Measurement characteristics of three surface profiling instruments (after [10]).
\r\n\tTo viable rural development has a vital role for rural communities. In the design of policies to be successful that affect them rural people have to decide and implement. According to this, it is a critical point to involve the poor and disadvantaged, along with related stakeholders, agricultural and rural development. Hence, for the sustainable development by international initiatives and all other institutions were searched and to be present the agricultural and related research results. To help support the effort, various governmental and non-governmental agencies established fundings for sustainable rural development research and fostered the development of human well-being goals in rural areas via national and international initiatives. In this context, most efforts resulted in successful cases. This book will intend to provide the reader with a comprehensive overview of the theory, approaches, strategies, and cases, and key elements and challenges of sustainable development, and Bioeconomy, Green and Circular economy for sustainability, and UN SDGs-Agenda 2030 and EU Green Deal.
\r\n\r\n\tI believe that this work will be fundamental in the field of SDG, and it will be a guiding, idea-generating key for researchers, practitioners, rural community, and policy decision-makers, and I hope that together we will establish sustainable rural life and development around the world.
\r\n\t
In this chapter, we will discuss in depth the pathology of diffuse axonal injury (DAI) touching upon clinical presentation/keynote characteristics, medical diagnosis, radiological imaging, treatment, prognosis, historical outcomes, and quality of life aftercare [1]. While diffuse axonal injury is included within the broader category of intracranial injury, it is essential to note the physiological severity it plays on the life of the patient. Trauma to any region of the head should prompt immediate concern and medical attention. While DAI is one of the worst forms of lesions to the brain, we would like to approach this topic with a sense of urgency as it is frequently seen in medical centers worldwide [2].
\nAlongside the many forms of intracranial injuries, the differential key characteristics of DAI are the lesions which occur within the white matter. White matter is composed of several bundles of myelinated axons which connects gray matter together. Gray matter houses the neuronal cell bodies within the brain and is highly regulated in regard to transmission of neuronal impulses [3–5]. Lesions of white matter can vary in size greatly, as they typically present as 1–18 mm wide in trauma and affect the frontal and temporal lobes mostly. However, it is not limited to that region entirely as regions of the brainstem and corpus callosum have also been affected quite frequently according to literature [6, 7]. Axonal injury to the brain is at times an irreversible trauma, which results in loss of consciousness and even death. Forces of greater magnitude striking the head almost immediately disconnect axons within the site of impact. Secondary axon disconnections also develop resulting in severe brain injury [8, 9]. Human physiological symptoms as a result of trauma also set in, such as swelling and degeneration of nerves. The bodily response places the brain under the extreme amount of pressure and is often exposed to irreversible damage [10, 11]. While it was once assumed that sheer force is the responsible factor for the disconnection of axons, it is indeed false to assume that. It is the biochemical response to the impact stimuli which causes that largest impact on axons. However, impact does in fact cause some lesions but not comparable to the damage done by biochemical cascades which follow the impact [12, 13]. Biochemical pathways within our bodies are greatly responsible for the axonal disconnect which occurs secondary to the traumatic impact. The biochemical response is due to the physical stress and stretching caused by the force of impact. The impact disrupts the proteolytic metabolism and degradation of cytoskeleton; sodium channels open within the axolemma causing a strong wave of neuronal depolarization. To balance the influx of cationic sodium, calcium channels also open allowing the stronger cation metal to leave the neuron and into the cell to depolarize the neuron. The excess of calcium ions within the extracellular cavity activates a cascade of enzymes, leading to the activation of phospholipases and other enzymes that act on the cytoskeleton and cause severe damage. This biochemical pathway ends with axonal separation and cell death [14]. Axonal stretching and disconnect occur 1–6 hours after initial trauma. While irreversible brain damage has already occurred, severe damage is yet to come. While the axonal network is compromised, the axonal transport still continues and is halted at any point where the neuronal network is cleaved or compromised. At the site of axon disconnect, transport products and cell debris begin to build up, causing local swelling and severe compression [15–17].
\nIn Figure 1, take note of the leading causes of diffuse axonal injury, their severity, and chance of recovery.
\nMost common causes of diffuse axonal injury. Listed from the highest to the lowest occurrence.
Many patients that have sustained a traumatic brain injury (TBI) to a certain degree suffer from diffuse axonal injury (DAI). Many patients presenting to emergency and trauma centers with DAI are unconscious and have strikingly poor neurological examination results. The Glasgow Coma Scale (GCS) (Figures 2 and 3) is a neurological scale which establishes an objective way to rate the state of consciousness of patients. The sum of the three categories will allow for the determination of the GCS score and patient consciousness [18]. Patients presenting with DAI are often reflecting vivid signs of functional impairment of the brainstem and impairment of the reticular activating system as many of the physiological vital signs are maintained through external sources (e.g., life support) [19]. While alertness and responsiveness may develop slowly over a longer course of time with intensive rehabilitation, the rate of mortality with patients presenting with DAI is extremely high, as high as 50% in severe cases. In patients whom consciousness can be restored, cognitive and memory impairments persist through the remainder of the patient’s life [20, 21].
\nThe Glasgow Coma Scale.
The Glasgow Coma Scale range.
The GCS ranges from 3 to 15, three being coma/death and 15 being a fully functioning and awake person. These scores can be the summation of the visual, motor, and verbal scores.
\nDue to the fact that there are no distinctive clinical symptoms that patients present with that allow medical professionals to immediately diagnose DAI, physicians must rely on neurological examinations and radiographic imaging to diagnose patients and predict their prognosis. Magnetic resonance imaging (MRI) is the preferred examination for DAI, accompanied with computed topography (CT) scans [22]. A key indicator for the onset of DAI is the minimal yet visible bleeding within the region of the corpus callosum and/or the cerebral cortex. It is essential to note that while trauma may cause axonal disconnect, the vast majority of axonal damage occurs through secondary biochemical degradation. Thus, patients may first appear to be in a functional state, but over 1–6 hours, a patient’s condition may drastically change [23, 24].
\nNewer radiographic studies such as diffusion tensor imaging (DTI) is an MRI technique, which enables radiologists to measure the diffusion of water in the tissue to then create neural tract images. This method provides pertinent structural information and can even do so for cardiac muscles and prostate muscles [25]. In cases where MRI may demonstrate a negative result to DAI, DTI has been able to show a degree of injury to the white matter fiber tract [26].
\nSensory-evoked potential examination studies the electrical activity within the brain and its responsiveness to stimulations such as light, sound, and touch. Neuronal impulses travel via chemical and electrical pathways; these studies detect electrical potentials within the cerebral neuronal network. When patients present to medical centers already in a state of a coma, medical teams must perform a series of neurological examinations which may be challenging when patients are unconscious. A neurological examination conducted typically by neurosurgeons is to test all the 12 cranial nerves and observe appropriate reflexes; a positive result indicates the level of intactness of the central nervous system [27]. Visual-evoked response (VER) test can be used to test and diagnose nerves that affect sight; these are called optic nerves. Electrodes placed along the patient’s scalp can detect and record electrical signals as the patient’s eyes are exposed to light stimuli [28]. Brainstem auditory-evoked response (BAER) test examines one’s hearing ability and the neuronal network involved in the detection of sound. Results that signify a compromised neuronal network can be indicative of brainstem damage or the presence of a tumor within the brainstem; for the sake of this chapter, we will assume that head trauma was the result of brainstem damage. Once again, through electrodes placed on the patients scalp and earlobes, auditory stimuli are presented to the patient, and the patient’s reactions are recorded. Auditory stimuli must vary in frequency and tone to establish a complete understanding of the patient’s responses [29]. Lastly, somatosensory-evoked response (SSER) examinations can be utilized to detect issues within the spinal cord often seen clinically with patients presenting with numbness of the arms and legs. In patients presenting with TBI, verbal communication is limited or unsustainable; thus SSER can be utilized to detect any neurological issues present within the spine [30]. Mild electrical stimuli will be presented to the patients scalp via electrodes; nerves will then transfer the electrical signal to the brain through which reading can be visualized on a medical recorder device. The duration of time which it takes for electrical signals to travel can indicate the presence of spinal trauma or compromise [31]. These examinations are utilized quite commonly throughout medical practice especially when neurological compromise is suspected; through the detection of electrical impulses through the scalp, medical personnel can gain an understanding of the patient’s neurological state, especially in suspected DAI patients where an unconscious state is commonly presented with.
\nTraumatic brain trauma is indicative of patients with suspected DAI; electroencephalograms provide medical teams a sufficient amount of information regarding a patient’s state of consciousness and cognitive processing. DAI patients have experienced a traumatic injury, which is accompanied with impaired consciousness and cognitive function as well as impaired motor functions with severe cases posing with damage to vital neuronal structures such as the brainstem [32, 33]. Essentially, the severity of the traumatic impact on the brain may alter or completely change the prognosis and outcome of rehabilitation efforts [34]. Within the chronic stage of diffuse axonal injury, it has been observed that the mean frequency of the brain alpha wave activity was dramatically low and remained low over the mean of all the wave peaks. Brain waves are monitored via electroencephalogram, and low alpha waves do indicate an abnormal brain function. In addition, brain spindle activation in normal patients appears to have similar activity and strengths; in patients presenting with DAI, activation spindle activity varies across the brain and greatly varies among slow to fast spindle fibers. Despite the low alpha waves observed in patients presenting with a coma, delta and theta waves are also diminished; thus, sleep cycles are dysregulated and abnormal adding to the uphill climb during the rehabilitation process [35–37]. While electroencephalograms carry a stigma that they present no meaningful results which a diagnosis can be based off of, we would like to emphasize the impactful contribution electroencephalograms have on medical diagnosis as well as their daily use in medical centers worldwide.
