\\n\\n
Dr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\\n\\nSeeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\\n\\nOver these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\\n\\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\\n\\nThank you all for being part of the journey. 5,000 times thank you!
\\n\\nNow with 5,000 titles available Open Access, which one will you read next?
\\n\\nRead, share and download for free: https://www.intechopen.com/books
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Preparation of Space Experiments edited by international leading expert Dr. Vladimir Pletser, Director of Space Training Operations at Blue Abyss is the 5,000th Open Access book published by IntechOpen and our milestone publication!
\n\n"This book presents some of the current trends in space microgravity research. The eleven chapters introduce various facets of space research in physical sciences, human physiology and technology developed using the microgravity environment not only to improve our fundamental understanding in these domains but also to adapt this new knowledge for application on earth." says the editor. Listen what else Dr. Pletser has to say...
\n\n\n\nDr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\n\nSeeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\n\nOver these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\n\nWe are excited about the present, and we look forward to sharing many more successes in the future.
\n\nThank you all for being part of the journey. 5,000 times thank you!
\n\nNow with 5,000 titles available Open Access, which one will you read next?
\n\nRead, share and download for free: https://www.intechopen.com/books
\n\n\n\n
\n'}],latestNews:[{slug:"intechopen-partners-with-ehs-for-digital-advertising-representation-20210416",title:"IntechOpen Partners with EHS for Digital Advertising Representation"},{slug:"intechopen-signs-new-contract-with-cepiec-china-for-distribution-of-open-access-books-20210319",title:"IntechOpen Signs New Contract with CEPIEC, China for Distribution of Open Access Books"},{slug:"150-million-downloads-and-counting-20210316",title:"150 Million Downloads and Counting"},{slug:"intechopen-secures-indefinite-content-preservation-with-clockss-20210309",title:"IntechOpen Secures Indefinite Content Preservation with CLOCKSS"},{slug:"intechopen-expands-to-all-global-amazon-channels-with-full-catalog-of-books-20210308",title:"IntechOpen Expands to All Global Amazon Channels with Full Catalog of Books"},{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"}]},book:{item:{type:"book",id:"58",leadTitle:null,fullTitle:"Holography, Research and Technologies",title:"Holography",subtitle:"Research and Technologies",reviewType:"peer-reviewed",abstract:"Holography has recently become a field of much interest because of the many new applications implemented by various holographic techniques. This book is a collection of 22 excellent chapters written by various experts, and it covers various aspects of holography. The chapters of the book are organized in six sections, starting with theory, continuing with materials, techniques, applications as well as digital algorithms, and finally ending with non-optical holograms. The book contains recent outputs from researches belonging to different research groups worldwide, providing a rich diversity of approaches to the topic of holography.",isbn:null,printIsbn:"978-953-307-227-2",pdfIsbn:"978-953-51-4515-8",doi:"10.5772/591",price:139,priceEur:155,priceUsd:179,slug:"holography-research-and-technologies",numberOfPages:468,isOpenForSubmission:!1,isInWos:1,hash:null,bookSignature:"Joseph Rosen",publishedDate:"February 28th 2011",coverURL:"https://cdn.intechopen.com/books/images_new/58.jpg",numberOfDownloads:60626,numberOfWosCitations:94,numberOfCrossrefCitations:28,numberOfDimensionsCitations:71,hasAltmetrics:0,numberOfTotalCitations:193,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 11th 2010",dateEndSecondStepPublish:"June 8th 2010",dateEndThirdStepPublish:"September 13th 2010",dateEndFourthStepPublish:"November 12th 2010",dateEndFifthStepPublish:"January 26th 2011",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7,8",editedByType:"Edited by",kuFlag:!1,editors:[{id:"16544",title:"Prof.",name:"Joseph",middleName:null,surname:"Rosen",slug:"joseph-rosen",fullName:"Joseph Rosen",profilePictureURL:"https://mts.intechopen.com/storage/users/16544/images/1608_n.jpg",biography:"Joseph Rosen is a professor at the Department of Electrical and Computer Engineering, Ben-Gurion University of the Negev, Israel. He received his BSc, MSc, and DSc degrees in electrical engineering from the Technion - Israel Institute of Technology in 1984, 1987, and 1992, respectively. \nHe is a fellow of the Optical Society of America. His research interests include holography, image processing, optical microscopy, diffractive optics, interferometry, biomedical optics, pattern recognition, optical computing, and statistical optics. 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\nDoppler ultrasound is a nontraumatic method that allows getting information about the linear and volumetric blood flow velocity in the carotid, vertebral, and other arteries; it is used to determine the degree of vessel stenosis and obturations and to outline the pathways of collateral circulation. The capabilities of Doppler ultrasound to determine the condition of carotid and vertebral arteries are verified by brain angiography, the coincidences reaching a high percentage. Doppler ultrasound is based on the Doppler effect, which refers to the change of sound, ultrasound, and light wave frequencies when they are reflected by a moving object. This phenomenon is used in the Doppler ultrasound exam, where erythrocytes and other forms of blood elements in the blood vessels are the moving objects.
\nUltrasound scanning (echography, B-mode) is a two-dimensional imaging in one plane, based on the reflection and diffusion of ultrasound rays from different density tissues. The ultrasound amplitude of the reflected signal is displayed on the screen as a point of varying grayscale intensity—white and black. Scanning is performed by a great number of parallel ultrasound rays, which pass through the scanned object with a frequency of 10–60 pulsations per second. Different frequency instant images of the scanned object appear during these ultrasound pulsations of reflected rays. Thus, vessels can be seen in motion. This real-time pulse scanning method is used in modern equipment. In that way, anatomical structures can be displayed on a two-dimensional plane in ultrasound scanning [1, 2, 3, 4, 5, 6, 7].
\nContinuous-wave Doppler ultrasound is the most common modern ultrasound method for examining extracranial cerebral arteries, peripheral arteries, and veins. The diagnostic frequency of the ultrasound emission is from 2 to 20 МНz. Deeper vessels are examined with transducers for a lower frequency of the ultrasound emission [8, 9].
\nThe objectivization of Doppler ultrasound is performed through spectral quantitative analysis of its frequency and amplitude characteristics. Frequency or velocity analysis of Doppler ultrasound, which is an expression of the blood flow velocity, is most widely used in all Doppler ultrasound exams. The Doppler velocity curve gives an approximate idea about the average velocity of the blood flow, passing through the artery cross section. In case of accelerated or turbulent blood flow due to artery stenosis, the velocity of a part of the erythrocytes changes dramatically and some of them receive a retrograde flow due to vortex formation. These changes may not significantly affect blood flow average velocity and velocity curve, but they change the Doppler frequency spectrum significantly [10].
\nThe amplitude or power spectrum shows the quantitative distribution of the power of movement of all blood components over a certain short interval of time in the cardiac cycle. In stenosis, the frequency or velocity increases, but the power of blood flow decreases due to turbulence, and therefore, the increase and especially the drop in amplitude is slow and the amplitude peak is low and shifted to low frequencies. Spectral width is an important indicator of amplitude analysis as it reflects the frequency, respectively the velocity, corresponding to 70% of the maximum blood flow power. This indicator makes it possible to assess the degree of damage to laminar blood flow in the presence of turbulence.
\nThis method makes it possible to simultaneously visualize the intensity and direction of the blood flow at different depths in the intracranial space. It provides information on the condition of the arteries emerging from the Circle of Willis. With this methodology, it is possible to select the most optimal Doppler signal from one or more different depths. This is convenient for monitoring the path of microembolic signals that are presented as high-amplitude signals through arterial blood flow. Transcranial Doppler sonography allows the monitoring of microemboli that emerge from the middle cerebral artery (MCA), proximal to stenosis, and chronic stenosis of the said artery. Fifty-eight patients with chronic stenosis of the MCA were examined. Twenty-three of them (29.5%) have low-grade stenosis, 18 (23%) had moderate-grade stenosis, while 37 (47.5%) were diagnosed with severe stenoses. Thirty-seven of the stenoses were symptomatic, and 41 were with asymptomatic carotid stenosis (ACS). Two ischemic strokes and seven transient ischemic attacks (TIAs) were observed during the follow-up. Twenty-four patients were treated with anticoagulants and 28 received aspirin. Microembolic signals were found in symptomatic and asymptomatic stenoses regardless of the medication received. These results indicate that chronic middle artery stenoses do not represent a significant source of emboli [11]. Transcranial Doppler sonography also allows for the monitoring of intracranial blood vessels in patients who had undergone thrombolysis [12] and also for the emergency diagnosis of ischemic stroke following head trauma [13].
\nThe method makes it possible to visualize extracranial brain vessels using the Doppler effect. Doppler sonography shows Doppler spectral analysis, which includes all velocities of the examined blood flow segment and an analog Doppler curve representing the mean velocity of the examined bloodstream segment.
\nThis method makes it possible to simultaneously analyze the blood flow of the studied artery in several separate blood volumes. A two-dimensional image of the velocity of all blood volumes and blood flow direction is obtained in a plane, the images being encoded in different colors. The resulting images are in real time [14, 15].
\nIt is a combination of echography, a real-time B-scanner, and a single-channel pulsed Doppler ultrasound system. In this way, the blood flow in the studied artery can be determined, as well as its speed and direction. The ultrasound determines the diameter of the vessel and the angle at which the ultrasound pulsating waves enter the longitudinal axis of the artery under study. Thus, these methods combine and complement each other. The method is used to examine the extracranial parts of the carotid arteries, the initial parts of the vertebral and subclavian arteries [16].
\nAn increase in the blood flow velocity is observed with acceleration of the systolic and diastolic part of the spectral form and the Doppler curve in the area above the stenosis. The laminar nature of the bloodstream is distorted, it becomes deformed and turbulent. After the stenosis, there is a slowing of blood flow and a turbulence increase [17].
\nThe method is important for clinical diagnosis because atherosclerotic plaques narrow the lumen of the blood vessel on the one hand and, on the other hand, are a source of emboli to the cerebral vessels.
\nThe most informative method for the detection of atherosclerotic plaques, originating from the vascular wall and various calcifications, is echography (B-mode). These plaques are often found in the arterial bifurcations and the end portions of the internal carotid artery [17].
\nIn the angiographic method, the vascular system of the brain is examined following the introduction of a contrast agent into the arteries. According to the type of arteries examined, we distinguish between carotid and vertebral angiography.
