the fluid. The left side of the equation represents internal accelerations, and the right side represents the stress force per unit volume resulting from a pressure gradient and the viscosity of the fluid. In microfluidics, body forces are negligible, leading to a simplified, linear equation:
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\n\nη\n\n∇\n2\n\nu\n=\n∇\np\n\nE2
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Treating the incompressible liquid as a continuum, the Navier–Stokes equation can be expressed as the continuity equation:
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\n\n∇\n·\nu\n=\n0\n\nE3
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This means that the flux of liquid into a volume is the same as the flux out of a volume over a period of time. Additionally, the continuity equation is time-independent, restricting fluid flow in microfluidic channels to be symmetric in time [8].
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To describe and compare phenomena on different scales, various dimensionless numbers for microfluidics were introduced. The most important is the Reynolds number (Re), showing the relation of inertial and viscous forces of a fluid. It is defined as:
where \n\nυ\n\n is the flow velocity and d the characteristic length of the system, which in microfluidics is the diameter of the channel. The Reynolds number decreases with decreasing size of the system, reflecting the increased importance of viscous forces. The transition from turbulent to laminar flow is represented by \n\nRe\n\n being below \n\n2040\n±\n10\n\n.
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The next most important dimensionless number is the Weber number (We), which describes the relation of the fluid surface tension to its internal forces, where γ is the surface tension of the fluid:
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\n\nWe\n≡\n\n\nρ\n\nu\n2\n\nυ\n\nγ\n\nd\n\nE5
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Microfluidic channel systems have generally a high surface-to-volume ratio, thus surface properties have significant effects on flow resistance and the velocity profile. To describe the interaction of a flowing liquid and a solid surface in microfluidic devices, Navier defined boundary conditions. The flow velocity tangential to the surface \n\n\nυ\nx\n\n\n is proportional to the shear stress at the surface and therefore given by:
β is the slip length, or Navier length, and is defined as the distance from a point inside the channel to the surface, where the velocity is zero. Where \n\nβ\n=\n0\n\n is a “no-slip” condition, describing the interaction between fluids and walls [9].
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Every biological process or chemical reaction is limited by the converging and mixing of the reactants. Mixing in fluidic systems can generally occur via two methods – diffusion or advection. On the macroscopic scale, mixing is achieved by “chaotic advection” or turbulence, while on the micron-scale it is driven by diffusion. Diffusion specifies the migration of particles along a concentration gradient, and thereby always takes place from an area of high concentration to an area of lower concentration. This flux is in proportion to the diffusion coefficient, D, given by Fick’s first law of diffusion. Solving Fick’s diffusion law for adequate boundary conditions, the diffusion coefficient can be described for spherical particles with radius r in low Re numbers by the Stokes-Einstein relation:
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\n\nD\n=\n\n\n\nk\nB\n\nT\n\n\n6\nπηr\n\n\n\nE7
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with kB\n as the Boltzmann constant, T as the temperature and η as the solvent viscosity. The relation between advection and diffusion for mass transport is described by the Péclet number (Pe) [8].
For turbulent mixing, advection dominates the above equation, leading to high Pe numbers. In microfluidics, turbulent chaotic mixing is very difficult to achieve, because the Reynolds numbers are almost always very low. Thus, in microfluidic channels, advection is almost always very small, and diffusion dominates, resulting in Pe numbers that are low. As such mixer design in microfluidics devices seeks to optimise diffusion [10, 11]. Along microfluidic channels, diffusion becomes insignificant when compared to convection occurring far downstream at the outlet channel. Thus most mixing devices incorporate some method for laminating flows to reduce diffusion distances, and reduce mixing times. Most commonly, these mixers are simple Y- or T-shaped cross channels, and diffusive mixing in these types of mixers for kinetic experiments can be described by the following equations:
where d is the thickness of the relevant layer, η the viscosity and Q the volume flow. The following assumptions must be fulfilled for these equations to be true:
The microchannel inhibits steady and laminar flow.
The fluids are all Newtonian.
Density and viscosity of all fluids is the same in all channels and do not change during the experiment.
The channel geometry is rectangular and all channel parts have the same height.
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\nEq. (9) applies to Y-shaped channel geometries where layer 1 and 2 are the spaces of two introduced liquid streams in the inlet channels, which merge in the outlet channel. For T-shaped channels where two side channels (SC1 and SC2) hydrodynamically focus a main channel (MC) stream, Eq. (10) applies [12].
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1.2 Principles of small-angle X-ray scattering
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Small angle X-ray Scattering (SAXS) is an extremely versatile technique used for investigating particle size, shape and dynamics that can be applied to a wide range of scientific problems. It is amenable to a wide range of particles, from the very small, of around a few nanometres, to very large sized structures in the order of a micron. It can be used to study mixtures, and the evolution of shape in reaction mixtures, and is widely used in biophysics and structural biology to confirm structure, and investigate structures that are not amenable to other structure investigations. SAXS can be used across all states of matter, including solids, liquids, gases, semisolid sample such as gels, and plasma. We will focus here on solution scattering, as this is the most applicable for microfluidic applications.
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We aim to provide a brief overview of SAXS for solution scattering and time resolved measurements, but highly recommend Feigin and Svergun, 1987 [13] for a more comprehensive in depth review of SAXS measurements. In general, a solution SAXS experiment is relatively simple (which is one of the great attractions for the technique). A sample, in an appropriate sample cell, is exposed to a focussed, collimated monochromatic X-ray beam, and at a distance away from the sample the intensity of scattered X-rays is recorded using a 2D X-ray detector (Figure 1B). The resulting image is termed a scattering pattern. Similarly, the scattering from a matched pure background solvent is collected, and then subtracted from the sample scattering pattern to provide a scattering pattern that arises purely from the sample particles. The variation of the scattered intensity with angle, where the measured angles are very small, is related to differences in electron density between the sample and solvent, and the interatomic distances inside the sample particle, and thus contains information on the size and shape of the particle.
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Figure 1.
(A) Schematic illustration of the Bragg equation with incident and reflected X-rays on two scattering planes, showing the lattice distance d, the half scattering angle θ, the wavelength λ and the path difference defined by Bragg’s law. (B) Geometric construction of the scattering vector q from the incident wave vector k0\n and the scattered wave vector k with the half scattering angle θ. (C) Schematic setup of a small-angle X-ray scattering setup.
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Scattering in solution is generally considered isotropic, as most particle systems adopt random orientations in solution. This allows for analytical mathematical descriptions of the scattering profile on the basis of particle shape. Scattered intensity (I) is described as a function of momentum transfer, q, and in a simplified form can be given as:
Where N is the concentration of the particle in the solution, V is the volume of the particle, \n\nρ\n1\n−\nρ\n2\n\n is the contrast in electron density between the solvent and the particle, and q is defined as:
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\n\nq\n=\n4\nπ\n\n\nsin\nθ\n\nλ\n\n\nE12
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Where \n\nθ\n\n is the angle from the incident X-ray beam to the point on the detector where the intensity is measured, and \n\nλ\n\n is the wavelength of the incident X-rays (see Figure 1A). The derivation of the dependence of scattered intensity on the volume, concentration and electron density contrast of a particle described in Eq. 12 is given in detail in [13], which we highly recommend for further reading. The form factor P(q) is typically a defined function, and varies depending on the physical parameters of the particle; for example a sphere with homogenous electron density has a different form factor function to that of a hollow sphere of the same size.
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The structure factor component (S(q)) of Eq. (11) is a further analytical function that describes how the particles are arranged in the solution, e.g. forming large ordered structures with defined correlation lengths. Largely, samples are measured in a dilute condition, where the concentration of the particle is kept low enough to avoid these secondary interference effects, and thus S(q) can be ignored. Where this effect cannot be avoided by reducing concentration, the use of hard sphere packing models or ionic charge–charge interaction models defining the effect as a function of q may be used to account for this effect, and provide information on changes in long range order in a sample.