\nAs we have discussed previously, diffuse axonal injury (DAI) is characterized through lesions within the white matter of one’s brain; severe case lesions are present within the corpus callosum and brainstem. Thus far, we have discussed many of the electro-neuromonitoring techniques utilized within medical centers, but to obtain a clear diagnosis, radiographic imaging techniques are coupled with electro-neuromonitoring practices and physician neurological exams to yield a confirmed DAI diagnosis. Within this section we discuss in depth the radiological examinations conducted to confirm DAI diagnosis. Computed topography (CT) scans is typically utilized first, while CT scans are not entirely as sensitive to visualize subtle DAI; a slight abnormality observed in a CT scan can spark the interest for further investigation by MRI. A non-contrast CT scan of the brain with head injury is a routine and can allow visualization of lesions which are overtly hemorrhagic. A hemorrhagic lesion within the brain will appear hyperdense and present as a few millimeters in diameter [38].
\nWhile lesions may be apparent on CT imaging following trauma, the highest visibility will be observed a few days after the trauma, followed by a significant amount of cerebral swelling, compression, and intracranial pressure [39, 40]. While computed topography is not recommended for the sole diagnosis of TBI, coupling with additional diagnostic data allows CT scans to add to the holistic diagnosis. CT scans have been shown to identify TBI in only 19% of nonhemorrhagic lesions; however, when utilizing T2-weighted imaging (T2WI), identification rate rises to 92% accurate diagnosis [41]. T2-weighted imaging (T2WI) is the basic pulse sequence within an MRI; weighting highlights the variability between T2 relaxation times. When lesions are of hemorrhagic entity, CT scans are sensitive enough to visualize lesions quite well; only for nonhemorrhagic lesions do CT scans have difficulty visualizing with appropriate detail. A general rule of thumb is that if small lesions are visible in CT scans, then the overall damage is greater than expected and often classified as severe trauma.
\nAs we mentioned above, a significant amount of damage results after the initial traumatic impact; Figure 4 illustrates the CT scan of a patient’s head for whom was diagnosed with DAI.
\nComputed topography scan of patient diagnosed with DAI [
While computed topography (CT) scans provide valuable information to the medical care team, the use of magnetic resonance imaging (MRI) is by far the modality of choice when a DAI is suspected [43]. If a CT scan shows a normal pathology, an MRI will be performed to validate those results. There are specific series of MRI’s that can be completed to assess for the presence of a DAI. In this section, we will discuss two forms of MRI. The first form is gradient-recalled echo (GRE) sequence imaging, and the second is susceptibility-weighted imaging (SWI) [44]. GRE imaging methods utilize gradient fields to produce transverse magnetism and flip angles that are less than 90°. SWI is an MRI sequence, which is particularly sensitive to substances which disturb the magnetic field; this method of MRI is extremely useful in detecting blood [45–47]. The use of SWI and GRE is paramount in analyzing the severity of lesions that occur in TBI and suspected DAI. As the junction point of white-gray brain matter is most susceptible to lesions, the use of MRI, specifically GRE and SWI, is crucial in obtaining a diagnosis and severity of DAI [48]. As lesions can be both hemorrhagic and nonhemorrhagic, the use of MRI with increasing fluid-attenuated inversion recovery (FLAIR) signal can be utilized to study lesions that are completely nonhemorrhagic [49]. A FLAIR is fluid attenuation inversion recovery, which utilizes a long inversion time (TI) of the pulse sequence such that at equilibrium there is no net-transverse magnetism of the fluid and thus is visualized. The use of FLAIR is quite common in evaluation of the central nervous system (CNS), especially for head injuries [50, 51]. While MRI technologies are among the most accurate in the field of medicine and modern technology has opened the door to even more precise medical diagnosis, just because the MRI does not show a problematic pathology for the diagnosis of DAI, it does not mean the patient is clear of that diagnosis.
\nIn Figure 5 through Figures 6–8, we can see the MRI scans of patients who were diagnosed with DAI using the GRE and SWI technologies we discussed earlier, as well as the T2 W1 and FLAIR methodologies.
\n(A) MRI-GRE image of a 30-year-old male patient presenting with head trauma. (B) Image depicting hemorrhagic DAI [
A 21-year-old patient presenting to ER following traumatic bicycle accident. Glasgow coma scale score of 6 (see
Additional imaging of the 21-year-old bicycle accident patient described above. Image captured using the FLAIR methodology also discussed above. Same patient as above (21-year-old bicycle accident patient) presenting with traumatic brain injury and nonhemorrhagic lesions of the splenium of the corpus callosum. This image is obtained using the fluid-attenuated inversion recovery MRI sequence, often called FLAIR sequence. This form of imaging is useful in suppressing the cerebrospinal fluid (CSF) effects on radiological imaging allowing the higher-intensity appearance of lesions. In this image, the FLAIR imaging also confirms the initial diagnosis [
Hemorrhagic DAI [
While there are many events that may bring on DAI, the treatment is very much similar to that of any head trauma. DAI-suspected patients present to medical centers worldwide with symptoms of being unconsciousness and/or in a severe coma to which the patient has sustain mild to severe brain damage often of the irreversible form. In the event that a patient regains consciousness and makes a near-full recovery through the management of brain swelling, hemorrhage, and neurological network status, there are a multitude of therapeutic modalities that can be pursued to maximize the chance of a near-full recovery. This plan entails a variety of medical professional care for the patient each in a specific regard [55]. Upon discharge from trauma and emergency centers, patients enter a long and intensive program for multiple forms of therapeutic care consisting of the following modalities: speech therapy, physical therapy, occupational therapy, recreational therapy, adaptive equipment training, and counseling [56]. Deficits resulting from TBI include impairments in movement, balance, and coordination, accompanied by sensory deficits, behavioral changes, cognitive defects, and communicative defects. In our efforts to restore quality of life back to the patient’s life, we will discuss the several modalities of therapy and their application to patients recovering from DAI.
\nSpeech therapy, conducted by a licensed speech and language therapist, first completes a formal evaluation of patients cognitive and communication skills as well as their swallowing skills. An oral examination is also conducted to ensure the strength and coordination of the muscles involved in producing speech. Following the assessment, therapists will engage in a series of short conversations to gage the patient’s ability to form understandable and coherent speech; patients are often presented with a series of questions relating to their life and daily tasks prior to the traumatic accident. In the event that a patient presents difficulty utilizing muscles involved in speech or forming speech in itself, therapists will then evaluate the patient’s ability to swallow or gag in the presence of a gag stimulus. Concluding the series of examination, the therapist conduct is a developed plan that highlights the focus areas for a patient, often separated into primary, secondary, and tertiary goals. Primary goals are to get the patients general responses to sensory stimuli to appropriate levels, followed by education of the patient’s family and friends on proper interactions with a person going through speech therapy. Secondary goals are to build cognitive skills such as attention and reduce any confusion a patient may have. Gaining a sense of balance while sitting and standing is also a secondary goal of therapists, allowing the patient to reestablish the necessary muscle memory and neuronal demands balance has on a human body. Later on, through the process of recovery, tertiary goals include the patient reestablishing cognitive maps and problem-solving skills. Often hard to accomplish even for the first time, therapists work on these skills as well as social skills for life outside of the medical center. While the title of speech therapy seems limited to the physical act of producing speech, it is actually a major component of not only speech-forming techniques but also techniques that must be remastered in areas such as cognition and basic physical skills such as balance [57–60]. The process of relearning task one learned earlier in life, involves the reconstruction of neuronal networks, is an example of the many neuronal networks and pathways within a human mind [61].
\nIn addition to speech therapy, patients also go through extensive physical therapy to restore the patient’s life as close to their pre-trauma life as possible. Physical therapists work closely with both the patient and their family to develop goals and an individualized treatment plan pertaining to the symptoms displayed by the patient. Depending on the severity of damage the brain has sustained and the patient’s level of consciousness, a series of daily task-specific trainings will be conducted. A patient who is said to be in a “vegetative state” has retained basic brain function but is unaware of their surroundings and requires assistance with body positioning. Additionally, patients who are said to be in “minimally conscious state” show beginning signs of inconsistent awareness; however, they require assistance with almost all physical movement. A vast majority of patients presenting to physical therapists are in a form of a vegetative state following a mild to severe head trauma, specifically when a DAI is diagnosed [62]. The primary goals for physical therapy are to aid the patient in regaining a sense of alertness, the understanding of physical movement, and the ability to follow commands. Secondary goals include movement, muscle strength, and flexibility. Additionally, movement around common daily objects such as beds is also a secondary concern for physical therapists. The activities conducted within physical therapy sessions include a tremendous amount of both mental and physical learning, balance and coordination, as well as strength and energy [63–65].