\nDiagnostic possibilities of digital subtraction angiography (DSA) were investigated in the diagnosis of cerebrovascular disease. A retrospective analysis was performed in 65 patients with various forms of cerebrovascular disease, taking into account the clinical characteristics and the risks accompanying them. In 75.4% of the patients, DSA found changes, with 85.5% having ischemic disorders of the cerebral circulation. The main diseases that led to the development of cerebrovascular disease were cerebral artery stenosis or atherosclerotic occlusions mainly in the extracranial vessels. Intraventricular hemorrhage was detected in four patients, and five patients had subarachnoid hemorrhage. Still DSA continues to be a gold standard in the diagnostics of the cerebrovascular disease.
\nComputed tomography angiography is an accurate means of determining intracranial occlusion in patients within the first 6 h of the onset of the cerebrovascular accident.
\nComputed tomography 3D-CT angiography of cerebral vessels is a technique that is particularly useful in the diagnosis of brain lesions and cerebrovascular disease. However, it does not provide information on the dynamics of blood flow changes. Therefore, a new technique has been developed—dynamic (D3D-CTA) angiography, which gives a 3D image of the vessels and allows assessment of hemodynamics and cerebral perfusion. Twelve patients were examined with CTA D3D (seven with brain tumors, four with arteriovenous malformations, and one with occlusion of the inner carotid artery). For all patients, information on changes in vascular structures, hemodynamics, and cerebral perfusion status was provided. Despite the relatively high risks, related to exposure to radiation, and limited scanning range, this technique is useful in the diagnosis of patients with cerebrovascular disease and brain tumors [18, 19, 20, 21].
\nAlthough 3D-CT angiography provides valuable anatomical information regarding the lesion and the adjacent vascular and bone structures, it cannot show lesions of the arteries and veins individually. 3D-CT venography allows for a more detailed study of vascular anatomy and allows improvement of the diagnosis and potentially safe surgical approach [20].
\nIt is a method of obtaining blood vessel images by using magnetic resonance. This method allows the assessment of the anatomical and functional characteristics of the bloodstream. Under the influence of a strong magnetic field, rotation of the hydrogen nuclei protons occurs and they change their location, positioning themselves along the magnetic field axis. The effects of the magnetic field and the radiofrequency emission of the protons are not constant and have no certain force, frequency, and time; after the radio frequency influence, the protons again return to the starting position, i.e., T1 and T2. The effects of the magnetic field and the radio frequency impulse of the hydrogen nuclei protons force them to rotate in relatively new axes over a very short period of time, which is accompanied by the emission and absorption of energy and the formation of their own magnetic field. The registration of these energy changes is the basis of the MRI image. The magnetic resonance angiography method allows obtaining images of the vessels without the use of any contrasting agents, but, in order to achieve a clearer picture, various contrast agents based on gadolinium can be used. The method finds less application for evaluation of carotid stenoses [22, 23].
\nIEFNS set up a working group with the aim of developing basic guidelines for the treatment and prevention of stroke patients in line with local and national requirements of neurologists from Europe. Due to increased population aging across Europe and socioeconomic and health issues, the opinion that the incidence and severity of ischemic strokes will increase in many countries over the next decades was formed. In addition, acute stroke mortality rate varies considerably across European countries, being the highest in many East European countries and considerably lower in West European countries. It was emphasized that the viability of ischemic brain tissue can be extended to 18 or even 24 h, experimental studies showing that the earlier intervention leads to a more favorable outcome. Thrombolysis is recommended to be used within a therapeutic window of up to 3 h after stroke, and it is currently being investigated whether it will be effective until the sixth hour. Neuroprotective agents are recommended up to 12 h from the vascular accident. The factors, delaying the onset of treatment due to later referral to a hospital, can be overcome if neurologists participate in special educational programs to improve initial diagnosis and manage emergency situations.
\nThere is an urgent need for a variety of diagnostic methods: computed tomography, Doppler sonography, electrocardiography, echocardiography, and laboratory tests, including coagulation status testing. Cardiac monitoring, blood pressure, blood gases, and body temperature monitoring are essential. If necessary, angiography, NMR, and EEG monitoring should be performed. After alleviation of the acute stroke, it is advisable to refer the patient to a rehabilitation unit.
\nA European guideline for the diagnosis of acute strokes was established. It emphasizes the need for neuroimaging techniques in the assessment of acute stroke, one of the leading causes of death and lasting neurological disabilities in developed countries. A comprehensive review of the literature, published in English for the period 1965–2005, was conducted and a set of methods for diagnosing stroke was created. Native CT of the brain is the first method of choice in diagnosis. Magnetic resonance tomography is a more sensitive computed tomography method and is particularly useful in the assessment of ischemic areas as well as in the diagnosis of acute and chronic intracerebral hemorrhages. Perfusion computed tomography and magnetic resonance angiography (MRA) are also very useful. MRT and MRA are the recommended techniques for the screening of brain aneurysms and for the diagnosis of cerebral venous thrombosis and arterial dissection. For noninvasive extra- and intracranial vessels study, extracranial and transcranial Doppler sonography are very useful. The transcranial Doppler sonography examination is very useful for monitoring arterial reperfusion after thrombolysis, for diagnosing intracranial stenosis and the presence of shunts, and for monitoring vasospasm after subarachnoid hemorrhage. Currently, single-photon emission computed tomography (SPECT) and positron emission tomography (PET) have a more limited role in acute cerebral strokes assessment [24].
\nA number of other scientific publications emphasize the role of neuroimaging techniques in brain stroke patients [24, 25, 26, 27].
\nIn modern emergency stroke therapy, many patients may temporarily improve, especially after thrombolysis, and worsen again to the original neurological deficit. Although mechanisms of such deterioration (DFI) may include development of brain edema, reperfusion hemorrhage, or other secondary factors such as cardiopulmonary decompensation, most DFIs are due to indefinite processes. Urgent sonographic assessment of patients with acute neurological deficits and DFI is not well characterized. The aim of the study was to evaluate the incidence and characteristics of vascular lesions in determining the acute spontaneous development of deficits and their potential links with subsequent DFI. Patients with focal neurologic deficit associated with cerebral ischemia, which was evaluated with a total NIH stroke score < 4 within 6 h of onset of symptoms, were prospectively studied.
\nTranscranial Doppler sonography (TCD) was routinely used and, when necessary, subsequent digital subtraction angiography (DSA), CT angiography (CTA), or MR angiography (MRA) was used. Vascular images were interpreted by a neurologist and a neuroradiologist for the presence of occlusions of large arterial vessels, stenoses, etc. Occlusions of large vessels were evaluated as atherosclerotic, in which Doppler sonography or angiography showed narrowing or occlusion of extra- and intracranial arteries greater than 50%. Stroke cases in which the potential source of emboli had been found were classified as embolic. In other cases, arterial dissection or coagulopathy was accepted as the cause of the stroke, and in some cases, the mechanism remained undetermined. Fifty patients with an average age of 61 + 14 years were studied, the women being 50%. The patients’ symptoms had occurred after 165 + 96 min. Transcranial Doppler sonography was performed in all patients, and subsequent angiographic studies (DSA 10%, CTA 4%, MRA 44%) were performed in 68%. In general, large artery occlusions during TCD exam were found in 16% of patients, stenosis was found in 18%, 54% had normal studies, and the study could not be performed in 10%. DFI was observed in 16% of patients, TCD and angiography showed occlusion data in 62%, 22% had stenosis, and 4% of the vascular exams had normal results. DFI occurred in 31% of patients with atherosclerosis in a large arterial vessel, 23% had cardiac embolism, and 9% had small vessels damaged. In conclusion, it is emphasized that DFIs are strongly associated with the presence of occlusion or narrowing of a large arterial vessel of atherosclerotic or embolic origin. The reliability of emergency TCD or angiography in the early diagnosis of vascular lesions is very high. This makes it possible to assess the condition of the patients and to determine the therapeutic strategy [4, 28, 29].
\nA 3D visualization method was established for the entire vascular system, which includes carotid and vertebral arteries. Spiral CT angiography (SCTA) was used, providing a precise, qualitative, and quantitative assessment of anatomical abnormalities, including the detection of additional lesions and an assessment of the degree of stenosis. Fifteen patients with pathological abnormalities of the arterial vascular system, detected by color-coded duplex ultrasound, were examined using digital subtraction angiography (IA-DSA) and SCTA. The results obtained from 3D SCTA showed a high correlation with those of IA-DSA and SCTA [30].
\nSevere intracranial artery stenosis is the main cause of acute ischemic stroke. Although the warning symptoms for such stenosis are rarely found, cerebral transient ischemic attacks and ischemic stroke require active and effective diagnosis and treatment. The study described the main diagnostic methods for the diagnosis of arterial stenosis. Digital subtraction angiography makes it possible to trace the entire vascular system by conducting dynamic observations through the introduction of contrast agent. Magnetic resonance angiography also provides information but cannot properly show changes in small blood vessels. Transcranial Doppler sonography makes it possible for the changes in large intracranial vessels, the blood flow velocity, etc., to be detected by noninvasive technique. In computed tomography angiography, performed with intravenous contrasting of iodine contrast media, the vessels of Circle of Willis can be examined.
\nMedical professionals should use different imaging techniques to evaluate patients with stroke. The main diagnostic methods are used in these cases. Computer tomography allows a series of brain slices to be made, excluding hemorrhage or brain tumor. Abnormal findings can usually be observed during a computed tomography scan from 6 to 8 h after the onset of stroke. Another diagnostic method is magnetic resonance tomography. Its advantage is that it can show brain edema a few hours after the stroke and is better than computed tomography in detecting small cerebral infarctions. Doppler sonography is a noninvasive method for investigating extra- and intracranial vessels. Other methods, used in acute stroke diagnosis, are magnetic resonance and conventional angiography, which is performed under stricter indications [11].
\nThe diagnostic merits of Doppler imaging, CT angiography, and digital subtraction angiography (DSA) for diagnosing carotid stenosis have been compared. DSA is considered a “gold standard” for confirming severe stenoses (70–99%) of internal carotid arteries; yet it is associated with a risk of complications. The aim of the study was to evaluate the accuracy of Doppler sonography, computed tomographic angiography, and their combined use for the detection and quantification of severe carotid stenosis as compared to DSA. 29 patients were included in the study and their results were compared. The results showed that DUS in combination with STA can be used for relatively reliable diagnosis of severe stenoses of the internal carotid artery. Thus, invasive digital subtraction angiography can be avoided in a significant number of patients [31].