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Thus, for a sufficiently monodisperse sample, or a defined mixture of particles, it is possible to define an analytical model that provides volume, size and shape information. In polymer and colloid science, SAXS is used for many applications, including analysing the hierarchical nature of polymers in solution to assess clumping, local structure, overall morphology, and subunit arrangement, assessing the shape, size and dispersity of nanoparticles in solution, and investigating the dynamics, and evolution of particle size and shape under varying solution conditions and chemical reactions. SAXS is clearly a versatile technique that can provide useful information on systems that are well behaved, and can also be applied to samples that may not display ideal behaviour (for example aggregation prone nanoparticles, or time dependent mixtures of particles). However, the measurement does have some drawbacks. SAXS analyses are heavily reliant on complementary information. SAXS cannot provide information at an atomic resolution, so high resolution structural information is lacking, and needs to be obtained by alternative methods such as NMR, chemical crystallography, or electron microscopy. Further, SAXS does not provide information on changes in chemical environment so correlating the particle shape and size evolution with changes in the chemistry of a system requires the use of other techniques that are sensitive to the chemical environment. Additionally, for in situ experiments, SAXS on high intensity beamlines has the disadvantage that intense dose of radiation are required to obtain high quality data at short time frames. This can result in radiation damage in the sample that can significantly influence results.
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1.3 Microfluidic devices and X-rays
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In SAXS analyses, there are a range of disadvantages that the current sample environments struggle to address. First and foremost is that in most solution SAXS measurements there needs to be a high concentration of particles in the solution to achieve a scattering signal with high enough signal to noise to be of use in further analysis. For the most part, this is not a significant issue as most samples are generally amenable to reasonably high concentrations. However, in a number of cases, the amount of sample can prohibit the use of standard sample environments, and limits the use of SAXS to samples that are not in limited quantities, or expensive to produce. Further, for a continuous flow mixing device, where many exposures are required at each time point, the sample consumption can reach many millilitres; again this may be prohibitive for a majority of samples. Additionally it can be difficult to apply high throughput methodologies to systems where flow, volume and data quality constraints limit the number of measurements that can physically be conducted in a period of time.
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The limitations of the current sample environments can be significantly mitigated by the use of custom microfluidic devices. The very low internal volumes mean that sample consumption is reduced, and the time that a volume of sample can be measured over under flow is increased, leading to a general improvement in measurement statistics. The lower spatial footprint, and lower sample consumption rates, means that a large number of measurements can be conducted in a very short period of time in parallel; increasing throughput for screening measurements. The lower volumes, and thus much more efficient mixing allows for much lower deadtimes then would otherwise be possible, and with the increasing access to microbeam SAXS measurements, the time resolution of the mixing experiments are greatly improved over conventional approaches. Further, the ease of design and modification of devices means that bespoke devices for specific applications can be achieved rapidly. Given that microfluidic devices can address many of the limitations of conventional SAXS sample environments, we believe that there will be increasing uptake and incorporation of these devices into SAXS measurements.
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2. Microfluidics for time-resolved studies
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2.1 Device design
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To successfully investigate time-resolved reactions in microfluidic devices, the channel design has to be carefully adapted to the requirements of each application. All experiments require planning and consideration of the simultaneous use of analysis, mixing and cleaning equipment due to the generally small dimensions of microfluidic devices. In the past decades, a very diverse range of microfluidic reactor devices have been designed for time-resolved studies of reactions. Designs such as continuous-flow, stopped-flow, droplet-based and digital microfluidics have been developed and applied to produce materials with sizes ranging from nanometres to almost millimetres. In this chapter, we are focusing on continuous and stopped flow devices, in particular on hydrodynamic focusing techniques. In comparison to droplet-based techniques, hydrodynamic focusing is a straight-forward approach to implement, due to its pure hydrodynamic principles. It only includes surface tension effects at the liquid–liquid interface in the outlet channel of the microfluidic device without the need of consideration of surface tension effects at liquid–gas interfaces. These devices offer stability at high flowrates, allow high-throughput applications and enable highly controllable operational conditions, as the flow behaviour is the only influential parameter that needs to be considered for time-resolved studies.
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2.1.1 Flow field considerations
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An understanding of flow fields at the microscale is required to understand the function of hydrodynamic focusing and device design considerations. No turbulent mixing occurs inside a microfluidic channel, as typically Re numbers below 100 are achieved, thus liquids can only mix by diffusion. This has the advantage of allowing predictions of the exact movement of particles by calculation, as no chaotic (turbulent) mixing needs to be considered.
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For microfluidic channels, assuming no-slip conditions in combination with pressure driven flow, Poiseuille flow with a parabolic shaped flow profile arises. Here, the highest velocity is in the middle of the channel, which decreases parabolically towards the walls until it reaches zero. For cylindrical shaped channel geometries with coordinate length x, radius r and azimuthal angle Φ, the velocity field can be derived as:
This understanding of this pressure-driven, steady-state flow in microfluidic channels is the basis of liquid handling in lab-on-chip systems. Especially in microfluidics, the channel cross-sections can be of various shapes, depending on the application and fabrication method. Eqs. (13) to (16) describe the velocity field and hydraulic resistance for spherical and rectangular cross-sections, which are the most common geometries used for the devices described in this chapter. The derivation of those values is exceedingly more complicated for arbitrary channel cross-section shapes.
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2.1.2 Continuous flow vs. stopped flow
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The first design consideration is how the device will enable time-resolved measurement of phenomenon. This can be achieved in two different ways. The first, and conceptually simplest method, is a static experiment, where a sample is firstly mixed and then introduced into a monitoring chamber and measured repeatedly at defined time periods. The most common apparatus for this style of measurement this is a stopped flow device, where mixing is achieved rapidly, and then flow is stopped as soon as the homogenously mixed sample fills the monitoring chamber. The measurement is triggered as soon as the flow is stopped, and generally continues as rapidly as possible until the reaction reaches completion. The second method is to use a continuous flow system, where the mixed sample is introduced into a flow-through system, and temporal measurements are achieved by varying the distance between the mixing point and the sampling point.
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Both styles of devices have advantages and disadvantages, and the choice depends strongly on several experimental considerations, including the time domain of the reaction, mixing efficiency, sample volume constraints, and sample chemistry constraints (e.g. resistance to photobleaching, or radiation damage). Stopped flow measurements are favoured when there is a small volume of sample that is resistant to measurement induced damage (for example a flurophore that is resistant to photobleaching), where the reaction is not extremely fast, and where the experimental measurements are not slow. In stopped flow measurements the initial point in the measurement is always some degree of time post the start of the reaction (given the time it takes to fill the sample cell, stop the flow and take the first measurement), and the temporal resolution of the measurement is given by the speed at which the measurement can be taken. However, agglomeration of the reacting sample on the channel walls can influence the quality of measurements and, due to the ongoing reaction, leads to only a small window that can be detected before the experiment needs to be repeated. Alternatively, continuous flow measurements favour samples that are sensitive to the measurement, are very rapid, and require temporal resolution finer then the measurement speed of the instrument. Continuous flow measurements allow for measurement very close to the point of mixing, temporal resolution is given by the spatial resolution of the measurement, and the time taken to travel to the point of measurement. Further, the deadtime and temporal resolution is heavily influenced by flowrate, allowing for fine control across many temporal regions. As a result, the observation of the reaction can be precisely controlled. It needs to be considered that continuous flow measurements need more sample volume in comparison to stopped flow methods, to provide a constant flow profile.
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2.1.3 Hydrodynamic focusing
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The basis of hydrodynamic focusing lies in a central solution that flows with a lower flowrate within an outer sheath fluid with a higher flowrate. This enables the compression, or focusing, of the central flow, and decreases the mixing times significantly by reducing the diffusion length. There are two main categories for microfluidic devices with hydrodynamic focusing: coaxial tube and planar on-chip devices. The design can be defined depending on the use, with adapted geometries for fast mixing (Figure 2A), gradients (Figure 2B), specific nanoparticle growth reactions or self-assembly processes (Figure 2C) [15].
\n
Figure 2.