\nWhile physical therapy focuses on movement, strength, and balance as a whole, occupational therapy takes a more targeted approach in dealing with day-to-day activities such as walking down stairs, brushing one’s teeth, and opening a door, to name a few. Occupational therapists, just like any other therapist, begin therapy by assessing the severity of the patient’s physical disability. Often, the Canadian Occupational Performance Measure (COPM) is used to assess the patient’s performance and life satisfaction [66]. Additionally, patient questionnaires are utilized to gain a psychological baseline as the school of thought behind occupational therapy strongly believes in the patient’s psychological motivation. The Community Integration Questionnaire (CIQ) and the Satisfaction with Life Scale (SWLS) both assess a patient’s social interaction, productivity, and cognitive judgments. With these metrics, occupational therapists are able to design personal goals for the patient to first improve self-awareness, then improve physical activity which related to daily life, and lastly to restore as much as memory recall as possible [67, 68]. Occupational therapy is not as structured as speech or physical therapy; this form of therapy truly evaluates a patient’s quality of life and psychological state prior to beginning any form of therapy which involves movement. Figure 9 illustrates the many factors of occupational therapy in a primary care setting, highly correlative to what is seen in post-trauma care [69].
\nFactors involved in occupation therapy [
While patients receive a tremendous amount of in-hospital care, they also receive a unique and more social form of treatment called recreational therapy. This form of therapy involves the therapist designing activities to improve and enhance the patient’s self-esteem and social skills while also practicing balance, coordination, strength, and additional motor skills. These therapists aim to design social outings for the patient and their friends/families to allow the patient to not only feel loved and supported but to also reintroduce key life skills such as team building and social interaction. Within this form of therapy, highly trained canines may be utilized as well as more hobby-like activities such as gardening, recreational sports, and even holiday functions, such as decorating or baking [70, 71]. While this form of therapy is less aggressive and directed, data has continuously shown the remarkable outcomes that recreational therapy has not only on the patient’s physical abilities but also on the overall happiness of the patient and their quality of life, a truly life-changing treatment in the posttraumatic realm [72].
\nFor many patients that have suffered from a severe form of DAI, adaptive assistive technologies will be essential to restoring the quality of life back for the patient. Adaptive assistive technologies are medical devices that are used to aid the patient in completing daily living activities such as bathing, walking, and eating [73]. These forms of medical devices are crucial for the treatment of DAI in that they provide patients who otherwise would be confined to a bed the ability to be mobile again. Common forms of these devices include wheelchairs, crutches, prosthetics, and orthotics. Despite the mobility, these devices can also assist with sensory such as hearing and touch, as well as safety with devices that alert the patient when an alarm may sound or a door bell may ring. For many of us, we take these devices for granted and do not understand their true lifesaving powers, especially for DAI patients who have experienced a great deal of trauma and require these devices in order to live a quality of life [74, 75]. Engineers today are working on the development of novel assistive technologies, such as the intelligent power wheelchair seen in Figure 10, which will allow many DAI patients who may never have the ability to walk again to be able to venture the world and be more independent. Many posttraumatic DAI patients buffer from immobility and are confined to the limits of a wheelchair; with technological advances such as these, we expect to see a tremendous gain in patient’s quality of life [76].
\nAssistive technology: Intelligent power wheelchair prototype for clinical applications.
We have currently discussed the many forms of treatment available to patients who have sustained a TBI, specifically DAI; however, despite all form of treatment to restore mental and physical quality of life, counseling is also just as an important characteristic. Any injury to the brain is catastrophic and especially for the patient and their family. One of the most highly utilized forms of treatment is counseling, often for patients that present with a sense of worthlessness, loneliness, and frustration over their predicament [77, 78]. Counseling sets out to answer a series of questions regarding the patient’s life; these questions tend to deal with first, identifying the problem and then understanding the severity of the problem. Through every second of counseling, it is important that the patient feels that counseling will be the solution to many of their problems as well as that patient’s privacy will be upheld to the maximum extent [79].
\nThrough the many different modalities of therapy, the treatment for DAI is one that can span over the year with no real guarantee that progress will be made. The diagnosis of DAI is life-changing at best and is often the result of severe brain trauma. In the event that a patient is successful in the battle to regain consciousness and expelled out of their coma, the uphill battle to restore a quality of life begins [80]. Through the many forms of DAI treatment available to patients today, slight improvements are possible, and faith in the various treatment methods is at an all-time high [81, 82]. The primary form of counseling patients receives frankly a conversation regularly with therapists focusing on reducing frustration and anxiety and resorting the sense of self-worth. At the end of the day, the patient must come to term with their new situation and establish a new life; while this is easier to be said than done, counseling has successfully completed this task multiple times. To patients climbing the uphill battle of DAI treatment, we wish you the best of luck and a speedy recovery.
\nIn 1956, Sabina Strich, the scientist known to have first identified and described the diffuse degeneration of white matter and white-gray matter lesions, published the first ever study focused on the matter seen within the cerebral region of five patients that had sustained closed-head injuries of severe form [83]. A case study of five patients set the landmark for pathological investigations into brain damage and traumatic head injuries, specifically diffuse axonal injury [84]. While in 1956, the human brain was not entirely understood as well as technology was not at the level it is today to have been able to radiographically or investigatingly screen for the presence of head trauma, thus the rate of mortality was strikingly high. Of the five subjects Strich was investigating, all patients succumbed to their brain injuries weeks to months after the initial trauma. While there was no striking evidence for the presence of DAI, Strich came to the realization that extended degeneration of axons over a time period after the trauma was responsible for the high rate of mortality. The pathologic term DAI was established after Strich published her findings; later, it was agreed that DAI was a multipart pathology in that not only does the initial trauma cause severe damage, but also secondary factors such as biochemical cascades, edema, and hypoxia also contribute to the pathology as a whole [85, 86]. It was in the early 1980s where the official term, DAI, was introduced and accepted worldwide as a pathology which played a key integral role in the posttraumatic development of the patient [87].
\nInflammatory response within the brain resulting after a traumatic brain injury, specifically a DAI, is mediated by microglia. Oehmichen et al. conducted an experiment in which microglia were immunohistochemically labeled to enable their ability to track areas of axonal injury by observing infiltration [88–90]. Microglia will localize to the region of trauma and become activated such that they are able to isolate compromised structures and locate injured axons. Infiltration mentioned briefly above will become evident after 24 hours in young patients or 48 hours in elder patients and can last for as long as 2 weeks or even a month for particular cases [91]. Cytokines are the key factor involved in inflammation; interleukin (IL) families 1, 6, and 10 also play a role as mediators of inflammation, accompanied by TNF, a tumor necrosis factor which is a cell signaling protein utilized by the body during inflammation. Within a rat model, traumatic brain injury is correlated with a rapid increase in cortical IL-1 alpha and beta sub-factors of the IL-1 family. These interleukins were demonstrated to rapidly increase the rate of inflammation within the rat model [92]. Additionally, interleukin-6 (IL-6) family has also been shown to increase in expression 1–6 hours after the traumatic brain injury. The highest levels of IL-6 mRNA transcription and IL-6 cytokine expression occurred in regions where diffuse axonal damage was the greatest [93]. Within the body, interleukin (IL)-6 plays a key role in the homeostatic control of inflammation-activating cofactors such as granulocytes, lymphocytes, and NK, which rapidly diffuse within the blood in the event of a traumatic injury [94, 95]. The inflammatory response while deadly if not controlled actually increases the likely hood of neuronal damage recovery; however, due to the constant volume of the given region and risk of cerebral compression, inflammation must be controlled to minimize any risks of mortality or compression-induced damage.
\nIn this chapter, we have discussed in detail the pathology of diffuse axonal injury (DAI) as a result of traumatic brain injury (TBI). Although this pathology represents a mild to severe disease which complicates or often deprives patients from a normal life, implementation of effective therapy and rehabilitation treatment, along with the adaptation of novel therapy methodologies, patient course and prognosis may be substantially improved, mitigating traumatic sequelae and long-term posttraumatic outcomes. We hope that you have learned a great deal in regard to DAI, its pathology, and biochemical characteristics. In Figure 11, we hope to visualize the most common physical action that results in DAI. Axonal injury is typically resulting from an external force that is acted upon the brain causing a rotational force to be acted upon the axon along with a severe impact of the brain along the skull. Stay safe!
\nDemonstration of the most common form of DAI impact injury [
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\nScanning Tunneling Microscopy (STM) and Atomic Force Microscopy (AFM) metrology as parts of more general Scanning Probe Microscopy has been around for a long time, and especially intense since it has been awarded by the Nobel Prize in Physics in 1986. In 1988, our team was one the first who designed, manufactured, and used the specialized scanning tunneling microscope to measure newly developed big-size surface-relief holographic diffraction gratings obtained in non-organic photoresist and having in an order lower roughness (Figure 1) [1]. For today, STM & AFM profile measurements on surface-relief diffraction gratings are presented as a matter of routine, see, e.g., in Refs [2, 3]. On the other side, precise microscopic surface-relief patterns are used as grating standards to calibrate atomic force microscopes (see, i.e., in [4]).