\nComputed tomography angiography (CTA) is a relatively new and minimally invasive method of visualizing the intracranial and extracranial blood vessels. The diagnostic capabilities of the CTA and the gold standard of arterial imaging (DSA) were compared. A total of 40 patients (80 carotid arteries), examined with STA, DUS, and DSA, were prospectively studied. Patients, selected for inclusion, had symptoms of cerebral transient ischemic attacks or stroke. The degree of stenosis and atheromatous changes were studied by the three methods. The results showed that STA had significant correlations with DSA, while the correlation with DUS was less obvious. STA showed good possibilities for detecting light carotid stenoses (0–29%) and arterial occlusions. Stenosis detection of more than 50% was achieved with DSA, while CTA showed a sensitivity of about 50%. In addition, CTA showed quite good correlations with DSA in detecting lesion atheromatous plaques in carotid stenosis. In conclusion, CTA shows very good capabilities for detection of carotid artery occlusions or stenosis up to 50% but is not able to reliably distinguish the differences between moderate (50–69%) and severe (70–99%) stenoses, which is important in determining the methods for the treatment of carotid stenosis [18].
\nInvasive diagnosing imaging of cervical and intracranial vessels, done with CTA, MRA, and DUS, has been studied in other clinical trials as well [32].
\nSingle-slice CT angiography (CTA) is an established method for imaging the vascular system of the brain (CVS), but it suffers from technical limitations for the visualization of long vascular segments such as intra- and extracranial vessels. The comparatively recently created multislice (MS) technology allows high-quality angiographic images due to increased scanning speeds and improved spatial resolution. The study was aimed at assessing the suitability of multislice CTA (MS-CTA) when examining the vascular system of patients with acute symptoms of arterial and venous occlusion. In 41 patients with a clinical suspicion of acute cerebral ischemia (29 in the hemisphere and 12 in the vertebrobasilar system), as well as in 4 patients with suspicion of cerebral venous thrombosis, MS-CTA was administered. Additionally, Doppler sonography was performed in 34 patients, magnetic resonance angiography in 5 patients, and digital subtraction angiography in 6 patients. All findings for extra- and intracranial blood vessel stenoses were correlated with clinical outcomes. The study showed that MS-CTA is a promising diagnostic tool for rapid and overall assessment of arterial and venous vessels in patients with clinical signs of acute cerebrovascular disease [33, 34].
\nTranscranial Doppler sonography (TCD) may localize arterial occlusion in patients with stroke. About 190 patients with, or without, proximal extra- and intracranial occlusions were examined by TCD. The obtained data were compared with those from DSA and MRA. Angiographic examination showed occlusion in 48 patients. The TCD showed Doppler signals unusual for the middle cerebral artery in 66.7%; reverse blood flow through the ophthalmic arteries in 70.6%; and blood flow through the anterior communicating artery in 78.6% and through the posterior communicating artery in 71.4%. The study showed that transcranial Doppler sonography data for large artery occlusions can be used to extend complex diagnosis and improve prognostic value for noninvasive screening in stroke patients [35].
\nFor a very long time, medical professionals believed that arteriography is a mandatory method for diagnosing the dissection of the internal carotid artery. With the introduction of transcranial Doppler sonography and magnetic resonance angiography, it is no longer the case. Thirteen patients with dissection of the internal carotid artery were diagnosed by extra- and transcranial Doppler sonography, computed tomography, and magnetic resonance tomography. Digital subtraction angiography, as a “gold standard,” confirmed the diagnosis in all cases. Thus, noninvasive techniques can be sufficiently informative in such patients [36].
\nThe diagnostic capabilities of digital intra-arterial angiography and transcranial Doppler sonography were compared in 48 patients with acute cerebral ischemia in the carotid artery basin on the fourth hour after onset of symptoms. Data from the TCD exam showed correlation with angiographic examination.
\nThe clinical manifestations of vascular hypoplasia were studied in 205 children aged 3–14 years. About 21% of them had transient ischemic attacks (TIAs), and 17% had cerebral infarction; focal or generalized epileptic seizures were found in 56.1%, while 4.9% had migraine headache. Cerebral arterial hypoplasia was diagnosed with angiography, MR angiography, and transcranial Doppler sonography [37].
\nAcute occlusion of the basilar artery is a common condition, but differential diagnosis is not always easy for patients with acute onset, change in consciousness, and progressive dysfunction of the brainstem. Intra-arterial thrombolytic therapy is a potential life-saving procedure in certain cases of acute occlusion of the basilar artery. Therefore, it is necessary to have reliable and widely available methods for assessing the patency of the basilar artery. Traditionally, digital subtraction angiography has been used for diagnosis in suspected cases of acute occlusion of the basilar artery. However, DSA is a laborious, costly, and invasive method that requires patient cooperation or general anesthesia. Extra- and intracranial Doppler sonography was used to diagnose clinical suspicion of acute occlusion of the basilar artery. Unfortunately, due to DUS technical limitations, especially for the study of distal portions of the vertebral artery, ultrasound diagnosis may be inadequate.
\nMagnetic resonance angiography has not been used so far in large groups of patients for the examination of the basilar artery occlusion. Difficulties can be explained with the specific patients’ condition—disturbed consciousness and intubation in patients with acute cerebral ischemia.
\nSpiral CT angiography (CTA) is a relatively new instrumental method for noninvasive vascular diagnosis in cases of acute cerebral ischemia. A prospective study was conducted with 19 patients of an average age of 58 + 11 years with clinical suspicion of acute vertebral artery occlusion. Criteria for inclusion of the patients were the clinical manifestations of sudden worsening of consciousness, dizziness, diplopia, dysarthria, oculomotor nerve lesions, and lesions of other cranial nerves or bilateral symptoms. Three patients were in coma. The diagnostic capabilities of CTA, DUS, and DSA, used for these patients, were compared. CTA revealed a complete occlusion of the basilar artery in nine patients and an incomplete occlusion in two of them. Due to severe vertebral artery calcification, one patient could not be examined. Doppler sonography was performed in 7 of 19 patients, with clear evidence of vertebral artery occlusion in 3 of them. In the remaining patients, the data were uncertain and two were false-negative, which was proved by CTA and DSA exams. In addition, CTA provided information on the exact place of basilar artery occlusion. These data allowed for intra-arterial thrombolysis to be used in five patients. In conclusion, CTA was more informative than DUS in assessing the patency of the basilar artery in patients with acute ischemia, especially in the distal artery occlusion. The study emphasizes the advantages of the combination of methods, used for the diagnosis of basilar artery occlusion [38].
\nThe role of CTA, MR angiography, DUS, and DSA for the quantification of atherosclerotic stenosis of the carotid artery was studied in 25 patients. The degree of stenosis was measured according to North American Symptomatic Carotid Endarterectomy Criteria: complete occlusion (100%), severe (70–99%), moderate (30–69%), and mild (0–29%). Degree of stenosis, measured by CTA, MRA, and DUS (Doppler ultrasound), was compared to the DSA results, used as the “gold standard.” Ninety-seven percent of the results obtained from MRA were equivalent to DSA and 3% did not match; 96% of CTA data were DSA equivalents, with 4% not matched; 77% of the results of Doppler sonography were equivalent to DSA, and 23% had a mismatch. In conclusion, it is emphasized that CTA and MRA are equally accurate methods for quantification of the degree of stenosis in carotid bifurcation [39].
\nIn 178 patients with cerebrovascular disease, studies were conducted to compare whether invasive CT angiography was an alternative to digital subtraction angiography and noninvasive Doppler sonography. CTA reported nine cases of significant stenosis, which were not thoroughly assessed by the DSA, and in two cases, it did not show any results. In addition, vascular wall calcifications were more easily evaluated by CTA [40].
\nAtherosclerotic diseases of the middle cerebral artery (MCA) are often met with Asian population. This abnormality can be diagnosed by noninvasive methods such as transcranial Doppler ultrasound (TCD) and CT angiography (CT). The diagnostic capabilities of these two methods were compared in 70 patients with suspicion of atherothrombotic occlusion of the middle cerebral artery. The study excluded cases of cardiac embolism, significant carotid stenosis, or classical lacunar syndrome. Transcranial Doppler ultrasound was performed within 2 days of hospitalizing the patients; it was followed by STA within 7 days of stroke. CTA showed stenoses of MSA exceeding 50% in 57 patients (81%), whereas only 29 patients (41%) had TCD visualized abnormalities. TCD results correlate well with those of CTA in all patients with proximal stenosis of the M1 segment. In contrast, transcranial Doppler sonography visualizes accurately distal M1 or M2 injuries only in 24% of patients. In this population, CTA showed better abilities than TCD in the diagnosis of thrombosis of MCA. Transcranial Doppler sonography should not be used as a basic method for the detection of MCA stenoses [41].
\nA pilot study of the diagnostic capabilities of CTA and TCD in the diagnosis of intracranial occlusion of intracerebral arteries was performed. Ten patients with acute ischemic stroke as a result of stenosis or MCA occlusion were studied. Seven stenoses and five occlusions of MCA were found. CTA confirmed all TCD results except for one patient with MCA occlusion, who had multiple embolisms. The results showed that CTA is an easily performed and useful method in the diagnosis of MCA occlusion [42]. A number of other studies have shown the high diagnostic value of TCD and CT angiography in basilar artery stenosis and occlusions [38].
\nTranscranial color-coded duplex sonography (TCCD), magnetic resonance angiography (MRA), and computed tomography angiography (CT) are relatively new noninvasive or minimally invasive techniques to study intracranial circulation. TCCD makes it possible to improve the accuracy and reliability of data supplied by conventional transcranial Doppler imaging. The main limitation of transcranial color-coded duplex sonography is related to the ultrasound windows that make it difficult to insonate the basilar arteries, especially in their proximal part, and has a lower resolution. MRA provides good morphological information on the condition of the cerebral vessels. CTA is a sensitive method for detecting occlusive changes in the large intracranial arteries. Transcranial color-coded duplex sonography and magnetic resonance angiography, used in combination or alone, can eliminate the need for digital subtraction angiography in most cases of occlusive cerebrovascular disease. Digital subtraction angiography can be used in cases where noninvasive techniques do not provide sufficient information, or for the diagnosis of brain aneurysms and arteriovenous malformations. The role of CTA for the detection of aneurysms by contrast agent injection is well established, whereas in cases of other lesions, the method does not always produce clear results [10].
\nPatients with acute ischemic stroke, having occurred with intracranial arterial obstructions, are with poor prognosis and a high probability of death up to 24 h. The diagnostic accuracy of Doppler ultrasound (PMD-TCD) and CT angiography is assessed as a standard in the diagnosis of intracranial artery occlusion in patients with ischemic stroke within 24 h. A total of 100 patients were studied. PMD-TCD showed intracranial occlusion in 34 patients, while the STA showed the same result in 33 patients. Six false-positive and four false-negative diagnoses were found by PMD-TCD. This methodology showed a high coincidence with CT angiography in the diagnosis of occlusion of arterial vessels in patients with acute ischemic stroke, especially in the middle cerebral artery basin [43].