Left: Scheme of microfluidic features for kinetic investigations in flow in a cross shaped mixer. (A) Hydrodynamically focused Centre stream for fast mixing experiments. (B) Mapping of concentration gradient across and along the channel through interdiffusion of different liquids from main and side channels. (C) Nucleation and growth of nanoparticles or self-assembly processes of nanomaterials as a function of time along the outlet channel. Schematic comparison of the provided time scales in continuous and stopped flow microfluidic devices. Right: Schematic illustration of microfluidic devices with various channel cross designs with the corresponding cross-sections through the outlet channel. (D) Coaxial tube reactor with two concentric channels/capillaries. (E) Y-shaped design, where mixing is solely based on diffusion. (F) Cross-shaped geometry at the inlets for hydrodynamic focusing. (G) Two-cross-section geometry, also known as double-focus device, where three different solutions can be introduced into the channels. Solutions introduced into the first side-channel (SC1) act as an inert buffer between reactants in main channel (MC) and second side-channel (SC2). (H) and (J) multilayer designs of the geometries from (F) and (G), respectively, avoiding contact between the central stream and channel walls. (K) Hybrid device consisting of multilayer focusing device (J) and an inserted glass capillary as outlet channel.
\n
The simplest type of coaxial tube reactors is a device consisting of two concentric capillaries (Figure 2D), which are connected to a channel where a central flow is injected through the inner capillary, with sheath flow injected from the outer layer. Coaxial tube microreactors find various applications, but are typically used as the interface for droplet-based reactors, as the transition from flow to droplet generation, dripping and jetting is defined by the flowrate of the outer sheath flow. However, this approach is of limited utility in time resolved mixing applications, as it only offers limited mixing geometries. Further limitations abound in the fabrication process for coaxial designs, which requires multiple steps and precise alignment and assembly of the parts [15].
\n
On-chip hydrodynamic focusing devices can be differentiated in two-dimensional (2D) and three-dimensional (3D) devices. In two-dimensional hydrodynamic focusing devices, the central flow is focused in the horizontal plane. The simplest geometry for a 2D device is a Y- or T-shaped mixer (Figure 2E), where the cross-sectional diffusion is broadened at the channel walls in comparison to the centre. However, this design is highly limited regarding flow stability and focusing and susceptible to variation in these parameters in operation. To avoid this, cross-shaped geometries can be employed, where the central flow is focused from both incoming side channels (Figure 2F). This provides good control over the thickness of the central stream. Furthermore, it allows a well-defined sample composition that can be adapted by variation of the volume flow in each inlet individually. To adapt the device design to multi-step synthesis, several side channels can be added to introduce additional reactants (Figure 2G). Thus planar on-chip hydrodynamic focusing is more highly favoured for flexible mixing devices, and is used much more often in general microfluidic designs.
\n
However, there are further considerations that need to be taken into account, particularly for chemical reactions or self-assembly processes. In coaxial and 2D channel geometries the interface of reacting solutions is in contact with the channel walls, and particles or macromolecules can stick and agglomerate on the channel surface and disturb the laminar flow conditions. Furthermore, this accumulation interferes with analytical investigations and, in the worst case, can cause complete blockage of the channel.
\n
To avoid channel contact, three-dimensional channel geometries can be used. 3D hydrodynamic focusing requires both horizontal and vertical focusing of the central reactant stream, leading to a complete enclosure with liquid from all sides (Figure 2H and J). The device design can be optimised to reach homogeneous mixing without integrating specific mixing regions before the measurement part of the microfluidic chip. Additionally, these devices are simple to fabricate and have easily adjustable designs. The most common design to achieve 3D hydrodynamic focusing is through multi-layer on-chip devices, which require precise alignment as part of the fabrication process. Alternate methods are single layer devices or novel fluid manipulation technologies like “microfluidic drifting”, which introduces lateral drifts or counter-rotating vortex forces to achieve vertical and horizontal flow focusing. These alternatives require less alignment in manufacturing and are thus much more user friendly in regards to fabrication.
\n
All previously described device geometries can be used to produce droplets, liquid jets and sprays under the right flow conditions, including ultra-high flowrates. These devices are not limited to constrained flows inside channels, and for time-dependent studies the use of free liquid jets is preferred. Measurements of free jets have significant advantages in many optical measurements, as there is little to no background signal from surrounding material. When employing free jet devices, the parabolic flow profile from laminar flow within channels turns into a plug flow profile after passing the nozzle outlet. The liquid–solid interface of the no-slip condition resulting in parabolic flow is replaced by the liquid–gas interface in air, which has lower friction with the fluid and can be accelerated in flow direction. Free jets, however, are also quite difficult to work with, and despite the advantages in background have not found widespread use in the field.
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2.2 Fabrication
\n
\n
2.2.1 Fabrication techniques
\n
Many different technologies exist for the production of microfluidic devices. In general, fabrication of microfluidic devices in hard materials is often very time-consuming and cost-intensive, thus polymers are generally preferred, particularly when cost and ease of fabrication are considerations in the design process. In most cases, designs are started in silicon, with a Computer-Aided Design (CAD) model of the device. The device is then fabricated using any of a number of different technologies following a process of rapid prototyping. We focus here on some of the more common approaches.
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Lithography. One of the most powerful methods in microfabrication is lithography. It can be differentiated by the type of radiation used, e.g. photolithography, electron-beam lithography, or X-ray lithography. With these different lithography methods, structures with sizes between 0.2 and 500 μm in hard materials like glass, or between 0.5 and 500 μm in soft materials like polymers, can be achieved. In the most common form of lithographic fabrication, a UV blocking mask is generated from the CAD model, and adhered to a silicon wafer. The master model for fabrication is then generated by photolithography, where the masked wafer is coated in a photosensitive epoxy monomer solution, and UV-cured. In general these silicon masters are then used to generate working devices via soft lithographic replication. The most common approach is to use the master chip as a mould, and poly(dimethylsiloxane) (PDMS) to form an imprinted device, which can be bonded to a glass-slide or a second PDMS part to form the final microfluidic device [16, 17, 18]. The replicated structure can be a positive or negative of the initial design, depending on which part of the structure was UV-cured on the silicon master.
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Hot embossing and micromoulding. Hot embossing is a micromoulding technique that uses thermoplastic polymers to imprint structures at elevated temperatures. It usually uses high-temperature polymers, e.g. PMMA, PC, PI, PE, PVC or PEEK, which are heated above their glass transition temperature (Tg\n) before being pressed into a mould with high pressure. The moulds have to withstand the applied pressure and high temperatures, and are often made of metal or silicon, fabricated via etching, lithography in combination with electroforming and moulding or CNC (Computerised Numerical Control)-machining. The accuracy of hot embossing is in the order of tens of nanometres, making it possible to obtain high aspect ratios of structure, while being a low cost and easy procedure. It is often used with a defined and tested device design as high throughput method with a very short fabrication time [19, 20].
\n
3D printing. Within the last decade, 3D printing technologies have advanced to astonishing precision, in size-regimes down to the micrometre scale. Additive manufacturing technologies like fused deposition modelling (FDM), stereolithography (SLA) or selective laser sintering (SLS), have been developed for various materials like polymers, resins, ceramics or metals. It is possible with these techniques to produce a complete microfluidic device in one step. The device material and process can thereby be selected with regard to required mechanical and chemical properties of the device. A channel size resolution of few hundred micrometres can be achieved, making this approach preferred for devices with wider channels [21, 22].
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2.2.2 Device materials
\n
Based on the desired purpose of the microfluidic chip, device materials must fulfil specific criteria. The most important requirements which will be addressed in this chapter are solvent stability, ease of fabrication, and optical and X-ray transparency.
\n
Solvent stability. Microfluidics deals with the manipulation of liquids, which means that the device material has to be resistant and inert to the solvent. This becomes especially relevant when using organic solvents, as they often cause swelling or dissolution of standard polymeric device materials. Swelling leads to deformation, which can cause channel closure. A number of device materials have been tested with regard to resistance to some common solvents for nanoparticle synthesis and self-assembly processes (Table 1). It is clear from these results that careful selection of polymer is necessary for long term stability.