STM images of holographic relief grating surfaces (Au-coated) obtained by (a) organic and (b) non-organic photoresists (after [
However, a wide analysis of the use of the STM and AFM methods for surface relief grating groove metrology has not really been undertaken in details. The following problems are discussed here: the tip deconvolution, geometry, and radius; groove shapes and abrupt groove slopes; roughness; PSD functions; other. The author demonstrates examples of AFM & STM data and comparisons with other widely-used metrology techniques for bulk, coated, and multilayer-coated ruled, or holographic, or laser-lithographic, or electron-lithographic gratings having lamellar, or sinusoidal, or blazed, or other realistic groove profiles. These gratings were chosen because high quality efficiency data exists, in particular, for flight gratings or/and X-ray gratings characterized by synchrotron radiation sources; and their groove profiles, together with random nanoroughness, were measured by AFM or STM to be included in rigorous efficiency and scattered light intensity calculus.
Here the author briefly compares various standard techniques for exact determining the digital profile and 3D topography of a surface relief grating. Several widely used direct (or semi-direct – ‘imaging’) methods and respective instruments applicable for this purpose are compared. The advantage of using direct and exact groove metrology to predict efficiency and polarization characteristics of gratings now is well-known and widely used. The main purpose of such modern approach is rejecting unusable samples on earlier stages and decreasing expenses for their production and research. This is much more effective in compare to the earlier approaches, wherein: (1) a master grating is fabricated, whether by mechanical burnishing with a ruling engine, or holographic writing (interferometry), or direct laser recording (DWL), or various newer writing techniques, like as electron-beam lithography (EBL) and Si-etching, or their combinations; then, (2) it is replicated or/and coated, and, finally, (3) tested for the diffraction efficiency and scattering light intensity. For mechanically ruled gratings, a ‘test’ ruling can quickly be checked with this approach, whereas a complete ruling sometimes requires several days or even weeks of continuous use of expensive ruling machines [5]. Even for holographic or EBL gratings, considerable efforts of writing, etching and coating the grating with specialized coatings, especially multilayer coatings, can be decreased additionally if metrology validates that an intermediate product is suitable in the planned application.
The author briefly discusses and compares in the first part of this chapter several basic, among many others, direct metrology techniques: microinterferometry (as one of optical methods) [6], stylus (mechanical) profilometry [7], scanning electron microscopy (SEM) [8], and AFM [9]. Several examples of groove metrology results are presented and discussed further including those obtained very recently.
Any method for measuring the profile of a surface relief grating requires some calibration procedure [10]. The considered here methods are also widely used for surface microroughness determination on a nanometer or sub-nanometer level. Measuring main groove parameters of a grating, in particular, the actual groove depth or blaze angle, adds to the requirements for the specific metrology method. The depth of the groove profile, defined depending on the accuracy of a vertical calibration, basically determine the wavelength for the peak efficiency in a given optical mounting geometry (classical or conical) [11]. The common error of the order of a few percent in the lateral calibration can affect the prediction of the blaze wavelength that should be within hard tolerance for many practical applications. This is because the groove vertical geometry is often expressed relatively to the grating period, in dimensionless units. Any lateral error becomes vertical error in the respective topographical transformation. Fortunately, lateral errors can be fairly determined because the grating period is well known beforehand with high accuracy and, thus, the grating data itself gives a calibration factor to correct the lateral scale unit. The accurate lateral calibration is also required for rigorous efficiency modeling codes, in which the use of the average groove profile shape is very important to obtain exact efficiency data in all significant diffraction orders.
The microinterferometer is sometimes called as ‘optical profilometer’. It is essentially an interferometric head on a microscope, where the reference arm of the interferometer views a small, highly polished reference plate [6]. Such a reference can be removed from the results of measurements on highly polished surfaces that is important for grating measurements because many state-of-the-art gratings, especially for X-ray and Extreme Ultraviolet (EUV) applications, have the root-mean-square (RMS) roughness of the same order as the best reference plates. A Phase Shift Instruments model MicroXAM [12] has been used in the discussed work [10]. It has variable magnification from 2× to 100×; values of range and resolution for the 50× magnification is listed in Table 1. The instrument uses the zero path difference calculations independently for each pixel from a series of images obtained during a vertical sweep. This increases the available vertical range and the available slope angle range substantially, however any microinterferometer has two lateral resolution-restricted factors, which are not limitations in the other considered methods. Namely, the optical resolution is due to the diffraction limit and pixel sampling is due to different magnifications and focusing. The theoretical limit on lateral resolution in such instruments is a half of the working wavelength, or, typically, about 0.1–0.3 μm. Thus, this method generally is not suitable to measure high-frequency (short-period) and/or low-depth diffraction grating.
Instrument | Microinterferometer 50× | Stylus profilometer | Atomic-force microscope | Units |
---|---|---|---|---|
Vertical resolution | 0.05 | 0.1 | 0.05 | nm |
Vertical range | 100 | 130 | ∼5 | μm |
Lateral resolution | ∼0.3 | ∼0.3 | 0.015 | μm |
Lateral range | 163 (more w/stitching) | > 25000 | 100 | μm |
Limiting factor(s) for lateral resolution | MTF, sampling, need for retroreflection over the whole profile | Tip radius & angle | Tip radius | |
Upper slope limit | – | 45 | ∼70 | deg. |
Measurement characteristics of three surface profiling instruments (after [10]).
The stylus profilometer has a diamond tip to brought into direct contact with the surface, with calibrated contact force. As the tip moves across the surface, the motion of the tip is amplified, filtered, and detected. The basic limits inherent to such metrology devices are well-discussed, e.g., in [7]. Care must be exercised to prevent indentations of the surface by the tip, depending on materials and forces used, as well as accounting the tip size. The model used in this work is a Tencor P-10 [13]. Table 1 presents the basic lateral and vertical ranges and resolutions typical for the instrument. Typical measurement parameters are: the tip radius of 0.1 μm (in the plane of dispersion), the tip speed of 5 μm/s, the digital sampling of 2 kHz, the tip force of 0.25 mg, and profile lengths of at least 100 μm (depending on the groove period). Note that in the last model of this instrument, KLA-Tencor HRP-260, the tip radius can be up to 25 nm and it has a high-resolution stage that produces scanning results similar to an AFM device. In the recent investigation we have used another model, namely, ХР-1 Stylus (Ambios Тechnology, USA) [14].
The AFM instrument model that has been used in the discussed earlier work was a Digital Instruments Nanoscope III [15]. The recent investigation was carried out using the atomic-force microscope model NT-MDT NTEGRA Aura [16]. NTEGRA Aura is a Scanning Probe Microscope for studies in the conditions of controlled environment and low vacuum. The Q-factor of the cantilever in vacuum increases, thus gaining the sensitivity, reliability and accuracy of ‘probe-sample’ light forces measurements. At that, the change from atmosphere pressure to 10−3 Torr vacuum provides the tenfold gain of Q-factor. By further vacuum pumping, Q-factor reaches its plateau and changes insignificantly. Thus, NTEGRA Aura comparing to the high-vacuum devices it needs much less time, about a minute, to get the vacuum that is needed for the tenfold Q-factor increase. NTEGRA Aura has built-in closed loop control for all the axes, optical system with 1 μm resolution and ability to work with more than 40 different AFM regimes.
We have used for the Si-grating technology investigation a flexible Carl Zeiss SUPRA 25 SEM system with a versatile analytical specimen chamber that can be easily expanded with a choice of optional detectors and a full range of accessories [17]. Utilizing the unique GEMINI field emission column, it delivers superb resolution over the complete high voltage range with the magnification of up to 500000. The large 5-axes motorized cartesian stage is particularly useful for handling a number of smaller specimens simultaneously. It is equally useful for accommodating bulky or irregular shaped specimens.
Table 1 summarizes the capabilities and limits of the three metrology devices, which have been characterized earlier for grating metrology. As one can see, the atomic-force microscope has the finest lateral and perfect vertical resolutions. The stylus profilometer and the microinterferometer have comparable vertical ranges, however, without a possibility to determine superfine (atomic-scale) structures, i.e., nanoroughness, and abrupt slopes (see, e.g., Figures 3–5). On the other hand, the stylus profilometer has significantly larger lateral range for probing to the millimeter spatial range. Also, the AFM data gives a typical example of non-linearity that should be accounted and described further.
In the groove profile experiment, a series of step height calibration standards [18] has been used [10]. The vertical axis was calibrated using one of the smallest steps of 10 nm. Then the rest of the step height series was measured. Small errors, up to 8%, were observed for heights much higher than that used to calibrate the atomic-force microscope. The fit to correct such nonlinearity was used when the nonlinearity gives a significant difference. The obtained results are summarized in Table 2.
Nominal height, nm | Microinterferometer | Stylus profilometer | Atomic-force microscope |
---|---|---|---|
8.7 | 7.92 | 8.1 | — |
25.8 | — | — | 25.7 |
42.7 | 43.4 | 42.4 | — |
530 | — | — | 520 |
1046 | — | — | 1005 |
1590 | — | — | 1469 |
960 | — | — | — |
Note No. | 3, 4 | 2 | 1 |
Step height data (after [10]).