\nA study was conducted to determine whether spiral CT angiography allows accurate quantitative assessment of anatomical abnormalities, including the detection of additional lesions, determining plaque morphology, and assessment of carotid artery stenosis. The diagnostic capabilities of spiral CT angiography and digital subtraction angiography were compared in 92 cases of carotid artery stenosis. The degree of stenosis was determined according to the North American Symptomatic Carotid Endarterectomy Trial (NASCET). All stenoses were diagnosed using CT angiography. It showed coincidence with digital subtraction angiography in 59% of the cases with mild stenosis, in 82% of the cases with moderate stenosis, and in 90% of those with severe stenosis. Calcified plaques were easily detected by spiral CT angiography, but discovery of lesion plaques was difficult. The study showed that spiral CT angiography gives enough information for carotid stenoses greater than 30% and for calcified plaque detection but is not sufficiently informative for detecting lesions [44].
\nCarotid artery examination is important for the evaluation of patients with ischemic stroke and cerebral transient ischemic accidents. CT angiography (CTA) of the head and neck is an easily accessible method that can be part of the routine imaging diagnosis in patients with stroke. In a large academic center, for the period 2000–2002, CTA and DSA examinations of the cervical part of the carotid artery were performed in 81 patients according to the NASCET criteria. For stenoses over 70%, the coincidence of both methods was 96%. The study showed that CTA is an excellent screening test for stenosis of the internal carotid artery [45].
\nIntravenous recombinant tissue plasminogen activator (TPA) has been shown to be effective in the treatment of acute ischemic stroke within the first 3 h of onset, but unfortunately the occlusion of the vessel may not always be well documented in due time. Digital subtraction angiography, performed within several hours, is a method of quickly and reliably validating the intracranial occlusion of the vessel. CT angiography is also potentially useful for this purpose, as it shows significant coincidence with DSA. About 54 patients with acute stroke were examined using the two methodologies. CTA has shown coincidence with DSA regarding occlusions in 86% of the cases [7].
\nThe possibilities of multidetector CTA as compared to DSA were studied in 35 patients (70 carotid arteries). The degree of stenosis was calculated according to NASCET. CTA was somewhat inaccurate for measuring the absolute minimum diameter in high-grade stenoses, while in stenoses exceeding 50% and above, the coincidence of both methods was 95%. The method confirms the suitability of CTA as a screening method for patients with carotid stenosis. In hemodynamically significant stenoses detected by STA screening, it appears that conventional angiography still needs to be applied [46].
\nThe diagnostic value of CTA in a study of the Circle of Willis in patients with acute stroke was compared to MR angiography and DSA in 145 patients. CT angiograms were estimated as good or excellent in 89% of cases, and MR angiograms were estimated as such in 92% of cases. Arterial stenoses or occlusions were found in 43% of CT angiograms; they were found in 48% of MR angiograms and in 21% of DSA angiograms. The study showed that CTA is an accurate and safe method for assessing arterial stenosis and occlusion of the blood vessels in the Circle of Willis [47].
\nThe diagnostic capabilities of CTA and MRA as noninvasive techniques were compared with DSA in 146 stroke patients. In comparison with DSA, STA and MRA showed inaccurate results in lower-grade stenosis. DSA methodology remains the gold standard in the diagnosis of patients with cerebrovascular injuries [48, 49, 50].
\nThe role of cerebral angiography in the diagnosis of cerebrovascular diseases is sometimes questioned by the increasing importance of MR angiography. Studies in patients with atherosclerotic cerebrovascular disease have shown that MRA can almost completely displace brain angiography as a screening method for carotid bifurcation. However, the discovery of “pseudo-occlusion” still requires the use of digital subtraction angiography for accurate diagnosis. DSA is more indicative in detecting distal artery occlusions. Subarachnoid hemorrhage, detected by computed tomography, must necessarily be examined by cerebral angiography, although magnetic resonance angiography may be used as a screening test for aneurysms larger than 3 mm. The cerebral angiography is still indispensable in confirming the diagnosis of cerebrovascular malformations, arterial dissection, and fibromuscular dysplasia [51, 52].
\nA significant number of patients with cerebral transient ischemic accidents develop ischemic stroke in the first few months and years. A multicenter clinical trial was conducted among 3886 patients who had had transient ischemic accidents with the aim of assessing the risk of developing an early stroke. Risk factors for cerebrovascular disease (high blood pressure, age, diabetes mellitus, carotid stenoses, etc.) were studied. Instrumental methods such as magnetic resonance tomography and Doppler ultrasound were used. The results were assessed by a point system. The authors recommend new studies to be conducted, aiming at verification of the use of the methods applied [53].
\nOutpatient diagnosis is an important initial step in emergency treatment of stroke. A number of screening tests have been developed to identify patients at high risk of stroke. Early transportation of the patient to the hospital allows thrombolysis to be administered and improves prognosis for the final outcome of the disease [54].
\nSymptoms, related to the damage to the internal and external carotid arteries, were investigated, and a clinical analysis of the progressive cerebral infarction was performed in 248 patients (142 men and 106 women, average age 67.2 years). Two groups of 60 patients with progressive and 188 patients with nonprogressive cerebral infarction, respectively, were formed, the infarctions having occurred as a result of mild, moderate, and severe carotid stenoses. All patients were examined with Doppler sonography, computed or magnetic resonance tomography. Some risk factors for cerebrovascular disease (hypertonic disease, smoking, alcohol abuse, hyperlipidemia, etc.) were studied.
\nSince carotid arteries are the major source of blood for the brain, intima-media increased thickness is a sign of early atherosclerosis, which gradually progresses. Thrombotic and embolic processes, as well as cerebral transient ischemic accidents, are often developed with a subsequent cerebral infarction. Studies have shown that the amount of atheromatous plaques in the carotid arteries is essential for the development of severe stenoses and hemodynamic disorders in the brain. At this stage, the treatment of progressive cerebral infarction is conducted with antiaggregants, fibrinolytic agents, etc., and in some cases, endarterectomy is administered, especially in severe stenoses of the carotid arteries. Doppler ultrasound exam of extra- and intracranial vessels should be conducted within the first 24 h of the onset of the vascular accident, followed by subsequent dynamic observation.
\nIschemic stroke and cerebral transient ischemic accidents are clinical diagnoses for the confirmation of which, as well as for the exclusion of cerebral hemorrhage, computed tomography and magnetic resonance tomography of the brain are performed. MRT is a more sensitive method but is often not available especially in smaller hospitals. In a clinical study in Australia, it was shown that the mean time (IQR) from hospital arrival to brain scanning should be 1.8 h (0.9–3.6 h); in this case, only 51% of the patients had their brain examined within 4.5 h of stroke. In addition, these patients should also be tested with Doppler ultrasound and electrocardiography.
\nEmergency diagnostics is also needed for the timely inclusion of thrombolytic therapy with RT-PA [24, 55].
\nGender plays an important role in cardiovascular disease. Epidemiologic studies have demonstrated that men have a higher incidence and prevalence rate of stroke than women. The strokes that do occur in women tend to be more severe, however. In terms of revascularization, the available literature suggests that women have higher risk of perioperative adverse events. This thus puts into question how much women actually benefit from carotid revascularization compared with men.
\nThe available literature suggests that women have a higher risk of perioperative adverse events during carotid revascularization. In the Asymptomatic Carotid Atherosclerosis Study (ACAS), women had a higher rate of perioperative events (3.6 vs. 1.7% for men) during CEA. Combining that with a lower rate of events for women (8.7 vs. 12.1% for men) treated with best medical therapy, this led to a much lower 5-year risk reduction for women (17%) compared with men (66%). Among patients with moderate stenosis in the North American Symptomatic Carotid Endarterectomy Trial (NASCET), the number needed to treat with CEA to prevent one ipsilateral stroke was 12 and the number needed to treat to prevent one disabling stroke was 16 for men. The corresponding numbers for women were 67 and 125, respectively, potentially suggesting a lower long-term benefit of surgery for women. The Asymptomatic Carotid Surgery Trial (ACST) produced similar findings, with men deriving a higher 5-year absolute risk reduction (8.21 vs. 4.08%) than women.
\nThe data are somewhat unclear in the recent trials evaluating CAS and CEA. Women in the International Carotid Stenting Study (ICSS) had a higher 120-day event rate for CEA (7.6 vs. 4.2%) but a lower rate for CAS (8.0 vs. 8.7%). The opposite was found in the Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST), with a lower periprocedural event rate for women undergoing CEA (3.8%) than men (4.9%) but higher in CAS (6.8 vs. 4.3%). With potentially higher perioperative event rates, these data raise the question of how much women actually benefit from intervention [50].
\nA database of 938 carotid arteriogram entries was established prospectively, with accompanying measurements of peak systolic velocity (PSV) and end-diastolic velocity (EDV). The percent of internal carotid artery stenosis seen on arteriograms was calculated according to criteria from the North American Symptomatic Carotid Endarterectomy Trial. Analyses were made in 536 carotid arteries in men and 402 carotid arteries in women. In addition, the single most diseased artery per patient was analyzed by gender. PSV and EDV were averaged for data subsets according to 10% intervals of internal carotid artery stenoses. Velocity for each interval was compared between men and women with the Student
For all intervals, PSV and EDV averaged 9 and 6% higher, respectively, in women than in men. Significant gender differences existed between PSV and EDV for 60 and 70% stenosis. When a single vessel per patient was analyzed, these observations persisted, but lost significance for PSV at 60% stenosis. Receiver operator characteristic curves at 90% sensitivity demonstrated that optimal PSV for 60% stenosis was 160 and 180 cm/s, and for 70% stenosis was 185 and 202 cm/s, in male and female patients, respectively.
\nWomen have higher carotid blood flow velocity than men do. Gender differences exist and are notably different at clinically relevant thresholds for intervention. These data indicate that different criteria should be used for interpreting carotid velocity profiles in women than in men and have potentially important implications for patient care [5].