\n
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\n\n
\n
Polymer Solvent
\n
PDMS
\n
NOA 81
\n
THV815 GZ
\n
THV610 AZ
\n
THV500 GZ
\n
THV221
\n
ET 6235
\n
HTE-1705Z
\n
PS
\n
PMMA
\n
TOPAS 8007/6013
\n
Bendlay
\n
SIFEL
\n
SU8 50
\n
\n\n\n
\n
THF
\n
x
\n
x
\n
x
\n
o
\n
o
\n
x
\n
o
\n
(x)
\n
x
\n
x
\n
x
\n
x
\n
o
\n
o
\n
\n
\n
Toluene
\n
x
\n
(x)
\n
x
\n
o
\n
o
\n
o
\n
o
\n
o
\n
x
\n
o
\n
x
\n
x
\n
o
\n
o
\n
\n
\n
Chloroform
\n
x
\n
x
\n
x
\n
o
\n
o
\n
o
\n
o
\n
o
\n
x
\n
x
\n
x
\n
x
\n
o
\n
o
\n
\n
\n
Dioxane
\n
(x)
\n
x
\n
x
\n
o
\n
o
\n
o
\n
o
\n
o
\n
x
\n
x
\n
o
\n
x
\n
o
\n
o
\n
\n
\n
Acetone
\n
o
\n
o
\n
x
\n
x
\n
o
\n
x
\n
o
\n
o
\n
x
\n
x
\n
o
\n
x
\n
o
\n
—
\n
\n
\n
Octadecene
\n
o
\n
o
\n
x
\n
o
\n
o
\n
o
\n
o
\n
o
\n
o
\n
o
\n
x
\n
o
\n
—
\n
—
\n
\n\n
Table 1.\n
Stability test of various polymers and the corresponding solvents.
x: dissolution or swelling of the material, o: no change observed, −: not tested. Results in () showed insignificant swelling, the device could be continued to be used [23].
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Ease of fabrication. While the solvent is important, it is also essential to consider the difficulty of working with the various polymers, and the end characteristics of the device. For example, NOA 81 is a turbid, commercially available, UV curable polymer mixture from Norland Optical Adhesive, which is relatively easy to work with. However, devices made from NOA 81 are thin and relatively flexible, even after sealing top and bottom half, so it should be avoided if stiff or thick devices are required. In comparison, SIFEL (SIFEL2610) is a fluorinated polymer distributed by Shin-Etsu that is liquid at room temperature and hardens at higher temperature, and is stable against all tested organic solvents. The device fabrication however, is time consuming, requiring the additional step of sputtering the silicon wafer with an inert chemical layer to allow release of the SIFEL device from the mould.
\n
Materials can also dictate the method of fabrication, for example THVs (fluorothermoplastics of blended tetrafluoro ethylene, hexafluoro propylene and vinylidene) must be fabricated by hot embossing. Glass or hard material devices are made with difficult fabrication techniques, like etching. In many cases prototypes are made with cheap, easy to fabricate materials, with the more difficult fabrication only for the final working devices where needed.
\n
Optical and X-ray transparency. The most commonly used method for alignment of device parts and analysis of ongoing reactions is optical microscopy. Hence, the optical properties, e.g. transparency, of the microfluidic devices should be considered. Further, the final measurement modality must be considered in material selection. For example, if three-dimensional confocal microscopic investigations of the whole channel volume are required, the selected device material should provide a low absorption behaviour in the range of the sample-specific selected laser wavelength, and low fluorescence background. Or as the focus of this chapter is SAXS, the material of the device should have high X-ray transmission, and low scattering in the q-range of interest. The material should also be able to withstand the X-ray radiation, which is present on high flux SAXS beamlines. In our experience, the lowest background scattering for higher q measurements above 0.05 Å−1 were achieved with glass, NOA81, PDMS and Kapton. Other polymers such as THV and TOPAS showed diffraction and correlation peaks in the high q region >0.1 Å −1, that interfere with background subtraction, and worsen signal to noise. For measurements at low scattering angles with q values under 0.05 Å−1, glass, PMMA, PS, NOA81 and TOPAS display flat scattering curves. All other tested materials at this q-range showed significant scattering signals from the device [23]. Furthermore, although showing a low scattering background at high scattering vectors, PDMS was extremely sensitive to radiation, deforming the channel and showing an increasing and changing scattering profile with exposure. This material is typically unsuitable for SAXS measurements.
\n
Hybrid microfluidic devices can marry the best characteristics of materials, to achieve a successful device. For example, the complex mixing cross section can be made from easy to handle materials, e.g. PDMS, and a robust X-ray transparent, low background scattering material inserted as an outlet channel after the last cross-section, e.g. a glass capillary (Figure 2K). These devices have the advantage of high optical and X-ray transparency in the measurement region, while allowing adjustment to the mixing cross design in the polymer part [23, 24].
\n
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2.3 Practical considerations for device handling
\n
\n
2.3.1 Fluid handling
\n
A key practical consideration for the use of microfluidics is the method for introducing fluid into the device. For the most part, each interface channel should have its own fluid handling system, which should be capable of smooth, pulse free flow, with no bubbles or leaks, and should have similar chemical compatibility to that of the microfluidic device [25]. We favour modular syringe pump systems, which have the ability to adapt the amount of dosing units to the number of channels. Other options include flow regulated gear pumps, positive air pressure systems or even on-chip fluid reservoirs. In any case, fluid flows should be accurately calibrated immediately prior to use, to ensure the correct dosage, flowrates and thereby the correct flow profile. A further consideration in fluid handling is minimising dead volumes (in particular by using appropriate fluidic connections and minimising tubing lengths), to prevent wastage of sample. Further, it is ideal, particularly for time resolved SAXS experiments where access to the system is restricted, if the fluid handling system can be controlled and triggered remotely, as this allows for accurate initiation of the reaction and data acquisition. The usability of all devices should be tested before each experiment to avoid leakage and proper function of the channels, especially with regard to flow focusing. Tubing and device failure are common frustrations in obtaining good data.
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2.3.2 Temperature control
\n
In general, homogeneous temperature control of the reaction solution has to be achieved. It is possible to submerge the whole microfluidic device and tubing in a water / oil bath. However, for in situ investigation, there needs to be unimpeded access to the channel, and this approach is thus not viable. In this case, custom designed heating elements, e.g. heated enclosures, are employed to regulate temperature. Temperature control is only limited by the geometric constraints of the measurement, and the heat transmission of the device material. For example, we have implemented copper heating tubes for surrounding the glass capillary of hybrid microfluidic chips, incorporating a window for the X-ray beam that provided excellent thermal control of the measurement [26, 27]. A key to good thermal stability is to also incorporate heating elements for the fluidics systems, to keep the reaction solutions at appropriate temperatures and ease the thermal load on heating elements in the device.
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3. Microfluidics and SAXS
\n
\n
3.1 Incorporating microfluidic experiments into SAXS
\n
After the microfluidic devices are designed, fabricated, tested and fluid control is established, final considerations involve the implementation of the complete setup in an X-ray beam, either in a SAXS lab instrument or at a synchrotron beamline. Depending on SAXS instrument design a number of adjustments and considerations are required to achieve good integration for the measurement. As every synchrotron has slightly different parameters and sample environments, it is recommended to contact the beamline staff if considering a microfluidic-based time-resolved SAXS experiment for specific advice.
\n
\n
3.1.1 Device modifications
\n
SAXS measurements are dependent on the volume and composition of all objects in the X-ray beam. Consideration should therefore be given to not only the material’s resistance to radiation damage, but also the relative volumes of device material and sample that are going to be presented over the measurement channel. For example, 2–3 mm of any device-polymer either side of a sample channel of 50 micron means that the scattering from the sample in the channel will be entirely masked by the scattering of the polymer device, even if the polymer scattering is low. Further, the more material that is in the beam pathlength the more attenuation of the X-ray beam will occur. This means that less photons will hit the sample, get scattered, and escape the device to be detected. Calculations based on composition and thickness of the material should be done in advance to determine the expected transmission of the device. In many cases, this requires a redesign of the device itself to thin down the supporting material around the channels, incorporate X-ray transparent windows, or change the device material.