1. Nonlinear at ∼8% at highest step when calibrated to a 10 nm step.
2. Using 0.1 μm tip, could not resolve depth of 3.3 μm period, AFM step height standard.
3. Used at 50× magnification.
4. At 100× did not have lateral resolution to see the 3 μm period samples tested using AFM.
In the manufacture and analysis of diffraction gratings, it is necessary to control certain of their parameters at each stage of the process. A SEM research [19] is permissible only at the stage of development of the manufacturing technology, because after each technological operation, see, e.g., [20] or Section 4.5, the sample of the Si-etched grating becomes less and less, since a fragment is separated from the sample to obtain a SEM image of a transverse cleavage (CS). In contrast to this, AFM studies are non-destructive; therefore, control of parameters in the manufacture of gratings is usually carried out with the help of AFM. We made a comparison between AFM (NTEGRA Aura microscope) topographies and SEM (SUPRA 25 system) images of Si-etched grating samples with the period of 2 μm. Table 3 shows the results of AFM and SEM investigations of Si-etched gratings obtained at different stages of their fabrication. Table also presents the numerical comparing between the AFM and SEM results of the measured groove geometric parameters for the samples studied. The calculated value of the blaze (working facet) angle from the SEM studies was obtained from the sine determined by dividing the experimental values of the groove depth by the width of the working facet.
Sample No. | Groove depth, nm | Working facet width, nm | Working facet angle, deg. | |||
---|---|---|---|---|---|---|
SEM | АFM | SEM | АFM | SEM | АFM | |
1 | 151 (47)* | 133 (38)* | 1571 | — | — | — |
2 | 149 (37)* | 141 (44)* | — | — | — | — |
3 | 111 | 121 | 1630 | 1710 | 3.90 | 4.05 |
4 | 111 | 111 | 1603 | 1594 | 3.97 | — |
5 | 105 | 114 | 1590 | 1580 | 3.89 | 4.13 |
AFM and SEM data for blaze Si-etched gratings.
Height of Si-nubs.
To measure the roughness of Si(100) plates etched through a DWL mask in KOH and intended for developing the technology of manufacturing Si-etched gratings, several high quality samples were selected using white light optical microscopy. The roughness of the etched bottom and the non-etched area was measured by two compared methods: Stylus Profilometry (XP-1 Stylus profilometer) and AFM (NTEGRA Aura microscope). Our studies were carried out on an atomic force microscope in the semi-contact or tapping mode; all scans had 512 × 512 points. We used TipsNano [4] silicon cantilevers with a typical radius of tips ∼6 nm. The results of roughness measurement by two methods on topological elements (stripes) of 50 μm wide are presented in Table 4. As follows from the presented data, the RMS roughness obtained by different methods may differ by more than an order of magnitude. This is due to the radius of the stylus and the scanning length, which in that case were 2 μm and 80 μm, respectively. However, this device is equipped with a stylus with a radius of 0.2 μm, which, in principle, allows one to measure low- and mid-frequency gratings with smaller roughness. Note that for the etched bottom, where the average roughness is several times higher, the scatter of results is much smaller and ranges from several tens of percent to several times.
Sample No. | RMS roughness, nm | |||
---|---|---|---|---|
Non-etched field | Etched bottom | |||
Profilometer | AFM | Profilometer | AFM | |
1 | 2.6 | 0.2 | 2.8 | 0.8 |
2 | 3.2 | 1.6 | 4.0 | 2.5 |
3 | 3.4 | 0.2 | 4.5 | 1.8 |
4 | 2.8 | 1.7 | 2.9 | 4.9 |
5 | 2.4 | 1.5 | 3.5 | 4.3 |
AFM and stylus Profilometry data for Si-etched plates.
A cantilever tip convolution, which limits the resolution of both the atomic-force microscope and the stylus profilometer, has been much studied and various algorithms to account for this effect has been developed and intensively used (see, e.g., [21] and also in this book). In the results presented in Table 2 such algorithms have not be used. However, the general used rule is that the known tip radius should be much less than the measured periods of gratings. Typically, the radius of a fresh AFM cantilever tip is about 5–15 nm; so, the rule of thumb is that for groove profiles of mid- and high-frequency gratings (say, periods of 100–300 nm and less) tip deconvolution algorithms should be used. In the vertical direction, the depth parameter is smaller, and, apparently, the groove profiles recorded somewhat non-correctly for high-frequency gratings only. However, it depends also on absolute values of the groove profile depth, which can vary in two orders of magnitude.
Another important and general AFM problem, in particular for fine-structure gratings with steep slopes and high aspect ratios of grooves, is the shape and the radius of AFM cantilever tips. Tip size has the major impact on the resolution of images obtained by any atomic-force microscope. The knowledge of the tip radius and shape is essential for the quantitative interpretation of nano-scale lateral steps, in particular, for roughness having short correlation lengths. Tip wear is therefore a key limitation in the application of AFM [22]. The results of nanoindentation experiments with diffraction gratings permanently confirm this conclusion. The measurement of the tip radius before and after measuring groove profiles of gratings was performed in Ref. [10], and they found that the radius to be in the range of 10–20 nm. One measurement found a fresh tip to be ∼10 nm radius and a used one to be ∼20 nm. Therefore, one should restrict an AFM-profiling work to gratings of period much longer than 10–20 nm, as it has been discussed above.
One more problem in AFM measurements of diffraction gratings is the grooves with steep facet slopes, which can be 80 degrees and more for echelle gratings [2]. This problem is similar to measurements of the rectangular (lamellar) groove profile in microelectronics [23]. To accurately measure such general trapezoidal profiles with steep or even negative sidewalls, a large change in the angle of inclination of a cantilever (or scanner, or sample) and/or special cantilever (tip) shape are required, as well as taking into account the aspect ratio of measured grooves [24]. Several studies applied to periodic structures demonstrate that some combination of the tilted probe, special orientations of AFM images and appropriate deconvolution algorithms allows the precise groove shape reconstruction at any aspect ratio [25]. An example of such problem successfully solved is the average groove profile (two grooves) of a 112/mm echelle R5 grating (blaze angle ∼78°) derived from AFM images and presented in Figure 2.
Average AFM groove profile for 112/mm echelle R5 grating.
In Figure 3, typical power spectral density (PSD) 1D functions for Si(111) substrate and Si-etched grating samples (see also Section 4.5) are shown. An estimator of the PSD function is factually the periodogram for any periodic, or quasiperiodic, or random profile, or some combination. Assuming the ergodicity of a stochastic process connected with a random generation of asperities, the PSD function can be found as the Fourier transform of the autocorrelation function [26]. Although these functions are mathematically equivalent, one can analyze easy any corrugations of the profile shape simultaneously, i.e., random roughness and groove depth variations, using the 1D or 2D PSD function. Then, the RMS roughness is directly calculated through PSD as the root square of the integral over an effective range of allowed spatial frequencies. Thus, a wide lateral scanning range may require for an AFM instrument to take into account in the evaluated RMS roughness all spatial frequencies (or correlation lengths). It is especially important for low-frequency (long-period) gratings having additionally large correlation lengths of random roughnesses. A good discussion related to this problem and devoted of the use of AFM and similar instruments for measurements of PSD functions of smooth mirrors for imaging systems working in the X-ray–EUV range can be found in [27]. So, if one need to use images with a scanning area of about 100 × 100 μm2 then thermal drifts, hysteresis, and essential scanner nonlinearities should be accounted.
PSD function: (left) for Si(111) substrate; (right) for Si-etched grating with 500/mm and 4° blaze angle.
The abovementioned metrology techniques were applied to validate the efficiency of a chosen grating from an ordered grating set which is mounted in the Space Telescope Imaging Spectrograph (STIS) flown aboard the Hubble Space Telescope (HST) [28]. A − 1-order reflection grating with 67.556/mm blazed for 750 nm (1.44° nominal blaze angle) working in the range from 500 to 1000 nm at 8° incidence angle was chosen by us for a certification [29]. The pattern size was 1.5 inches by 1.5 inches, and the ruled area was 30 mm by 30 mm. A sister-replica to this grating, designated ‘Ng41M’ or by its manufacturers’ (Richardson Gratings of Newport Corp.) serial number, 1528, is in use on the HST/STIS as a red survey grating (blazed in the red visible and near infrared range) [10]. In its flight application, this grating had a reflective overcoating of 100 nm Al plus 25 nm MgF2. However, in these wavelengths the effect of the MgF2 layer is minor and simulations have showed no valuable difference, within a small part of the accuracy in the measured diffraction efficiency) with such coating or without it. This grating was chosen as an example because: (1) high quality efficiency data exists for it, including rigorous efficiency calculus using the realistic groove profile shape; and (2) groove profiles can be measurable by the mentioned above three methods for a direct comparison.