\nWe examined 974 subjects aged 25–88 years (478 men and 496 women) in whom we considered heart rate, smoking status, and the presence of hypertension, diabetes, hypercholesterolemia, and hypertriglyceridemia. Ultrasound examination of the neck vessels included measurement of intimal medial thickness (IMT), vessel diameter, and outflow area/inflow area ratio. We established plaque location, echogenicity and echostructure, and the percentage of stenosis owing to plaque and measured systolic velocity, flow direction, and the depth of detection of these parameters. We used the apnea and hyperpnea test to assess cerebrovascular reactivity. Hypertension and hypercholesterolemia were the most frequent risk factors. Women had a higher heart rate, whereas men had significantly greater IMT. The presence of atheromatous plaque was significantly correlated with age in both sexes, with men having a higher prevalence of carotid plaques. The sexes differed significantly with regard to plaque location, echogenicity, echostructure, and intracranial circulation. Women had a slightly higher blood flow velocity in the intracranial arteries. Risk factors affected plaque formation and extent more in men than in women. These findings suggest that carotid stenosis is a gender-related trait [47].
\nHigh-resolution Doppler ultrasonography of 500 carotid bifurcations was performed in 192 women and 308 men before surgical treatment. Carotid stenoses averaged 70 ± 11% (30–95%) in women and 72 ± 12% (40–98%) in men. The prevalence of 90–99% stenosis was greater in men, 14.3 vs. 7.8%. Carotid plaques were longer in men, 2.3 ± 0.8 vs. 1.9 ± 0.6 cm. Mean diameters of the distal internal carotid artery, 4.9 ± 0.9 vs. 4.6 ± 0.8 mm, and of the common carotid artery, 7.6 ± 1.3 vs. 7.1 ± 1.4 mm, were greater in men. The distance from the ear lobe to the bifurcation was also greater in men, 5.9 ± 1.1 vs. 5.3 ± 0.9 cm. Doppler ultrasonography preoperative mapping demonstrated that the parameters measured were greater in men than in women. Detailed planning of carotid plaque treatment must take into consideration individual differences such as those associated with the patient’s gender [36].
\nThe large number of diagnostic methods and combinations of these allow early and accurate diagnosis of carotid diseases. However, it is not possible in the day-to-day practice to apply several of them at the same time. The combination of noncontrast computed tomography of the brain with Doppler ultrasound exam of the neck and head vessels in most cases provides sufficient data both for morphological changes in brain tissue and for various carotid stenoses, which are one of the well-documented risk factors for cerebrovascular disease.
\nMicrofluidics is a broad terminology covering various disciplines and scopes while focusing on life science, biochemical and chemical applications. It applies to the devices that process fluids at a dimension below the millimeter scale, and the maximum fluidic volume is within milliliters. Current applications are more related to fluids from microliters to nanoliters in volumes [1, 2]. Two devices in the late 1970s marked the birth of microfluidics. IBM first reported the inkjet printer heads [3] in 1977, and now millions of such units have been shipped worldwide, enabling color printing into every corner of human life. Another device is the micro gas chromatography made on a 5 cm silicon wafer by Stanford University in 1979 [4]. This
The majority of applications of the current microfluidics are for liquid handling other than the gaseous materials. DNA/Gene analysis and point of care disease diagnosis are extensively studied with microfluidic devices [12, 13, 14, 15]. The microfluidic devices can integrate both active and passive elements inside the fluidic channels, enabling the polymerase chain reaction devices that help the DNA amplification. The detailed analyses of the DNA samples become possible. Such information is critical for identifying diseases and understanding the origins of the abnormality to the search for possible recovery routes. The other important and advantageous benefits of these microfluidic-based diagnostic devices are fast processing time with small sample volume. These features are combined with today’s communication infrastructure, making the remote diagnosis a fascinating scenario. However, current devices are still less sophisticated to acquire the necessary data for the desired tasks. Most of the devices available are based on colorimetric or optical images or limited electrical signals. These data are similar to the analog ones in the electronic age. Additional
Microfluidics advancement, on the other hand, greatly relies on the device fabrication technologies of micromachining. The earlier simple passive microfluidic chips having the only microchannels are no longer the mainstream but components of the current devices. A sophisticated microfluidic chip would have both passive structures and active components, which is a challenge for the micromachining process technologies that do not have standard protocols. The multi-discipline features further complicate the availability of process tooling. Fortunately, microfluidics’ growth is parallel with the significant advancement in the MEMS and LSI/VLSI IC industry. With ever-improving micromachining device fabrication technologies, the microfluidics once was only viable on a 2″ wafer, and now 8″ and even 12″ wafers are being routinely produced. Many more foundries are available with specialized alternative substrates of glasses, plastics, polymers, and even papers. In recent years, 3D printing, precision micro-injection, laser processing, hot embossing [20, 21, 22, 23], and other alternative tools also greatly enriched the variety of microfluidic devices. The progress significantly solves the issues for chemical and bio-compatibility and, in some cases, for commercialization, but the cost to fabricate a desired microfluidic chip is still far from satisfactory. Moreover, the interactions among the device components and the fluids are also likely and sometimes are mandatory, adding additional requirements for better materials and fabrication technologies. Several key components, including microfluidic channels, microvalves, micropumps, needles, mixers, and sensors, are considered the necessary ones for the desired microfluidic chip or system. These relatively complicated components and the substrate make the process compatibility with the electronics a dilemma. Therefore, package, interface, and system design will become critical for the device’s final footprint, manufacturability, and successful deployment.
The inkjet printer head that handles the ink droplets remains an outstanding example of a successful microfluidic application. The envisioned microfluidic future in life science and others are still missing a bridge, mostly from the ease of reach and cost-effectiveness [9, 24, 25, 26]. The research data for the current microfluidic market have excluded the inkjet applications, addressing only the diagnostic devices and pharmaceutical and life science tools [27]. Nevertheless, by comparing the market reports from the same market research firm issued a decade ago to the current data, one could find that even the most optimal old forecast has nothing to beat the real growth. On the other hand, today’s multi-billion dollar market and the double digital growth predicted by various market research firms are more from the companies making the system level products but not the direct values of the key components. These data for the value-added systems are, in a sense, could deceit the current research focus on components. While the system level products enable various applications, the lack of a miniaturized, standalone, performance dramatizing, and cost-effective device would not maintain the expected or envisioned phenomenal growth. In this chapter, standalone flow sensor products for microfluidics will be discussed, including the technologies, standards, factors that will impact the performance, integrations, and manufacturability or scalability.
Microfluidic studies have covered a huge spectrum of processes. For this chapter’s limited space, only continuous flow sensing technologies are discussed with applicable pulsed flow features. Droplet flow, nanofluidic flow, microfluidic manipulation or handling, and biological and chemical-related flow phenomena will not be addressed.
Microfluidic sensors are critical components for a complete system. Many research works on sensors have been dedicated to the biomedical and chemical sensing development based on electrochemical, optical, mass, or magnetic sensing principles. Electrochemical sensors are mostly studied and often composed of several electrodes that are easy to fabricate together with the microchannels. This limited integration with a simple configuration allows a fast response with reasonably good sensitivity and enables multiple reagents on a single microfluidic chip. The electrode embedded inside a microfluidic channel can also be used for cell counting and estimate the flow volume. With the assistance of a miniaturized LED, pH measurement could be achieved as well [28, 29, 30, 31]. However, many of the proposed biosensors or chemical sensors are very specific, and most are research-orientated, as being determined by the catalytic or affinity properties of the biological recognition agent in a particular study and the sensor itself requires a sophisticated electronic system for readout or analysis. The standalone or large scale commercial applications are yet to emerge.
Flow meters using traditional thermal capillary and Coriolis measurement are commercially available for micro flow measurement before the microfluidics being intensively studied. Researches on microfluidic flow sensing approaches are for miniaturized, cost-effective, and integrable products. In this scope, both flow and pressure sensors have been extensively studied [28]. In some cases, the differential pressure sensor can be used for flow measurement. Flow measurement is one of the most important factors in microfluidic handling for data analysis and precise system control. Without the knowledge of the fluid quantity in the process, analytical results would not be easy to establish the needed and convincing statistics. The conventional flow sensors might be the first commercially available standalone sensing products for microfluidics. The technologies are still limited, and their package formality is bulky and far off the cost target for the desired microfluidic system. Many studies proposed integrating flow sensors into the microfluidic system. However, there are still many factors that impact data acquisition. The existing sensor products on the market also have some unsolved reliability issues in applications. The commercialization route to a well-performed and cost-effective sensor is yet to be demonstrated.
The available flow sensors applied to microfluidics are classified as thermal and non-thermal sensors [1]. Thermal flow sensors have been applied to small flow measurement for both gas and liquid before the microfluidic concept emerged. Therefore thermal flow sensors are mostly studied and applied in microfluidic applications, and products with various thermal sensing principles are commercially available. Coriolis microfluidic sensor is a non-thermal sensor, and it has an even higher cost. Other “non-thermal” flow sensors are mostly at the research stages. Before the form factor, cost, and reliability issues can be solved, large scale applications are still not possible.
For the traditional flow sensors, the metrology characteristics will hardly enable a self-calibration. Therefore, a primary standard or a reference defined by an international norm governs the manufacture of a flow sensing product with specific sensing technology. The same should then apply to microfluidics. Demanding to establish an international standard for microfluidics has long been proposed [32, 33]. Still, only in recent years, an international microfluidic association has been established, and an international standard (ISO) working committee has been organized with a serial of workshops [34]. It has been proposed that the new ISO standard for the microfluidic shall be having four sub-standards, including
Several efforts to establish a primary standard or a traceable reference system for flow metrology in microfluidics applications have been made in the past years [35, 36, 37]. The widely adapted primary standards are the gravimetric and volumetric principle. The comparison of such standards among different European national metrology institutes indicated an uncertainty (
For almost all flowrate ranges in microfluidics, the Reynold numbers are within 1000, indicating that the flow of interests is within the laminar flow regime. Therefore in a desired large dynamic range, the flow profile would not be the same at the different flowrates, which adds complexity to maintain the measurement accuracy. Meanwhile, the flow channels are small in micrometer dimensions. The interfaces between fluid and channel wall become pronounced, which differ from those described for laminar flow by Moody Diagram in the classic fluid dynamics. Besides, cavitation would play a critical role, and dissolution will also contribute to metrology. These are among the new challenges for the on-going metrology standards for microfluidics.