\n
\n
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3.1.2 Device mounting in beamline/SAXS instrument
\n
It should be expected that the device will be required to be perpendicular to the beam. Further consideration should also be given to the orientation of the channels, with respect to the beam dimensions. Generally, it is optimal to orient the channels so that as much of the beam is going through the channel as possible, and as little as possible is hitting the device body. This minimises background, and optimises the signal that can be achieved. In the best case scenario, the beamline will have the capability to generate micro beams of a few micron in any dimension. This allows for optimal exposure for the sample, and greatly increased time resolution in time-resolved samples.
\n
It is best if the device has a chip-holder to mount the device in, which in most cases is specific to the setup and design. This holder must allow for any necessary connections of inlet and outlet tubing while holding the microfluidic device steady and without tension on any connections to pumps or vials. Ideally, this holder would be placed on a motor-controlled, adjustable stage to facilitate precise alignment in the X-ray beam and movement of the device to scan along outlet channels for different points in time of reaction kinetics.
\n
In many cases, beamlines and lab instruments will maintain a vacuum along the complete X-ray flight path, and may include a vacuum sample environment. As X-rays interact with all matter, it is a requirement that there not be air in the majority of the SAXS instrument. Vacuum sample environments take this further by removing all air in the system to reduce and minimise background scattering. If a vacuum sample environment is in use, the microfluidic device must be designed to withstand the vacuum levels, and to minimise outgassing and other deleterious effects.
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\n
\n
3.2 Nanoparticle nucleation and growth
\n
A fundamental principle in nature and technology is self-assembly – the formation of ordered structures of components of a system out of chaotic arrangements without external forces. These processes can be induced by a multitude of parameters, e.g. change of solvent, pH, temperature, pressure or by introduction of additional reactants. SAXS, being sensitive to length scales of 1–100 nm is an ideal technique for studying nanoparticle size and structure from nucleation to the final particle. In situ SAXS measurements of nanoparticle synthesis is typically used to monitor the kinetics of this process [7], and increasingly incorporates microfluidics.
\n
Metal nanocrystals. Metal nanoparticle syntheses is particularly amenable to SAXS analysis, as their high electron density contrast allows measurements in dilute suspensions even at the very early stages of particle nucleation. This has been employed for investigating silver (Ag) and gold (Au) nanoparticle formation and structure [28, 29, 30, 31]. The first steps towards microfluidic setups were stopped flow measurements, for example the kinetics of gold nanoparticle formation, and the concurrent evolution of the optical properties of the particle at room and high temperature was very successfully investigated at millisecond resolution with this method by Abécassis et al. [32, 33] and Chen et al. [26]. Further development by Polte et al. provided in situ studies on the nucleation and growth of Au and Ag nanoparticles in stopped and continuous flow microfluidic devices [34, 35] Free liquid jets coupled to microfluidic mixers have aided in reducing background and improving signal to noise of SAXS measurements [36].
\n
When combining microfluidic setups and X-ray scattering for nanoparticle investigation, not only the reaction kinetics of nucleation and growth processes can be measured, but also agglomeration kinetics and structures. For example, Gerstner et al. combined a static microfluidic mixing device with in line absorption and SAXS measurements to study the rapid superlattice formation of alkylthiol-coated Au nanoparticles at different temperatures, which showed a differentiation between long- and short-range self-assembly effects of temperature on a time scale down to 3 seconds [37]. A further example is the time-resolved analysis of polystyrene (PS)-coated Au nanoparticles by Merkens et al. in a Kapton-based 3D hydrodynamic focusing microfluidic chip, that revealed the subsecond kinetics of structural transitions involved in solvent induced collapse [38].
\n
Semiconductor nanocrystals. Inorganic semiconductor nanoparticles, also called quantum dots (QDs), have received much attention due to their bright and size-tunable photoluminescence, which is commonly used as a key measurement property during synthesis [41]. During a synthesis of QDs, inorganic particles undergo a process of nucleation, growth and agglomeration, followed by dispersion into a buffer solution to quench the reaction. In order to synthesise homogeneous particles it is important to induce rapid nucleation and control the growth rate. Microfluidic devices with hydrodynamic focusing have been extremely useful in achieving this controlled synthesis process [15]. We have used 3D hydrodynamic focussing device for the synthesis of CdS nanoparticles, both studying the reaction by confocal laser scanning microscopy (CLSM) and SAXS. The CLSM measurements, using a full-PDMS device, showed the increase and shift of photoluminescence related to the nucleation and growth of CdS nanoparticles along the outlet channels. Hybrid microfluidic chips, consisting of the mixing cross section in PDMS and an inserted glass capillary as outlet channel (Figure 3D-F D-F), were developed for in situ SAXS measurements with low scattering background [24]. Employing a stopped flow setup, the nucleation and growth of ZnO nanoparticles was characterised at the timescale of seconds [27]. Further work elucidated the kinetics of the process at the microsecond timescale, using a free-jet device with a microfluidic T-mixer setup with a nozzle outlet to perform synchrotron SAXS measurements of the reaction in air (in the free jet). These setup enabled the investigation of QD synthesis with and without stabilising agents [42], highlighting the use of microfluidics and SAXS in the development of straightforward processes for nanoparticle synthesis.
\n
Figure 3.
Schematics and images of microfluidic devices used for time-resolved nanoparticle nucleation and growth and macromolecular self-assembly. (A) T-shaped, single layer (B) hydrodynamic focusing microfluidic device, made from Kapton (C) [\n\n39\n\n]. (D) Three-dimensional (multilayer) hybrid hydrodynamic focusing device (E), made from PDMS with inserted glass capillary (F) [\n\n24\n\n]. (G) Double stream hydrodynamic focusing device, which can be aligned without optical access (H), made from SIFEL with a thin PDMS carrier layer and inserted glass capillary (J) [\n\n23\n\n]. (K) Multilayer (L) micro-jet device with hydrodynamic focused spray out of a nozzle, made entirely from PDMS (M) [\n\n40\n\n].\n
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\n
\n
3.3 Macromolecular self-assembly
\n
Structural evolutions of pure and mixtures of surfactants that are often used in nanoparticle synthesis reactions, can also be investigated by a combination of microfluidic platforms and SAXS. Fürst et al. used a simple, T-shaped microfluidic chip to measure the structural assembly of tetradecyldimethylamine oxide (TDMAO) and lithium perfluorooctanoate (LPFO) in combination with synchrotron SAXS. This revealed the kinetic fusion mechanism of the cylindrical TDMAO and spherical LPFO micelles to disk-like micelles as a diffusion limited process, resulting in lamellar correlations at final stages [23].
\n
Amphiphilic diblock copolymers show fast self-assembly processes at a timescale of seconds. These can be followed in situ with specially designed equipment by synchrotron-based SAXS, as shown by Stegelmeier et al. for PS-P4VP block copolymers by rapid removal of solvent [43]. An elegant way to study these fast self-assembly processes in situ in solution is shown by With et al. by measuring the concentration-induced lyotropic phase transition of PI-PEO polymers. Employing a simple cross-shaped multilayer Kapton microfluidic device (Figure 3A-C) in combination with synchrotron microfocus SAXS, time-resolved self-assembly of the used PI-PEO polymers via a spinodal microphase to micelles into FCC liquid-crystalline phases could be studied with millisecond resolution [39]. A more sophisticated channel design was used to study the self-assembly of PI-PEO block copolymers via spherical micelles into a FCC lattice (Figure 3G-J) and the solvent-induced self-assembly of PEG-PLAinto spherical micelles, cylindrical micelles and vesicles by Fürst et al. [23].