Portion of a trace of grating No. 1528 taken with the microinterferometer is shown in Figure 4. Both the depth and the profile shape are somewhat distorted in compare with the groove profiles in Figures 5,6 obtained by the other considered methods. However, as one can see, the overall groove depth and profile are evident. It is clear from the all figures that the profile roughness is higher on the upper sloped portion than on the steep edges. Difficulties in holding the sample steady during ‘flyback’ prevented reproducibility of measurements for that microinterferometric study.
Portion of a microinterferometer trace of ruled grating No. 1528 (after [
Portion of a stylus profilometer trace of ruled grating No. 1528 (after [
AFM image of two grooves of ruled grating No. 1528 (after [
The groove profile was characterized in details AFM measurements. The tips used here were 10 or 20 nm in radius. An example of the typical groove profile of No. 1528 grating is presented in Figure 6. Figure 6 shows an example of AFM data for a portion of the surface of the investigated ruled grating. The basic groove profile shape is clearly evident, along with portions of the profile that are rougher than others, and some roughness along the grooves is indicated as well. Figure 6 shows that the minimum of the grooves is clearly visible in the AFM image. If, as usually, one selects the bottom of the groove as the minimum value, there are two complete grooves in each scan.
The resulting average groove profile – with averaging performed both across the grooves and along as well – is shown in Figure 7. The solid line is based on the AFM data, and the dotted line is based on the stylus profilometer data: the groove tops are aligned for the purpose of this comparison; the relatively sharp groove bottom is not as well resolved by the stylus profilometer. The periodicity of the profile is shown by comparing a model of the averaged scan based on the average groove profile shape to the average scan. This is demonstrated by dotted lines plotted against the initial data in Figure 4 (microinterferometer) and Figure 5 (stylus profilometer). Once the average profile has been determined, the fitting routine finds the sawtooth and two-angle shape fits by the method of least squares. It is found in the considered case the blaze angle of 1.45° and the anti-blaze angle of 30° (Figure 8). The efficiency in general is fairly insensitive to the anti-blaze angle, and the fitting procedure does not fit it as consistently as it does a case of the blaze angle. Thus, the final average groove profile derived from AFM measurements for efficiency modeling purposes is shown in Figure 8 with 100 discretization points [29].
Average groove profile for grating No. 1528 based on AFM and stylus profilometer data.
Models of normalized to period groove profiles of No. 1528 grating.
The surface of gratings, namely, the master [30] and replica [31] gratings, as examples of ‘good’ products, were characterized using a Topometrix Explorer Scanning Probe microscope [32], a type of atomic-force microscopes. The gratings have 2400/mm, a concave radius of curvature of 2.0 m, and a patterned area of size 45 mm by 35 mm. The master grating was fabricated by Spectrogon UK Limited (formerly Tayside Optical Technology). The groove pattern was developed in fused silica by a holographic technique using ion-beam etching to produce an approximately triangular, blazed groove profile. Ion-beam etching results in a groove profile much closer to triangular than the ideal blazed (sawtooth) profile with the apex angle of ∼90°. The master grating was uncoated. The replica of the master grating was produced by Hyperfine, Inc. As a result of the replication process, the replica grating had an aluminum surface. A thin SiO2 coating was applied to the Al surface for the purpose of reducing the nanoroughness and protecting the surface from an additional oxidation.
The AFM images typically had 500 × 500 pixels and a scan range of 1 to 20 μm (pixel size 20 to 400 Å). The silicon probe had a pyramid shape. The base of the pyramid was 3 to 6 μm in size, the height of the pyramid was 10 to 20 μm, and the height to base ratio was approximately 3. The tip of the pyramid had a radius of curvature 100 to 200 Å. The AFM scans were performed using the non-contact resonating mode, where the change in the oscillation amplitude of the probe is sensed by the instrument. A surface topology reference sample was used to optimize the AFM scanning parameters, to calibrate the height scaling of the instrument, and to evaluate the performance of the AFM. This was essential for the accurate characterization of the gratings. The surface topology reference sample consisted of an array of approximately square holes fabricated on the silicon dioxide surface of a silicon die by VLSI Standards, Inc. [18]. The top surface of the die was coated with a thin layer of Pt. The hole array had a pitch of 3 μm and a hole depth of 180 Å.
One typical AFM image of the master grating measured using 16-Å pixels is shown in Figure 9, where the vertical scale has been scaled to reveal the texture of the groove surface. The RMS roughness, determined by integrating the PSD function over 2–40 μm−1 range, was 3.2 Å. Most of the roughness is concentrated at low spatial frequencies as is apparent from the analysis of the PSD function. The central portion of the AFM image shown in Figure 9 that covers one period of the grating pattern was selected for further investigations. An analysis program was written in the Interactive Display Language (IDL) for this purpose and it is discussed in detail in Ref. [31].
AFM image of 2400/mm holographic (master) grating (after [
The histogram of the pixel heights, for one period of the grating pattern, is shown in Figure 10. The maxima at 10 Å and 85 Å in Figure 10 are caused by rounding of the groove profile at the peaks and the troughs which is a result of the pattern fabrication process. An ideal groove profile, either sawtooth or triangular, would have a flat height histogram. The separation between the peaks in Figure 10 represents the average groove height, approximately 75 Å. The local blaze angle at each pixel was determined by using a least squares algorithm to fit a linear curve to the data points in a sliding window. The window was 25 pixels (400 Å) long in the direction perpendicular to the grooves and one pixel wide parallel to the grooves. The blaze angle is the arctangent of the fitted slope. The histogram of the blaze angles, for all rows of data in one period of the grating, is shown in Figure 11. The peak at 2.5 deg. represents the classical blaze angle, and the peak at 5.5 deg. represents the steep facet of the ideal sawtooth profile as modified by the ion-beam etching process. For a density of 2400/mm and for facet angles of 2.5 deg. and 5.5 deg., an ideal grating would have a groove height of 125 Å. However, the measured value of 75 Å (Figure 10) indicates a significant degree of rounding at the peaks and troughs of the groove profile. In addition, the measured ratio of the heights of the 2.5 deg. and 5.5 deg. features in the angle histogram (Figure 11) is approximately 3, greater than the ratio of approximately 2 that is expected based on the average facet angles.
Histogram of pixel heights from AFM image of 2400/mm holographic grating (after [
Histogram of blaze angles from AFM image of 2400/mm holographic grating (after [
The interpretation of the widths of the features in Figure 11 is difficult because they are complicated functions of the surface roughness, the width of the sliding window, and the probe geometry. This is addressed in the publications [30, 33, 34]. The feature at −2 deg. in Figure 11 results from the fits to the peaks and troughs of the groove profile, where the local slope is changing rapidly but has an average value near zero. Simulations show that the −2-deg offset of this feature from zero is a consequence of the unequal average blaze angles of the two facets. To provide a groove profile for the efficiency calculation, a representative AFM scan perpendicular to the grooves was chosen at random and scaled to the average groove height. The resulting groove profile is shown in Figure 12. This groove profile has 210 points.
Average groove profile from AFM image of 2400/mm grating: (1) 7.5-nm- deep master; (2) 9.0-nm-deep replica; (3) 6.6-nm-deep scaled replica (after [
AFM image of 2400/mm replica grating (after [
An AFM image of two grooves of the replica grating is shown in Figure 13. The scan was performed across the grooves over a range of 1 μm (20-Å pixels). The vertical scale in Figure 13 has been expanded to reveal the texture the texture of the grating surface. The PSD function derived from a 2 μm-size image spanning nearly 5 grooves is shown in Figure 14. The peak in the 2 to 3 μm−1 frequency range results from the 0.4167 μm groove period. The RMS roughness is 7 Å in the 4–40 μm−1 frequency range. By comparison, the RMS roughness of the master grating measured by the same type of AFM instrument was 3.2 Å, and this implies that the replica grating is significantly rougher than the master grating. This may result from the replication process, which for a concave grating is at least a two-step process. Furthermore, the master grating was fabricated on a fused silica surface by a holographic technique and was ion-beam polished, while the Al surface of the replica grating may contribute to its larger nanoroughness. The replica grating without the SiO2 coating was not characterized by AFM. Typical average groove profile derived from the AFM image (1 μm in size) of the replica grating is shown in Figure 15. The groove profile is approximately triangular in shape with rounded corners and troughs and with facet angles of 3.4 deg. and 6.2 deg. The average groove depths derived from the AFM images are in the range 85 to 95 Å. These values of the facet angles and the groove depth are larger than the corresponding values for the master grating, 2.5 deg. and 5.5 deg. facet angles and 75 Å average groove depth (Figure 12). Thus, the grooves of the replica grating are deeper and the facet angles are steeper compared to those of the master grating.
PSD function of 2400/mm replica grating from AFM image (after [
Average groove profile from AFM image of 2400/mm Mo4Ru6/Be grating (after [
Multilayer gratings were produced by application of Mo4Ru6/Be multilayer coatings [35, 36] to two replicas of the described holographic master grating. Beryllium-based multilayer coatings can provide substantial reflectance at wavelengths near 11 nm. Such a Mo4Ru6/Be multilayer coating with 50 bi-layers was applied to the grating substrate. The coating was deposited by the magnetron-sputtering technique. Here we describe one of the multilayer gratings.