The thermal mass flow measurement using calorimetric capillary sensors has been used to measure a very low flow to nanoliter per minute for quite a long time [40]. The sensors are composed of thin metal wires winded outside the wall of a tiny tube of a micrometer in diameter. The tube is usually made of thermally conductive materials such as stainless steel or fused silica. These sensors normally require a higher power to ensure the heat transfer resulting in a small dynamic measurement range and a low accuracy towards the low measurement end. The required manufacture process makes these sensors very costly without being able to be volume produced. Integration of such a sensor into a microfluidic system would be unlikely. In the following discussions, only micromachined sensors will be addressed. The micromachined sensors are mostly made on silicon or glass substrate. A microheater and plural numbers of sensing elements are deposited on a membrane structure, and the air or gas-filled cavity below the membrane provides the desired thermal isolation. The tiny sensing elements enable a fast response time. The membrane is frequently made with silicon nitride or silicon nitride and oxide combination. The sensing elements can be metals with a large temperature coefficient such as platinum, nickel, tungsten, or in the case for the process compatibility, doped polycrystalline silicon is used instead. The micromachined thermal flow sensors’ structure has no moving parts, and the surface can be treated with various passivation and post-process coating for better reliability. The micromachining process for the flow sensors is well established today. Most MEMS foundries have the necessary equipment for manufacturing such sensors, which allows a very favorable cost and makes it possible for high volume applications. The first micromachined thermal flow sensor made for microfluid is used in micro gas chromatography [4]. It is for gaseous flow and not a standalone product and only manufactured in a minimal quantity as the OEM product. The commercially available micromachined thermal microfluidic flow sensors for liquid were incepted in the last decade. These commercial products utilize different thermal sensing principles [41, 42, 43] that cover the three major technologies with thermal calorimetry, anemometry, and thermal time-of-flight approaches. There are some research activities on other thermal flow sensing designs, such as thermal capacitive utilizing the temperature dependence of dielectric constants, [44] and temperature dependence of the PN-junction in a diode [45]. The measurement scheme of flowrate with these alternative thermal sensing designs could also be classified into the above three thermal sensing principles. Figure 1 is the graphic illustration of these three measurement principles for the typical micromachined thermal flow sensors on a silicon substrate.
Graphic illustration of the micromachined thermal flow sensors (on silicon) with the flow sensing principles: (a) calorimetry; (b) anemometry and (c) thermal time-of-flight.
The majority of the current micromachined commercial thermal flow sensors are utilizing the calorimetric principle. Most successful applications are for gaseous fluids, of which the automotive airflow sensors for fuel control are the dominant application. The structure showed in Figure 1(a) is a typical one for a micromachined calorimetric mass flow sensor on which a microheater is placed at the center of the membrane. Two temperature sensors are made symmetrically at the up and downstream of the microheater. These two temperature sensors can be simple resistors of identical resistance values or identical thermal-piles. There are a variety of approaches to realize data acquisition. The commonly used ones are either to keep the microheater at a constant heating power or to maintain a constant temperature from the up and downstream sensor and then measure the heat transfer or temperature differences between the measurements of the up and downstream sensors as the flowing fluid will take away the heat from the microheater resulting in a heat redistribution. By calibration, such heat transfer can be correlated to the mass flowrate of the fluids. In this approach, the measurement is susceptible to low flowrate. As its nomenclature indicates, the measurement is dependent on the fluidic thermal properties of thermal capacitance and thermal conductivity. The thermal sensing using the resistor-based microheater and resistor sensing has the intrinsic temperature effects associated with the environmental conditions, which need to be compensated for better accuracy. For this purpose, another sensor placed on the substrate (the yellow element shown in Figure 1) is used to gauge the environmental temperature and correct the resistance value due to environmental temperature variations. The detailed theoretical interpretation and governing physics can be found in the literature as well as the international standard [1, 46].
The major challenge of applying the micromachined thermal sensor to meter microfluidic is the package. For the gaseous sensors, the membrane often has openings that balance the surface’s fluidic pressure against the membrane deformation. The change of the membrane position will greatly impact the measurement as the sensor position will be significantly altered with membrane flatness changes. However, for microfluidic measurement, the opening will be detrimental once the liquid-filled up the cavity underneath the membrane. Therefore, the commercially available approach [41] for the package is to have the sensor placed outside the channel with the sensor’s surface close to the outer channel wall. Therefore, the channel will need to be thin enough and have good thermal conductivity for heat transfer effectiveness. One of the selections of the channel is a fused silica tube. As the membrane that supports the sensing element is typical with a thickness of 1 micrometer, attach the think tube to the sensor is a very tedious process with a high cost. In addition, compared to the applications for gaseous fluids, the thermal wall of the fused silica also reduces the sensitivity of the sensor, leading to a significantly smaller measurement dynamic range (<50: 1), which is certainly not desired for microfluidic applications. The commercially available calorimetric microfluidic sensors offer a typic <40:1 dynamic range with the lowest detection flowrate of 7.5 nL/min and the best accuracy of ±5% of reading at the full scale. There are also concerns about the constant thermal power at the channel’s specific area during the measurement in practical applications. This will be discussed later in detail.
The first micromachined thermal flow sensor on silicon is made with the anemometric flow sensing principle [47]. Thermal anemometry is also known as energy dissipative sensing, and its measurement scheme is relatively simple, as shown in Figure 1(b). Only one sensing element is placed downstream. Alternatively, the sensing element can also be placed upstream, as the measurement of the fluidic flowrate is only from the microheater (a sensing element). The temperature sensor is used as a fluid temperature reference. Therefore, instead of measuring the fluidic flow-induced changes of the temperature profile at the centralized microheater with calorimetry, the anemometry measures the heat loss due to the forced convection. In this case, with the supporting control circuitry, adjusting the microheater power will allow the measurement to be much easier for higher flowrates. Simultaneously, the sensitivity at low flow will be lower compared to the sensing principle of calorimetry. Another character of the anemometry is that its correlation with the fluidic thermal properties has a larger nonlinear effect resulting in the difficulties to apply a constant fluidic conversion factor for correction of the flowrate data when the measured fluid has different thermal properties from those of the calibration fluid. For the same reason, the temperature compensation scheme for the anemometry is more complicated than that for the calorimetry.
One commercially available anemometric microfluidic flow sensor, per the structure described in the company’s webpage, [43] also takes the package approach similar to the earlier mentioned one of the calorimetric microfluidic sensors. The sensor is placed at the outer wall of a thermally conductive fine quartz glass tube by machining the tube surface into a smooth flat. Instead of a single micromachined sensing chip, two chips are used. A special glue was applied to attach the chip to the quartz tube’s flat surface, forming a close contact for the required heat transfer. The heater chip and temperature chip are separated at a certain distance forming the configuration of an anemometer. The heat transfer needed for the measurement provided by the sensor is achieved via thermal diffusion. These package approaches are also similar to the traditional capillary thermal mass flow sensors, where the hot wires are winded onto the surface of a special stainless tube. However, the micromachined sensor will have a much lower heating temperature than those by the capillary sensor. Because of the heat diffusion, control the heat for the low flowrate measurement would be very challenging, resulting in a small dynamic range and large measurement errors (full-scale error rate) towards the low detection limit. The current offered anemometric microfluidic flow meter has a guaranteed dynamic range of 50:1 with the lowest detectable flowrate of 100 μL/min and the best accuracy of ±5% of reading.
Both the calorimetric and anemometric flow sensors require a calibration of the real fluid for the desired precision or metrological accuracy, as the fluidic properties will have a nonlinear response in the full dynamic range. The limited dynamic range and the accuracy would not be desirable for the precision requirements for many microfluidic applications such as drug infusion. Also, these flow sensing products could only provide mass flowrate measurements. The microfluidic applications would appreciate additional fluidic information such as fluidic concentration, physical or even chemical properties of the fluids at the same time. To this end, thermal time-of-flight sensing technology offers much of the competitive advantages. The thermal time-of-flight sensing concept can be traced back to the late 1940s [48] and has been an interest in many subsequent research works [49, 50, 51]. The thermal time-of-flight sensing measures the heat transfer transient time as well as the responses at each sensing element. Several sensing elements can be placed downstream of the microheater. Consequently, this approach can measure additional parameters other than the flowrates [52]. The sensor works with a thermal pulse or modulated thermal wave signals. Compared to calorimetry or anemometry, the transient time-domain data are much more immutable to the background interferences. Despite the advantages, a commercially available thermal time-of-flight flow meter is not seen until the past decade [42]. One reason could be that the microheater must possess a mass as small as possible for the needed thermal response to enable the measurement scheme. In the traditional approach, such a tiny wire is extremely vulnerable for reliability in actual applications. On the other hand, pure time-of-flight will only measure the flow velocity. In contrast, the other parameters require advanced and complicated electronics that are not readily accessible until recent years. Nevertheless, the sensor build and package limitation will still lead to a non-pure time-of-flight, and calibration will be required to remove those effects. On the other hand, these effects can also be used to provide additional fluidic information. For the microfluidic applications, the microheater is driven with a modulated microheater, the constant heating spot in the flow channel is therefore eliminated. The sensor outputs flow velocity as well as fluidic mass flowrate and the additional data of the fluidic properties, making the thermal time-of-flight technology an ideal approach for the desired microfluidic flow measurement applications.
Figure 2 shows a typical structure of a micromachined thermal time-of-flight sensor chip [53]. The micromachined process has a wide spectrum of materials selection to allow the sensor with excellent thermal isolation while not sacrificing reliability. This is particularly important for the thermal time-of-flight sensing that requires a super-fast thermal response. The blue materials showed in Figure 2(b) can be silicon or glass substrate. The gray colored block will be for thermal isolation. For example, a 10 ~ 15 μm parylene conformal layer will provide the properties of the good material of stiffness and robustness for the application. The green-colored materials need to have good thermal conductivity while excellent surface passivation for reliability. Ideal materials include multi-layered silicon nitride or silicon carbide. Underneath the microheater and sensing elements, a cavity will enhance the thermal performance of the sensor chip. The brown-colored elements are for microheater and sensing elements. One sensing element is placed directly on the substrate to measure the environmental temperature that provides the compensation of the microheater’s temperature performance and control. In the photo shown in Figure 2(a), the central element has another sensing element at the proximity of the microheater, which is used to fine-tune the microheater temperature or power with those other physical properties such as thermal conductivity can be precisely acquired.
Example of a micromachined thermal time-of-flight sensing chip: (a) optical photo of the chip, top view; (b) cross-section schematic.