\n
Apart from surfactants, polymers and polymer coated particles, other materials have self-assembly properties and can be investigated with a combination of microfluidics and X-ray scattering. Seibt et al. followed the pH-induced, rapid assembly of disk-shaped hydrogelators (N,N′,N″-tris(4-carboxyphenylene)-1,3,5-benzene tricarboxxamide) to nanofibrils of several hundred nanometres length by CLSM and SAXS. The measurement of the self-assembly process utilised 3D hydrodynamic focusing microfluidic devices (Figure 3D-F). Even bigger structures could be followed in the case of collagen and collagen derived fibres by pH-induced self-assembly. Here microfluidic chips provide an excellent platform for wet-spinning processes, shown by Haynl et al. [44] and Hofmann et al. [45], while SAXS can provide important information about the internal structure of the fibres during formation [46]. Furthermore, the alignment of macromolecular structures, such as worm-like micelles, patchy polymers and nanoplatelets can be investigated in (tapering) channels on chip [47] as well as in free jets (Figure 3K-M) [48].
\n
\n
\n
\n
4. Conclusion and outlook
\n
Many hypotheses posed by researchers across the world would be answered by observing reactions in real time. To achieve this, two major technologies provide significant opportunity when merged: SAXS and optimised microfluidic setups. Although the last decades of research lead to significant developments in combining these fields, it remains a demanding intersection of methods with the potential to answer many fundamental questions around nucleation, growth and self-assembly of materials on the nanoscale. New three-dimensional hydrodynamic focusing device designs show great promise in studying a variety of systems – from organic to inorganic and crystal growth to self-assembly processes. Nevertheless, this is still an emerging field, with microfluidic and synchrotron technologies continuing to push the boundaries of possible experiments, opening up new possibilities for further reducing dead times, and thereby understanding the earliest parts of synthesis reactions, which are of critical importance in future control and modification of nanoparticles for a wide variety of purposes. Micro-focused X-ray beams and beamline optimisation, meanwhile, will be a key component to access faster timescales with SAXS. We hope that this overview of microfluidics and SAXS analyses, along with some of our insights will aid future investigations into this challenging, but exciting field.
\n
\n
Acknowledgments
\n
The authors greatly thank Stephen Mudie and Calum Kinnear for useful remarks and comments.
\n
Conflict of interest
The chapter was written through contributions of all authors. All authors have given approval of the version of the chapter. The authors declare no competing financial interest.
\n',keywords:"micro and nanoscale, systems design, lab-on-a-chip devices, SAXS, nanoparticles, time-resolved SAXS, microfluidics, hydrodynamic focusing",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/74378.pdf",chapterXML:"https://mts.intechopen.com/source/xml/74378.xml",downloadPdfUrl:"/chapter/pdf-download/74378",previewPdfUrl:"/chapter/pdf-preview/74378",totalDownloads:84,totalViews:0,totalCrossrefCites:0,dateSubmitted:"September 10th 2020",dateReviewed:"November 19th 2020",datePrePublished:"December 11th 2020",datePublished:null,dateFinished:"December 9th 2020",readingETA:"0",abstract:"With the advent of new in situ structural characterisation techniques including X-ray scattering, there has been an increased interest in investigations of the reaction kinetics of nucleation and growth of nanoparticles as well as self-assembly processes. In this chapter, we discuss the applications of microfluidic devices specifically developed for the investigation of time resolved analysis of growth kinetics and structural evolution of nanoparticles and nanofibers. We focus on the design considerations required for spectrometry and SAXS analysis, the advantages of using a combination of SAXS and microfluidics for these measurements, and discuss in an applied fashion the use of these devices for time-resolved research.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/74378",risUrl:"/chapter/ris/74378",signatures:"Susanne Seibt and Timothy Ryan",book:{id:"10374",title:"Advances in Micro- and Nanofluidics",subtitle:null,fullTitle:"Advances in Micro- and Nanofluidics",slug:null,publishedDate:null,bookSignature:"Prof. S. M. Sohel Murshed",coverURL:"https://cdn.intechopen.com/books/images_new/10374.jpg",licenceType:"CC BY 3.0",editedByType:null,editors:[{id:"24904",title:"Prof.",name:"S. M. Sohel",middleName:null,surname:"Murshed",slug:"s.-m.-sohel-murshed",fullName:"S. M. Sohel Murshed"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_1_2",title:"1.1 Microfluidic principles",level:"2"},{id:"sec_2_2",title:"1.2 Principles of small-angle X-ray scattering",level:"2"},{id:"sec_3_2",title:"1.3 Microfluidic devices and X-rays",level:"2"},{id:"sec_5",title:"2. Microfluidics for time-resolved studies",level:"1"},{id:"sec_5_2",title:"2.1 Device design",level:"2"},{id:"sec_5_3",title:"2.1.1 Flow field considerations",level:"3"},{id:"sec_6_3",title:"2.1.2 Continuous flow vs. stopped flow",level:"3"},{id:"sec_7_3",title:"2.1.3 Hydrodynamic focusing",level:"3"},{id:"sec_9_2",title:"2.2 Fabrication",level:"2"},{id:"sec_9_3",title:"2.2.1 Fabrication techniques",level:"3"},{id:"sec_10_3",title:"Table 1.\n",level:"3"},{id:"sec_12_2",title:"2.3 Practical considerations for device handling",level:"2"},{id:"sec_12_3",title:"2.3.1 Fluid handling",level:"3"},{id:"sec_13_3",title:"2.3.2 Temperature control",level:"3"},{id:"sec_16",title:"3. Microfluidics and SAXS",level:"1"},{id:"sec_16_2",title:"3.1 Incorporating microfluidic experiments into SAXS",level:"2"},{id:"sec_16_3",title:"3.1.1 Device modifications",level:"3"},{id:"sec_17_3",title:"3.1.2 Device mounting in beamline/SAXS instrument",level:"3"},{id:"sec_19_2",title:"3.2 Nanoparticle nucleation and growth",level:"2"},{id:"sec_20_2",title:"3.3 Macromolecular self-assembly",level:"2"},{id:"sec_22",title:"4. Conclusion and outlook",level:"1"},{id:"sec_23",title:"Acknowledgments",level:"1"},{id:"sec_26",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'\nManz A, Graber N, Widmer HM. Miniaturized total chemical analysis systems: A novel concept for chemical sensing. Sensors and Actuators B: Chemical. 1990;1:244–8.\n'},{id:"B2",body:'\nKopp MU, Mello AJ, Manz A. Chemical amplification: continuous-flow PCR on a chip. Science. 1998;280:1046–8.\n'},{id:"B3",body:'\nHarrison DJ, Fluri K, Seiler K, Fan Z, Effenhauser CS, Manz A. Micromachining a miniaturized capillary electrophoresis-based chemical analysis system on a chip. Science. 1993;261:895–7.\n'},{id:"B4",body:'\nHadd AG, Raymond DE, Halliwell JW, Jacobson SC, Ramsey JM. Microchip device for performing enzyme assays. Anal Chem. 1997;69:3407–12.\n'},{id:"B5",body:'\nWoolley AT, Mathies RA. Ultra-high-speed DNA sequencing using capillary electrophoresis chips. Anal Chem. 1995;67:3676–80.\n'},{id:"B6",body:'\nManz A, Harrison DJ, Verpoorte EMJ, Fettinger JC, Paulus A, Lüdi H, et al. Planar chips technology for miniaturization and integration of separation techniques into monitoring systems. Journal of Chromatography A. 1992;593:253–8.\n'},{id:"B7",body:'\nIngham B. X-ray scattering characterisation of nanoparticles. Crystallography Reviews. 2015;21:229–303.