The surface of the multilayer grating was also characterized using the same Topometrix Explorer scanning probe microscope. The grating topography was measured merely for the master, replica, and multilayer gratings. The scan was performed across the grooves over a range of 1 μm (2-nm pixels). Typical groove profiles derived from the AFM image (1 μm in size) of the master, replica, and multilayer gratings are shown in Figures 9,13,15, respectively. These groove profiles have from 120 to 210 points. The groove profiles are approximately triangular in shape with rounded corners and troughs and with facet angles of 2.5° & 5.5°, 3.4° & 6.2°, and 3.0° & 4.1°, respectively. The average groove depths derived from the AFM images are in the range 7 to 8 nm, 8.5 to 9.5 nm, and 8 to 9 nm, respectively. Within the AFM groove-to-groove variation of the facet angles, the border shapes did not significantly change after multilayer coating. As determined above the average surface of the multilayer grating was characterized using a scaled replica AFM profile (Figure 12).
The aforementioned AFM method was applied to simulate the efficiency of a 5870/mm G185M grating intended for operation at vacuum-ultraviolet (VUV) wavelengths below 200 nm [37]. This grating has the highest groove density and the shortest operational wavelength range of all Cosmic Origins Spectrograph (COS gratings planned for the last servicing mission to the HST) [38]. The G185M master grating was recorded holographically on 40 mm by 15 mm rectangular fused silica blank and the Pt coated at HORIBA Jobin Yvon Inc. [3]. An adhesive Cr coating, a working Al coating, and a protective (from oxidation) MgF2 coating were deposited on Au-coated replica gratings at NASA/GSFC.
Resonance efficiency anomalies associated with waveguide funneling modes inside the MgF2 dielectric layer degrading the G185M COS NUV grating performance were measured and qualitatively described at NASA/GSFC [39]. We used PCGrate-SX v. 6.1 [40] to model the efficiency of the G185M subwavelength grating with real boundary profiles (measured by AFM) and refractive indices (RIs) taken from different sources, including best fits of the calculated efficiency data to experimental ones [37].
The border profiles were characterized using AFM measurements. The profile of the G185M grating (replica C) intended for operation in the 170–200-nm range was AFM-measured before and after deposition of the Cr/Al/MgF2 coating (Figure 16). As seen from the figure, after the deposition the profile depth decreased by about a factor of 2.05 (46.4 nm against 22.6 nm), and the profile shape changed noticeably too, thus evidencing the case of nonconformal layering of the grating. For the reason that all G185M gratings were manufactured from the same master and by the same technology, one may suggest that all of them share before- and after-coating profiles. The average before-coating groove profile had 165 points and the average after-coating profile had 163 points.
G185M AFM-measured surfaces before (left) and after (right) coating Al plus MgF2 (after [
To determine which of the two AFM-measured boundary profiles, MgF2 (border profile 1 measured after Cr/Al/MgF2 coating) or (Cr)-Au (border profile 2 measured before Cr/Al/MgF2 coating), is closer to the MgF2-Al boundary, we started with modeling the non-polarized (NP) efficiency of a two-boundary grating. We assume a conformal MgF2 layer (the lower MgF2-Al boundary is identical in shape to the MgF2 one) with the 40.1 nm thickness. The calculated efficiencies (Figure 17, pink curve) differ from the measured values in time throughout the whole wavelength range, thus implying invalidity of a model with a conformal layer. All calculated efficiency data presented in Figure 17 were obtained with the RIs of Al and MgF2 taken from the handbook of Palik [41]. Although hereinafter the experimental efficiency data of two grating replicas (A and B) are displayed, we will focus primarily on discussing the grating A data (solid dark blue squares in Figure 17), because replica A is the grating on which more measurements were performed.
G185M –1st-order NP efficiency measured and calculated for different layer shapes.
The next step is to use two models with nonconformal layers, one with the lower boundary being the same as border 2 (Figure 17, yellow curve) and the other with the boundary scaled from border 2 at all points by a factor of 0.488 to the profile depth of border 1 (Figure 17, bright green curve). In both cases, a vertical displacement of one boundary with respect to the other (shift of the boundary reference levels) was 40.1 nm, as in the conformal model. As evident from Figure 17, the nonconformal model with unscaled lower boundary yields a noticeably superior qualitative agreement with experimental data. This suggests that the MgF2-Al boundary more closely resembles border profile 2 than border profile 1. The model takes into account the fact that the thickness difference of 23.8 nm between the lower and upper boundaries should be added to the conformal vertical displacement (40.1 nm) to obtain an adequate vertical displacement for the nonconformal MgF2 layer. In this way the period-averaged thickness of the nonconformal MgF2 layer is kept approximately equal to 40.1 nm within the boundary shape distortion.
To determine the effect of profile shape, we set up models with equal depths and vertical shifts. The first one has border 1 scaled to the depth of border 2 (making it grater by a factor of 2.05) and a vertical displacement between the zero boundary levels equal to 63.9 nm. As seen from Figure 17, the efficiency of this model (orange curve) is close to that of another model with unscaled border 2 and a vertical shift of 63.9 nm (sky blue curve), while it is inferior by 40% or more as far as matching the experimental efficiencies. The latter suggests that, to set up an exact model, one has not only to determine the depth of the MgF2-Al boundary but also to take into account the shape of its profile – see Figure 18.
Average G185M AFM border profiles before and after coating Cr/Al/MgF2.
Having determined the type of the MgF2-Al boundary profile, we have to refine it by scaling the shape in depth and then comparing the efficiencies obtained for each model with experimental data. Another fitting parameter is the vertical displacement of the boundaries. By automatic modeling of the efficiency over a small-meshed grid of these two parameters and wavelength, one can determine the average thickness of the MgF2 layer from the best fit between the calculated and the experimental efficiencies. Even slight changes (with a few nanometers) in profile depth and vertical displacement give a noticeable rise to the efficiency at fixed wavelengths, particularly in resonance regions. Figure 17 presents an efficiency curve (heavy dark blue) for the model with a lower-boundary scaling factor of 1.04 and a vertical displacement of 68.5 nm. The model with these parameters of the layer geometry provides the better least-squares fit (not worse than 20%) of calculated efficiency to experimental data, both in the medium and in the long-wavelength ranges. As to the short-wavelength part, no variations in the lower boundary profile chosen within our approach yield theoretical values of the efficiency close enough to the measured ones.
Five-boundary G185M grating model. Horizontal and vertical scales are different (after [
What only remains is to check whether the average-thickness parameters of the MgF2 nonconformal layer used in the final model provide a better fit between the calculated and experimental values of efficiency throughout the wavelength range with a new MgF2 RI library (Keski-Kuha–Goray) [37]. To do this, we scale the vertical displacement and boundary parameters for the final model. Graphical results of this three-parameter optimization (scale, shift, and wavelength) are displayed in Figure 19. The final geometrical model of border shapes and layer thicknesses is demonstrated in Figure 18. The optimization procedure using different thicknesses for all the layers accounted has been applied using the least-square method. An analysis of these results shows that the parameters of the final model do indeed provide the best agreement between the measured and calculated values of efficiency throughout the wavelength range. The relative deviation of experiment from theory for all wavelengths at which grating A was studied does not exceed 10% throughout the wavelength range. Figure 21 presents also an efficiency curve (sky blue curve) calculated by use of the approximate values of the MgF2 absorption index; all other parameters of the final model remain intact. A comparison of the curve efficiencies based on scaled (sky blue curve) and exactly calculated (heavy dark blue curve) values of absorption shows that the efficiency changes at the wavelengths where the RI imaginary values scale only slightly are indeed appreciable.
Grazing-incidence off-plane gratings have been suggested for the International X-ray Observatory (IXO) [42]. Compared with gratings in the classical in-plane mount, X-ray gratings in the off-plane mount have the potential for superior resolution and efficiency for the IXO mission [43]. The results of efficiency calculations for such a 5000/mm gold-blazed soft-X-ray grating in a conical (off-plane) mount using the average groove profile derived from AFM measurements was presented in [44].
An AFM study of the grooved area confirmed the larger than expected blaze angle. The AFM scans across the grooves near the center of the grating are shown in Figure 20(a), where each scan is displaced vertically by 1 nm for ease of viewing. The standard deviation of the data points from the average scan curve is 0.89 nm and is a measure of the roughness of the groove profile. The histogram of the angles between each pair of scan points is shown in Figure 20(b), where a Gaussian curve is fitted to the angle distribution. The top corners of the groove profiles are rounded, and this results in a rather broad distribution of angles with a centroid value of 13°.
(a) AFM scans across the grooves near the center of the grating; (b) histogram of the angles of pairs of points on the AFM scans giving a measure of the average blaze angle (after [
The average values of the blaze angles measured at seven points distributed on the grooved area ranged from 8.9° to 15°, and the RMS roughness values ranged from 0.66 to 0.92 nm. Thus, there was considerable variation of the grooves over the 5 cm patterned area. AFM data that were taken before the titanium and gold coating of the imprinted grating showed RMS roughness of approximately 0.2 nm and blaze angles of around 8°, which indicate that deposition of the metal films onto the polymer-based imprint resist led to the observed changes in groove profile [45]. High diffraction efficiencies of the Au-imprinted 5000/mm grating using the average groove profile with 123 nodes of the polygonal groove profile derived from the AFM measurements (Figure 21) are demonstrated in Refs [44, 46].