The heat transfer in the thermal time-of-flight configuration is measured by the temperature
Where
Therefore, if the sensor only has a microheater and a sensing element pair, the measurement will still be dependent on the flow medium properties. The microheater and the sensing elements all have the fluidic dependent response that needs to be removed for the complicated fluids. Simple calibration with the conventional fluid can be applied for the fluid measurement without losing the metrology accuracy. A micro-machining process’ advantages allow placing multiple sensing elements on the same chip without adding any cost that makes it possible to have the measurement independent of the fluidic properties. The thermal time-of-flight will not be a simple flow velocity measurement. The measured changes in the amplitude are directly proportional to the heat transfer between the microheater and the sensing elements that will provide the mass flowrate similar to the calorimetric or anemometric approach per the data acquisition process. The time-domain data yield additional information, which allows the acquisition of additional fluidic thermal dynamic properties such as thermal conductivity and specific heat. In the microfluidic flow measurement, the liquid is generally non-compressible. The pressure effects of compressibility can be considered secondary. Compared to the gaseous fluids, liquid has a much large heat capacitance making the sensing element resistance-related temperature effects less pronounced. And most importantly, with the multiple sensing elements on a single chip, the measurement dynamic range can be substantially extended. A practical 7500:1 dynamic range can be achieved with two or three pairs of sensing elements.
Coriolis mass flow sensing principle has been well documented, and the first commercial product was introduced to the market in 1977 by Micro Motion. It is a true mass flow sensing technology with very high precision by utilizing an exciting tube which fluid is flowing through, and the tube oscillates artificially. The changes of the tube oscillation in time and space are a direct measure of the mass flow. One advantage of the Coriolis sensing approach is that the fluid density can be simultaneously determined from the oscillation frequency of the measuring tube. But it also requires a minimum density of fluid such that the resolution of the oscillation can be registered. It also suffers a high-pressure loss and a smaller dynamic range. The high cost of the measuring tube manufacture sparked the attempt with micromachining, and the first research paper was published in 1997 [55]. With the micromachining process, the MEMS Coriolis mass flow sensor can be well applied for microfluidic flow measurements. The commercially available Coriolis meters sensors via micromachining either consists of a silicon microtube via silicon wafer fuse bonding and an integrated temperature sensor [56] or a silicon-rich silicon nitride tube coupled with a strain gauge readout [57, 58]. The micromachined Coriolis sensor using silicon nitride tube has a thin tube wall of about 1.2 μm and is much lighter than the silicon tube. Hence, the light-weighted tube would have a smaller mass than the fluid it measures that simplify the package, and leads to the possibility to measure the fluids at ambient pressure. The demonstrated Coriolis sensor could measure liquid mass flow, density, and temperature (if a temperature sensor is integrated) simultaneously. Another advantage for the MEMS Coriolis mass flow sensor is that it usually operates at a much higher resonant frequency with substantially less vibratory influences from the environments than those for the traditional Coriolis mass flow technology.
Like the MEMS thermal mass flow sensors, the micro Coriolis mass flow sensor also requires clean fluid. Even fine particles can damage or clog the sensor, considering the measuring tube’s tiny channel. Besides, the sensor will not function well in liquid with high viscosities and liquid with chemical reactions. The high-speed liquid flow may also alter the performance of the sensor unless bypass configuration is applied. The superior true mass flow accuracy of a Coriolis sensor is overshadowed by its footprint, complication in the package, and cost in the manufacturing process that diminishes high volume and/or disposable applications, which would be a necessity in some microfluidic applications for cross-contamination prevention. The fluidic property independence measurement characteristics also limit its measurements only for flowrate and density. Other fluidic property measurements will require integrating additional sensing elements, further enlarging the sensor footprint, indicating an even higher cost for the final product manufacture. Therefore, although the micromachined Coriolis sensor’s demonstration has been over two decades, the applications are still very limited.
Flow sensors are likely the ones that can be made with the most versatile technologies and are vastly selectable to the applications. More than twenty different physical measurement principles are commercially available on the market for flow metrology. However, for microfluidics, the options are limited. Other than the commercially available thermal mass flow sensors and Coriolis flow sensors, micromachining advancement offers opportunities for many studies with a wide spectrum of technologies applied for microfluidic flow sensing. But commercialization of many of those is still in question. Some selected researches micromachined flow sensing technologies are discussed below.
In addition to micromachined thermal and Coriolis sensors, micromachined ultrasonic sensors are also commercially available. Ultrasonic flow sensing is one of the well-documented technology for flow metrology with high accuracy. By measuring the time differences of the ultrasonic signals propagating in the opposite direction of a fluidic medium, the flow speed can be accurately measured. Therefore, it has the advantage of a pure velocity measurement independent of the fluidic properties. As a sound propagation, it will not require direct contact with the fluids that it measures, or it is non-invasive, which is very attractive for microfluidic related medical applications. However, it will normally require dual transducers placed in opposite directions or at a certain angle with respect to a reflector. This prevents the reduction in footprint and cost. For the microfluidic applications, its signals reduce significantly at the low flow speed, and it is also very sensitive to the fluids where cavitation or dissolution may exist. The current commercially available ultrasonic flow meters for microfluidics have about a 50:1 dynamic range and a detection limit of 300 μL/min [59]. Some research indicated that the ultrasonic transducer could be integrated into the microfluidic channel, but the capability for flow metrology is yet to be demonstrated [60].
Acoustic device applications in microfluidics are mostly for fluid handling, and surface acoustic wave (SAW) sensing and actuation is another approach that can be integrated into the microfluidic channels [61]. Some efforts were also made to measure the flowrate with the SAW devices. It has been reported that a micromachined interdigital transducer (IDT) could direct the fluidic droplets via the excited acoustic streaming that is fast and material independent [62]. In another study, [63] a SAW sensor with dual symmetrical IDTs made on a 30 mm by 30 mm square quartz crystal substrate was used to measure the flowrate in a designed channel by recording the delay times and the corresponding frequencies. A close to a linear correlation between the phase shift from the delay time and flowrate was established. The SAW sensors can be independent of the fluidic properties; however, they require a much larger footprint, and temperature compensation is also complicated compared to thermal sensing approaches.
Measurement of flowrate with differential pressure is one of the oldest flow sensing technologies. Micromachined differential pressure sensors have been well established and are widely available on the market at a very low cost. Most sensors are made on a silicon nitride membrane or diaphragm with the piezoresistive sensing elements at the edges of the membrane or with a capacitance measuring principle for the low differential pressures [64, 65]. The advantages of a differential pressure sensor for flow measurement are lower power consumption and relatively easy installation with fewer effects on the flow conditioning. They are also independent of the fluidic properties. The microfluidic flow regime is purely laminar, and the pressure loss is linear with the flow velocity. However, limited by its sensitivity, the measurement dynamic range of a differential pressure sensor is normally small. In particular, for microfluidic applications, the pressure drop at a tiny distance may not even generate enough sensitivity for the measurement. The dependence of the microfluid’s pressure loss on the dynamic viscosity also requires a temperature sensor at the proximity for the needed compensation. Other phenomena such as cavitation or multi-phase flow will have a big impact on the measurement of the pressure and hence the accuracy of the deduced flowrate.
Flow measurement with drag force is an alternative pressure-related flow sensing approach. Due to the size restriction, such a sensor does not favor being placed inside the microfluidic channel. However, in an ideally integrated microfluidic system, there will be valves and other actuators. The drag force-sensing approach could be combined with the actuation parts in the system. A typical drag force sensor is to utilize a cantilever or a diaphragm [66]. The mechanical deflection can be read out with an optical microscope or photodiode. Another approach to measuring the deflection is to utilize the piezoresistive or piezoelectric elements embedded at the positions where maximal deformation could occur at the designed cantilever or diaphragm. To increase the measurement sensitivity, the Fabry Perot spectrum’s fringe shift was used to measure the cantilever movement correlated flowrate, which, however, complicated the data acquisition and limited the package options [67]. The materials used to make the micro-cantilevers are silicon nitride, SU8, and polydimethylsiloxane (PDMS). An integrated micro-cantilever inside the microfluidic channel via the microfluidic favorable PDMS process achieved a capability of detecting 200 μL/min flowrate but only have a small 5:1 dynamic range [68]. Most of the micro-cantilevers measure microliter per minute flowrate, even though nanoliter per minutes sensitivity was reported, but the required optical readout often makes the fine readings and subsequent digitization a challenge [69]. While piezoresistive or piezoelectric configuration is more preferred as no optical assistance in readout will be needed. On the other hand, as the piezoelectric cannot detect a static flow, piezoresistive is considered a better choice. The cantilever sensors are more sensitive than diaphragm sensors, but there are still concerns for their reliability and repeatability per the moving cantilever. The sensitivity of these sensors also requires meaningful pressure or critical mass to activate the deformation of the cantilever or diaphragm. Such pressure is not necessarily existing in the microfluid subject to measurement.
The non-invasive approach is always preferred in microfluidic applications, for which life science is the major focus. A microwave microfluidic flow sensor is reported [70] to achieve a large dynamic range of 1-300 μL/min with a high resolution of 1 μL/min. The detection of the flowrate with the microwave is via the measurement of a membrane that was a part of a microfluidic channel and on which the fluid is flowing over, causing the deflection of the membrane. Therefore, it could also be a type of differential pressure sensing. The measurement element is the microwave resonator that detects the effective capacitance because of the changes in the deflected thin membrane’s effective permittivity due to the channel pressure changes by the flowing fluid at different flowrates. This configuration is much easier to be packaged with the microfluidic channel, and it is a true noncontact detection that can be miniaturized compared to the optical assisted readout. The microwave flow sensor is consisting of two critical components. One is the microfluidic channel with the membrane that was micromachined with PDMS soft lithography and replica molding. PDMS is a preferred material for microfluidics for its compatibility, and more importantly, it is transparent to microwave with a low loss. The membrane is about 1.5 to 3 mm in diameter and 100 μm in thickness, strong enough to hold the fluidic pressure inside the microfluidic channel. Simultaneously, it is thin enough for the sensitivity of the resonator function needed for the measurements. The second component of the flow sensor is the microwave resonator, designed into an open-ended half-wavelength ring resonator with a microstrip structure on a high-performance microwave substrate made of a 35 μm copper layer on top and bottom surfaces. The resonator operated at a 4 GHz resonant frequency. The fabrication is via the cost-effective conventional printed circuitry board processing. However, the integration with the microchannel made strong application dependence and difficulties in controlling the cost. Also, the metrological performance of this sensor was not well documented.