\n'},{id:"B8",body:'\nSquires TM, Quake SR. Microfluidics: Fluid physics at the nanoliter scale. Reviews of Modern Physics. 2005;77:977–1026.\n'},{id:"B9",body:'\nNeto C, Evans DR, Bonaccurso E, Butt H-J, Craig VSJ. Boundary slip in Newtonian liquids: a review of experimental studies. Reports on Progress in Physics. 2005;68:2859–97.\n'},{id:"B10",body:'\nLee CY, Chang CL, Wang YN, Fu LM. Microfluidic mixing: a review. Int J Mol Sci. 2011;12:3263–87.\n'},{id:"B11",body:'\nWard K, Fan ZH. Mixing in microfluidic devices and enhancement methods. J Micromech Microeng. 2015;25.\n'},{id:"B12",body:'\nCapretto LC, W; Hill, M; Zhang,X. Micromixing Within Microfluidic Devices. Microfluidics. Berlin, Heidelberg: Springer; 2011. p. 27–68.\n'},{id:"B13",body:'\nFeigin LA, Svergun DI, Taylor GW. Structure Analysis by Small-Angle X-Ray and Neutron Scattering. Boston, MA: Springer US; 1987.\n'},{id:"B14",body:'\nBruus H. Theoretical microfluidics. Oxford: Oxford University Press; 2008.\n'},{id:"B15",body:'\nLu M, Ozcelik A, Grigsby CL, Zhao Y, Guo F, Leong KW, et al. Microfluidic Hydrodynamic Focusing for Synthesis of Nanomaterials. Nano Today. 2016;11:778–92.\n'},{id:"B16",body:'\nMcDonald JC, Duffy DC, Anderson JR, Chiu DT, Wu H, Schueller OJA, et al. Fabrication of microfluidic systems in poly(dimethylsiloxane). Electrophoresis. 2000;21:27–40.\n'},{id:"B17",body:'\nDuffy DC, McDonald JC, Schueller OJ, Whitesides GM. Rapid Prototyping of Microfluidic Systems in Poly(dimethylsiloxane). Anal Chem. 1998;70:4974–84.\n'},{id:"B18",body:'\nXia Y, Whitesides GM. Soft Lithography. Angewandte Chemie International Edition. 1998;37:550–75.\n'},{id:"B19",body:'\nHeckele M, Bacher W, Müller KD. Hot embossing - The molding technique for plastic microstructures. Microsystem Technologies. 1998;4:122–4.\n'},{id:"B20",body:'\nBecker H, Heim U. Hot embossing as a method for the fabrication of polymer high aspect ratio structures. Sensors and Actuators A: Physical. 2000;83:130–5.\n'},{id:"B21",body:'\nAmin R, Knowlton S, Hart A, Yenilmez B, Ghaderinezhad F, Katebifar S, et al. 3D-printed microfluidic devices. Biofabrication. 2016;8:022001.\n'},{id:"B22",body:'\nBishop GW. 3D Printed Microfluidic Devices. Microfluidics for Biologists: Springer; 2016. p. 103–13.\n'},{id:"B23",body:'\nFuerst C. Kinetic studies of lyotropuc structure formation with microfluidics and small angle X-ray scattering [Dissertation]. Bayreuth: University of Bayreuth; 2016.\n'},{id:"B24",body:'\nSeibt S, Mulvaney P, Förster S. Millisecond CdS nanocrystal nucleation and growth studied by microfluidics with in situ spectroscopy. Colloids and Surfaces A: Physicochemical and Engineering Aspects. 2019;562:263–9.\n'},{id:"B25",body:'\nSeibt S. In-situ Investigations of Molecular Self-Assembly Using Microfluidics [Dissertation]. Bayreuth, Melbourne: University of Bayreuth, The University of Melbourne; 2018.\n'},{id:"B26",body:'\nChen X, Schroder J, Hauschild S, Rosenfeldt S, Dulle M, Forster S. Simultaneous SAXS/WAXS/UV-Vis Study of the Nucleation and Growth of Nanoparticles: A Test of Classical Nucleation Theory. Langmuir. 2015;31:11678–91.\n'},{id:"B27",body:'\nHerbst M, Hofmann E, Forster S. Nucleation and Growth Kinetics of ZnO Nanoparticles Studied by in Situ Microfluidic SAXS/WAXS/UV-Vis Experiments. Langmuir. 2019;35:11702–9.\n'},{id:"B28",body:'\nPolte J, Ahner TT, Delissen F, Sokolov S, Emmerling F, Thunemann AF, et al. Mechanism of gold nanoparticle formation in the classical citrate synthesis method derived from coupled in situ XANES and SAXS evaluation. J Am Chem Soc. 2010;132:1296–301.\n'},{id:"B29",body:'\nHarada M, Tamura N, Takenaka M. Nucleation and Growth of Metal Nanoparticles during Photoreduction Using In Situ Time-Resolved SAXS Analysis. The Journal of Physical Chemistry C. 2011;115:14081–92.\n'},{id:"B30",body:'\nHenkel A, Schubert O, Plech A, Sönnichsen C. Growth Kinetic of a Rod-Shaped Metal Nanocrystal. The Journal of Physical Chemistry C. 2009;113:10390–4.\n'},{id:"B31",body:'\nGarcia PRAF, Prymak O, Grasmik V, Pappert K, Wlysses W, Otubo L, et al. An in situ SAXS investigation of the formation of silver nanoparticles and bimetallic silver–gold nanoparticles in controlled wet-chemical reduction synthesis. Nanoscale Advances. 2020;2:225–38.\n'},{id:"B32",body:'\nAbecassis B, Testard F, Spalla O, Barboux P. Probing in situ the nucleation and growth of gold nanoparticles by small-angle X-ray scattering. Nano Lett. 2007;7:1723–7.\n'},{id:"B33",body:'\nAbecassis B, Testard F, Kong Q, Francois B, Spalla O. Influence of monomer feeding on a fast gold nanoparticles synthesis: time-resolved XANES and SAXS experiments. Langmuir. 2010;26:13847–54.\n'},{id:"B34",body:'\nPolte J. Fundamental growth principles of colloidal metal nanoparticles – a new perspective. CrystEngComm. 2015;17:6809–30.\n'},{id:"B35",body:'\nPolte J, Erler R, Thunemann AF, Sokolov S, Ahner TT, Rademann K, et al. Nucleation and growth of gold nanoparticles studied via in situ small angle X-ray scattering at millisecond time resolution. ACS Nano. 2010;4:1076–82.\n'},{id:"B36",body:'\nPolte J, Erler R, Thunemann AF, Emmerling F, Kraehnert R. SAXS in combination with a free liquid jet for improved time-resolved in situ studies of the nucleation and growth of nanoparticles. Chem Commun (Camb). 2010;46:9209–11.\n'},{id:"B37",body:'\nGerstner D, Kraus T. Rapid nanoparticle self-assembly at elevated temperatures. Nanoscale. 2018;10:8009–13.\n'},{id:"B38",body:'\nMerkens S, Vakili M, Sanchez-Iglesias A, Litti L, Gao Y, Gwozdz PV, et al. Time-Resolved Analysis of the Structural Dynamics of Assembling Gold Nanoparticles. ACS Nano. 2019;13:6596–604.\n'},{id:"B39",body:'\nWith S, Trebbin M, Bartz CB, Neuber C, Dulle M, Yu S, et al. Fast diffusion-limited lyotropic phase transitions studied in situ using continuous flow microfluidics/microfocus-SAXS. Langmuir. 2014;30:12494–502.\n'},{id:"B40",body:'\nTrebbin M, Kruger K, DePonte D, Roth SV, Chapman HN, Forster S. Microfluidic liquid jet system with compatibility for atmospheric and high-vacuum conditions. Lab Chip. 2014;14:1733–45.\n'},{id:"B41",body:'\nNette J, Howes PD, deMello AJ. Microfluidic Synthesis of Luminescent and Plasmonic Nanoparticles: Fast, Efficient, and Data-Rich. Advanced Materials Technologies. 2020;5.\n'},{id:"B42",body:'\nSchiener A, Wlochowitz T, Gerth S, Unruh T, Rempel A, Amenitsch H, et al. Nucleation and growth of CdS nanoparticles observed by ultrafast SAXS. MRS Proceedings. 2013;1528.\n'},{id:"B43",body:'\nStegelmeier C, Exner A, Hauschild S, Filiz V, Perlich J, Roth SV, et al. Evaporation-Induced Block Copolymer Self-Assembly into Membranes Studied by in Situ Synchrotron SAXS. Macromolecules. 2015;48:1524–30.\n'},{id:"B44",body:'\nHaynl C, Hofmann E, Pawar K, Forster S, Scheibel T. Microfluidics-Produced Collagen Fibers Show Extraordinary Mechanical Properties. Nano Lett. 2016;16:5917–22.\n'},{id:"B45",body:'\nHofmann E, Kruger K, Haynl C, Scheibel T, Trebbin M, Forster S. Microfluidic nozzle device for ultrafine fiber solution blow spinning with precise diameter control. Lab Chip. 2018;18:2225–34.\n'},{id:"B46",body:'\nDehsorkhi A, Castelletto V, Hamley IW, Adamcik J, Mezzenga R. The effect of pH on the self-assembly of a collagen derived peptide amphiphile. Soft Matter. 2013;9.\n'},{id:"B47",body:'\nTrebbin M, Steinhauser D, Perlich J, Buffet A, Roth SV, Zimmermann W, et al. Anisotropic particles align perpendicular to the flow direction in narrow microchannels. Proc Natl Acad Sci U S A. 2013;110:6706–11.\n'},{id:"B48",body:'\nSchlenk M, Hofmann E, Seibt S, Rosenfeldt S, Schrack L, Drechsler M, et al. Parallel and Perpendicular Alignment of Anisotropic Particles in Free Liquid Microjets and Emerging Microdroplets. Langmuir. 2018;34:4843–51.\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Susanne Seibt",address:"seibts@ansto.gov.au",affiliation:'
Australian Synchrotron, ANSTO, Melbourne, Victoria, Australia
Australian Synchrotron, ANSTO, Melbourne, Victoria, Australia
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The first part compares the diagnostic efficacy of traditional OCT and cross-polarization OCT (CP OCT); CP OCT and fluorescence cystoscopy (FC) for detecting flat lesions in the bladder at the early stages of cancer. The second part contains a report on achievements in application of CP OCT for detection of recurrent carcinoma in the scar area that is a hardly distinguishable form of bladder cancer using an optimized CP OCT image analysis. The third part of the chapter reviews the results on CP OCT usage for in vivo diagnosis of the bladder cancer after radiation therapy of cervical cancer.",signatures:"Elena Kiseleva, Gladkova Natalia, Streltzova Olga, Kirillin Mikhail,\nMaslennikova Anna, Dudenkova Varvara, Yunusova Katerina and\nSergeeva Ekaterina",authors:[{id:"68196",title:"Prof.",name:"Natalia",surname:"Gladkova",fullName:"Natalia Gladkova",slug:"natalia-gladkova",email:"natalia.gladkova@gmail.com"},{id:"191970",title:"Dr.",name:"Elena",surname:"Kiseleva",fullName:"Elena Kiseleva",slug:"elena-kiseleva",email:"kiseleva84@gmail.com"},{id:"191990",title:"Dr.",name:"Olga",surname:"Streltzova",fullName:"Olga Streltzova",slug:"olga-streltzova",email:"strelzova_uro@mail.ru"},{id:"191992",title:"Mrs.",name:"Varvara",surname:"Dudenkova",fullName:"Varvara Dudenkova",slug:"varvara-dudenkova",email:"orannge@mail.ru"},{id:"191993",title:"Prof.",name:"Anna",surname:"Maslennikova",fullName:"Anna Maslennikova",slug:"anna-maslennikova",email:"maslennikova.anna@gmail.com"},{id:"191994",title:"Dr.",name:"Katerina",surname:"Yunusova",fullName:"Katerina Yunusova",slug:"katerina-yunusova",email:"katyayunusova@yandex.ru"},{id:"191995",title:"Dr.",name:"Mikhail",surname:"Kirillin",fullName:"Mikhail Kirillin",slug:"mikhail-kirillin",email:"mkirillin@yandex.ru"},{id:"193422",title:"Dr.",name:"Ekaterina",surname:"Sergeeva",fullName:"Ekaterina Sergeeva",slug:"ekaterina-sergeeva",email:"sea@ufp.appl.sci-nnov.ru"}],book:{title:"Bladder Cancer",slug:"bladder-cancer-management-of-nmi-and-muscle-invasive-cancer",productType:{id:"1",title:"Edited Volume"}}}],collaborators:[{id:"68196",title:"Prof.",name:"Natalia",surname:"Gladkova",slug:"natalia-gladkova",fullName:"Natalia Gladkova",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Nizhny Novgorod State Medical Academy",institutionURL:null,country:{name:"Russia"}}},{id:"157535",title:"Associate Prof.",name:"Bulent",surname:"Erol",slug:"bulent-erol",fullName:"Bulent Erol",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"191356",title:"Dr.",name:"Alejandro",surname:"Sousa-Escandón",slug:"alejandro-sousa-escandon",fullName:"Alejandro Sousa-Escandón",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Santiago de Compostela",institutionURL:null,country:{name:"Spain"}}},{id:"191970",title:"Dr.",name:"Elena",surname:"Kiseleva",slug:"elena-kiseleva",fullName:"Elena Kiseleva",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/191970/images/system/191970.jpg",biography:"Elena B. Kiseleva, has a PhD in biology (Biophysics), she is a researcher of Laboratory of Optical coherence tomography (OCT) of the Privolzhskiy Research Medical University (Nizhny Novgorod, Russia). Her research ranges from optical imaging of biotissues, in particular, cross-polarization (CP) and angiographic OCT, polarization and nonlinear microscopy to histological evaluation of tumor and normal tissues response to different types of treatment (PDT, radiation therapy). She has contributed to the development of the numerical processing of CP OCT images (quantification of OCT signal and improvement the OCT contrast) for differential diagnostics of mucosal and brain diseases; to studies of myelinated fibers changes due to glioma invasion and radiation-induced changes of bladder and rectum collagen structure. Her research experience includes over 12 years in application of OCT devices in experimental and clinical studies. She is an author more than 70 publication on OCT.",institutionString:"Privolzhskiy Research Medical University",institution:{name:"Nizhny Novgorod State Medical Academy",institutionURL:null,country:{name:"Russia"}}},{id:"192375",title:"Prof.",name:"Mariapia",surname:"Viola-Magni",slug:"mariapia-viola-magni",fullName:"Mariapia Viola-Magni",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Perugia",institutionURL:null,country:{name:"Italy"}}},{id:"192686",title:"Dr.",name:"Turgay",surname:"Turan",slug:"turgay-turan",fullName:"Turgay Turan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"195411",title:"Prof.",name:"Asif",surname:"Yildirim",slug:"asif-yildirim",fullName:"Asif Yildirim",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"195412",title:"Prof.",name:"Turhan",surname:"Caskurlu",slug:"turhan-caskurlu",fullName:"Turhan Caskurlu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"197851",title:"BSc.",name:"Samuela",surname:"Cataldi",slug:"samuela-cataldi",fullName:"Samuela Cataldi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"197852",title:"Dr.",name:"Daniela",surname:"Marocco",slug:"daniela-marocco",fullName:"Daniela Marocco",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null}]},generic:{page:{slug:"open-access-funding-funders-list",title:"List of Funders by Country",intro:"
If your research is financed through any of the below-mentioned funders, please consult their Open Access policies or grant ‘terms and conditions’ to explore ways to cover your publication costs (also accessible by clicking on the link in their title).
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IMPORTANT: You must be a member or grantee of the listed funders in order to apply for their Open Access publication funds. Do not attempt to contact the funders if this is not the case.
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UK Research and Innovation (former Research Councils UK (RCUK) - including AHRC, BBSRC, ESRC, EPSRC, MRC, NERC, STFC.) Processing charges for books/book chapters can be covered through RCUK block grants which are allocated to most universities in the UK, which then handle the OA publication funding requests. It is at the discretion of the university whether it will approve the request.)
UK Research and Innovation (former Research Councils UK (RCUK) - including AHRC, BBSRC, ESRC, EPSRC, MRC, NERC, STFC.) Processing charges for books/book chapters can be covered through RCUK block grants which are allocated to most universities in the UK, which then handle the OA publication funding requests. It is at the discretion of the university whether it will approve the request.)
Wellcome Trust (Funding available only to Wellcome-funded researchers/grantees)
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I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. 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After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. 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