Optical flow sensing is attractive to the microfluidic application for its non-invasive and high accuracy features. Laboratory flow measurements such as particle image velocimetry, infrared thermal velocimetry, and laser interferometry are reported for microfluidic metrology studies [71, 72, 73, 74]. These optical technologies are all having complicated bulk settings and require the microfluidic channels to be optically transparent. While the miniaturization efforts continue to focus on microfluidics, optofluidics is now a dedicated field for the studies of the combined optics and microfluidics with targeted miniaturized optical integration sensing functions into a single microfluidic chip. In a microscale optical flow sensor report, [75] an optical fiber structure was fabricated in the form of a drag force cantilever to measure the microfluidic flow. A stripped single-mode optical fiber was positioned across a microfluidic channel and aligned with a multi-mode fiber receiver. The microfluidic flow in the perpendicular directions will displace the fiber cantilever tip, causing the light intensity change at the aligned receiver. The reported sensor had achieved a measurement dynamic range over 60:1 and a minimal detection of 7 μL/min. However, the making of the sensor would be quite complicated with the fiber alignment, and direct contact of the flowing fluid with the fiber cantilever is also required. In another report using the optical approach for flow sensing, miniaturized fluorescence sensing is attempted for micro molecular tagging velocimetry in microfluidics [76], but these methods are not cost-effective and yet to reach the small footprint.
In an alternative optical sensing approach, [77] a collimated light beam was employed to excite the surface plasmon resonance at a gold film on top of a polymethyl methacrylate (PMMA) microfluidic channel. The fluidic flow will cause the temperature redistribution inside the microfluidic channel, which alters the refractive index above the metal film. The refractive index is inversely proportional to the temperature. By acquiring and analyzing the image of the excited surface plasmon, the flowrate could be measured. However, since surface plasmon resonance is very sensitive to temperature, and the response is nonlinear, a full functional measurement scheme and affirmation of metrology parameters will need additional efforts.
The impedance flow sensing principle is also a topic in the studies for microfluidics. The electrical impedance flow measurement has the advantage of simplicity. The configuration has fewer requirements for environmental parameter compensation and can be applied to a wide range of fluids. A cascade finger structure of the electrical impedance sensor could help the measurement accuracy of pulsed flow. However, the electrical impedance measurement is strongly dependent on the fluid properties and is only applicable to conductive fluids. In a report [78] of an electrical impedance microfluidic flow sensor, the simple two surface electrodes are embedded inside a microfluidic channel. An alternating current signal was applied across the microfluidic channel. The fluid is equivalent to a diffuse layer capacitance impedance or the parallel capacitance impedance, and the electrode forms the serial capacitance impedance with the fluid. By optimizing the applied voltage frequency, the measured impedance can be well correlated to the flowrate. The reported data achieved a 50 nL/min detection limit and about 10:1 dynamic range.
In another approach, the measurement of the magnetic impedance of a hair microfluidic flow sensor offers the ultra-low-power option [79]. The sensor was made by depositing a giant magnetoimpedance (GMI) layer on top of a glass substrate. A PMMA master pillar mold was then applied to the pre-formed magnetic nanocomposite of permanent magnetic nanowire and PDMS mixture on the GMI layer. The formed flow sensor was placed inside the microfluidic channel. When the fluid flows through the pillars, the flow will force the pillars to bend, resulting in the change of the magnetic field sensed by the GMI layer and output the signals that can be correlated to the flowrate. The results showed a measurement of the water flow speed up to 7.8 mm/sec and a resolution of 15 μm/sec with a typical power of 31.6 μW. The study also indicated that by optimizing the parameters, the power could be further lowered to about 80 nW.
The flow metering at the microfluidic scale is quite different from those in a large pipeline. Many factors that may be trivial in the conventional fluidic dynamics become critical for microfluidic metrology. In this section, some critical factors are discussed.
In the classic fluidic dynamics, the Moody chart indicates that at laminar flow, the friction factor is inversely proportional to Reynolds number where only viscosity of the fluid plays the role and diffusion is normally not in consideration. In the dimension of a microfluidic channel, the surface area relative to the volume is dramatically larger than those in a large pipe. For the flow speed of interests, factors such as surface tension and diffusion are all having their critical contributions to the microfluidic flow metrology. The capillary number then would be much more important than the Reynolds number [80]. Besides, the majority of microfluidic processes are water-based. Water has a molecular size of about 0.27 nanometer, and it is dipolar in nature. Water interaction with the solid surface is inevitable, and such interaction will be pronounced as interaction will involve a significant portion of the total volume of the microfluidics. Most of the solid surfaces at the microscale would be imperfections that are full of defects with dimensions larger than the water molecule. Water viscosity is also very sensitive to temperature in the applicable ranges. These effects will be even more pronounced in the biological fluid case where the electrolyte is often present as the chemical state of the surface would be altered, either by ionization of covalently bound surface groups or by ion adsorption [81]. Hence, to ensure the accuracy in the flow measurement for microfluidics, the interactions between fluid and solid channel surface must be considered, especially for the long term repeatability, reproducibility, or reliability.
The detailed studies on the fluidic handling and flowrates impacted by the fluid and microchannel interactions are not well documented. However, in a few reports on the long-term stability of the commercially available calorimetric flow sensors for microfluidics, it was reported that the measurement accuracy tended to have a time-dependence. The long-term
Cavitation is often known as a detrimental phenomenon in high-speed flows that leads to mechanical damages at the flow path. However, it can also be utilized for industrial processing in classic fluidic dynamics. In microfluidics, cavitation inception is via the diffusion of dissolved gas into the available nuclei. It can occur even at a pure Stokes flow, but the cavitating flow will not normally lead to mechanical defectiveness due to the relatively low energy release, but it can dramatically generate the local flow speed spike. Cavitation has become a growing research topic in microfluidics. It is not only because the cavitation flow is inevitable in many applicable microfluidic flow conditions, but it can also be employed as a tool for microfluidic manipulation such as pumping and mixing via the control of cavitation size alternation. The cavitation can harvest and release energy upon collapse in the microfluidic process. The removal of cavitation can be done with properly designed materials for the microfluidic channels [83, 84, 85, 86].
The cavitation presence will greatly impact the measurement reproducibility or accuracy for any flow sensors regardless of the measurement principles. The calibration setup for a microfluidic meter normally requires a degassing device in serial to the calibration line, and degassing is always performed before the start of calibration [39]. The cavitating flow is in fact a two-phase flow. Therefore when a flow sensor calibrated at a cavitation-free condition is applied to measure a cavitating flow, the measurement deviations will be inevitable. The current tools of the cavitation studies are visualization approaches such as colorimetry or via high-speed camera for which a transparent flow channel will be required to collect the data. However, in practical applications, the channels are often opaque. Therefore, it is of interest to have additional measurement approaches that can alert
Left - Example of the response of a micromachined thermal time-of-flight sensor to air bubbles passing in a DI-water microfluidic channel; and right – shows the same sensor response at 20mL/min flow to the channel conditions: A – as calibrated DI water; B – tested after sensor powered on in a null flow DI water channel for 48 hours; C – After B test and degassing for 15 minutes; D – after C and full scale full (30mL/min) flow for 30 minutes; E – after D, the channel dried with N2 and re-test.
While manipulating the microfluidics inside the designated microchannel, mixing two or more fluids is a common practice. The mixture of the fluids, depending on the physical properties, can be miscible or immiscible. The miscible fluids will result in a fluid with a new
Microfluidic dissolution phenomena impose big challenges in metering the flow for a desired metrological accuracy, either with immiscible or miscible fluids. The dual-phase or multi-phase flow for the immiscible fluids would involve various liquid–liquid, gas–liquid, liquid–gas–liquid, and supercritical fluid flows beyond the capabilities of the conventional flow sensing approaches. Even with the miscible fluids, the microbubbles would likely present in all cases. The changes in the mixture’s density and physical properties will lead to completely different heat and mass transfer, which will significantly deviate the metering values that are always reference to those at the calibration conditions. Optical or image processing would help understand the physical or even chemical process, but it would not help improve the flow measurement accuracy. Therefore, new flow sensing technologies are required for metering these types of microfluidics.
Figure 4 shows the polar plots of a thermal time-of-flight sensor measurement of the deionized water and methanol, respectively, at 3 individual flowrates of 1, 3, and 5 mL/min. The flowrates were set via a precision syringe pump. The sensor’s microheater was modulated with a sine wave, and the phase-shifts at the sensing elements were recorded for the flowrate calibration. The fluidic dependent measurement can be seen for the single sensing element configuration as indicated by the differences in measured polar angles between water and methanol. With the dual-sensing elements, the measurements of the two polar plots are overlapped. Therefore, the water calibrated sensor can be directly applied to measure another fluid with different fluidic properties. For the fluidic mixing process with miscible fluids, this dual thermal time-of-flight sensing approach can provide a more desirable measurement than the other thermal sensing approaches. Moreover, as each sensing element’s data can be individually acquired, the sensor can also output any changes in its measured fluid. The concentration of the dual miscible fluids can be deduced from the thermal properties measured by comparing the data in the registers at the calibration.
Thermal time-of-flight measurement of deionized water and methanol flow rates.
Drug infusion has been in medical practice for over 300 years. Precision control of drug delivery is getting increasing attention in recent years. In a European
Drug infusion example: left – commercial infusion pump (Alaris 8100 ) output at 0.1 mL/hr; and right comparison between the outputs at 20mL/hr by Alaris (red) and a precision syringe pump (blue, KD Scientific Legato 210) measured by a thermal time-of-flight sensor.
Metering the microfluidic flow is critical for many microfluidic applications requiring precise control of the desired microfluidic process or handling. Precision in the flow metering will also improve the performance of the current instrumentation, including the widely applicable drug infusion apparatus, which are nontrivial for the advancement in the medical application and general applications in microfluidics. At the dimensions of interest, current flow sensing technologies are not fully capable of serving the demands. Factors such as fluid and channel interface/interactions, cavitation, and dissolution play critical roles in impacting microfluidic metrology. Additional sensing elements must be integrated with the current flow sensing approaches to compensate, assist, and enhance the flow metrology. In a most recent review, [95] many available technologies can be used to acquire the microfluidic thermodynamic properties such as viscosity, density, diffusion coefficient, solubility, and phase equilibrium directly from the microfluidic channels on a chip. However, many of these technologies are bulky, costly, and not easily integrated with the microfluidic channels. They also often require a transparent microfluidic channel, which would not be readily available in real applications. Although the advancement of micromachining in both the process tooling and application technologies greatly enrich the options for microfluidic flow sensing, a capable device is yet to be demonstrated. The recently developed thermal time-of-flight sensing technologies for microfluidics offer a multiparameter capability and unprecedented dynamic measurement range. The surface acoustic wave flow sensing as a simple yet non-invasive approach is also very promising. Integrating with additional sensing elements and decomposing the acquired information might provide additional viable tools serving to understand, advance, and better control the microfluidic process and handling.
The author appreciates his colleagues at Siargao Ltd., who have been dedicated to the challenges and innovations in the commercialization of microfluidic sensing devices since 2009.
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