Normalized average groove profile of an Au-imprinted 5000/mm grating measured by AFM (after [
For medium- and high-frequency diffraction gratings, classical (in-plane) diffraction gives acceptable values of the efficiency of working orders only in the soft X-ray and EUV ranges [47]. However, grazing conical (off-plane) diffraction schemes have great advantages in efficiency when such gratings operate in short-wavelength regions of the X-ray spectrum (hard X-rays and tender X-rays), including in high orders and to obtain high dispersion and resolution. With such a mount, record efficiency, close to that of a respective mirror, can be obtained for sawtooth gratings with blaze angles of several degrees, which are much easier to manufacture. For a theoretical analysis of the diffraction efficiency of such gratings, the use of rigorous electromagnetic theories is required [48, 49].
The manufacturing process of a reflective Si-etched grating of a triangular groove profile (sawtooth or blaze) can be conventionally divided into four main steps: (1) obtaining a pattern of a protective mask for etching grooves (DWL or EBL, in our case); (2) anisotropic etching of grooves in a solution of potassium hydroxide (KOH); (3) etching to smooth the grating profile and polish the surface of the reflective (working) facets; (4) coating to increase reflectivity. In turn, each step consists of several operations that should be controlled using AFM and, if possible, SEM. Some AFM results (NTEGRA Aura microscope) obtained during the grating manufacturing process are considered further in detail.
To transfer the grating pattern directly to a silicon wafer (stage 2), it is etched in KOH with various concentrations at a temperature from room temperature to 50°C with vigorous stirring of the solution [20, 50, 51]. KOH etches the {111} planes more slowly than the rest of silicon, which leads to angular facets with a facet tilt determined by the orientation of the {111} planes relative to the surface plane (i.e., vicinal Si(111) plates). Therefore, KOH etches the pattern of the grooves in the Si while simultaneously setting the blaze angle of grating facets. The author uses here the results of our original Si-etched grating production technique, however, with references to the similar methods for mastering such gratings.
In our AFM studies, the following was performed: measurement of the surface roughness of the working facet on an area of 1 × 1 and 10 × 10 μm2 and measurement of the grating profile, etching depth and blaze angle of the working facet when scanning 10 × 10 μm2. The measurements were made in the tapping mode using scans of 512 × 512 pixels. We used TipsNano [4] silicon cantilevers with a typical radius of tips ∼6 nm. Examples of the AFM topography of Si-etched grating samples with a smoothed profile on the area of 1 × 1 and 10 × 10 μm2 are shown in Figure 22a,b for sample No. 5.
Surface topography obtained by AFM scanning of area of sample No. 5: a) 1 × 1 μm2; b) 10 × 10 μm2.
Figure 23a shows the topography profile of specimen No. 5 along line 1 (black curve) and the blaze angle of the working facet (blue curve). The angle is calculated as the arctan of the coordinate derivative and converted to degrees. Figure 23b shows the profile of the slope of the non-working facet along line 1 for sample No. 3/1.
Profile topography obtained by AFM scanning of area of 10 × 10 μm: a) surface and blaze angle of the working facet, sample No. 5; b) anti-blaze angle of the non-working facet, sample No. 3/1.
The results of AFM studies of the geometrical groove parameters of the samples of Si-etched gratings with a period of 2 μm are presented in Table 5. In the results presented in Table 5 the deconvolution algorithms have been used, although we evaluated mid-frequency gratings. The histogram (normalized density of probability) of blaze, anti-blaze, and apex angles of grooves of the grating with 500/mm and 4° blaze angle is demonstrated in Figure 24 (left). The three peaks on this curve are clearly associated with the corresponding working and non-working facet angles, as well as with the angle of the smoothed top of the groove profile. The average groove profile topography and the respective angles one can see in Figure 24 (right). The peak corresponding to the blaze angle is pronounced and indicates a high quality of the developed sawtooth grating. The average groove profile derived from AFM data for one grating was used then for rigorous calculus of 3D diffraction efficiencies of orders vs. incidence angle and wavelength in the soft-X-ray–EUV range and classical mount (Figure 25). The other AFM groove profile data for similar Si-etched gratings produced by DWL, or EBL, or holographic recording can be found in [52, 53] and references there in.
Sample No. | Groove depth/Si-nub height, nm | Working/non-working facet width, nm | Working facet RMS roughness, nm | Blaze angle, deg. | Anti-blaze angle, deg. |
---|---|---|---|---|---|
1 | 95/38 | 1512/340 | 0.462 | — | — |
2 | 97/44 | 1544/340 | 0.345 | — | — |
3/1 | 121 | 1710 | 0.278 | 4.05 | 20 |
3/2 | 111 | 1594 | 0.340 | — | — |
5 | 114 | 1580 | 0.337 | 4.13 | 20 |
Groove geometrical parameters of Si-etched grating samples according to AFM.
AFM groove parameters of 500/mm and 4° blaze grating: (left) histogram of groove angles including smoothed groove top (‘transition’); (right) average groove topography and respective angles.
3D diffraction efficiency in principal orders of 500/mm Au-coated Si-etched grating rigorously calculated using the realistic groove profile vs. incidence angle and wavelength.
In order to reduce the roughness of the grating surface, the authors of [54] use a nine-cycle RCA-1/HF etching procedure to remove any irregularities and roughness, i.e., perform both smoothing and polishing etching; and they report submicron roughness. To reduce the roughness of the working facet at the polishing stage, several etchants have been tested, including tetramethylammonium hydroxide (TMAH) and the isotropic silicon etchant HF: HNO3: H2O. Table 6 shows the AFM results of processing in different etchants of the surface of samples, punctured from the same grating immediately after anisotropic etching in KOH. As one can see from Table 6, the RMS roughness of working facets can be reduced to <0.3 nm for a few etching processes. The initial RMS roughness (before a polishing process) was ∼1.2 nm (compare with results in Table 5).
Sample No. | Working facet RMS roughness, nm | Polishing etchant/etching time, s |
---|---|---|
1 | 0.269 | Isotropic/30 s |
2 | 0.244 | Isotropic/20 s |
3 | 0.271 | Isotropic, using HF before/60 s |
4 | 0.315 | Isotropic/60 s |
5 | 0.246 | TMAH/2 min |
6 | 0.291 | TMAH/4 min |
7 | 0.336 | TMAH/6 min |
8 | 0.312 | TMAH/8 min |
76KDB Si(111)4°- substrate, ∅76.2 mm | 0.149 | No process |
Groove roughness of Si-grating samples according to AFM after polishing.
In the chapter, some earlier and recent results of the use of AFM & STM methods for groove metrology of various surface relief (ruled, holographic, lithographic, imprinted) diffraction gratings, mostly intended for short wavelengths, were described and discussed. Examples of a few comparisons with the other widely-used direct metrology techniques, such as SEM, stylus profilometry and microinterferometry, were also demonstrated and compared. In addition, the most critical problems connected with AFM methods for groove metrology of bulk, thin-film-coated and multilayer-coated gratings were discussed, such as: the tip deconvolution and its radius; groove shape and abrupt groove slopes; RMS nano-roughness and PSD functions.
The detailed AFM groove metrology results were presented by the author for several important grating samples: the Space Telescope Imaging Spectrograph grating flown aboard the HST and working in the Visible–NIR; the similar master, replica and multilayer soft-X-ray–EUV blaze gratings; the Cosmic Origins Spectrograph grating used in the last servicing mission to the HST and working in the VUV–NUV; imprinted off-plane blaze grating planned for the International X-ray Observatory and working in the soft X-rays; and recently developed Si-etched blaze diffraction gratings indented to work in the X-rays–EUV at high efficiency and a very low level of scattering light. These gratings were chosen because high quality efficiency data exists, in particular, for space gratings or/and X-ray gratings characterized by synchrotron radiation sources; and their groove profiles, together with random nanoroughness, were measured by AFM to be included in rigorous efficiency and scattered light intensity calculus.
The rigorous calculation accounts for the real profile of the grooves and their thickness as well as suitable refractive indices. It was not possible earlier to achieve such good agreements between measured and calculated efficiencies of high- and mid-frequency gratings working in the short spectral ranges due to the lack of realistic, i.e., measured using the AFM technique, groove profile shapes, as it has been demonstrated in the present study. Today, using an appropriate AFM instrument and the respective method one has a possibility to determine with a superfine (atomic-scale) spatial resolution grating-like structures, i.e., their groove profiles including abrupt slopes and random nanoroughness. Moreover, such non-destructive AFM analysis is the only suitable one to apply to current production and evaluation of such complicated and expensive devices like as most of X-ray diffraction gratings are.
I thank David A. Content, John F. Seely, Tamara N. Berezovskaya, Vladislav A. Sharov for the information provided.
This work was partially supported by the Russian Foundation for Basic Research (RFBR) (Grant No. 20-02-00326) and the Russian Science Foundation (RSF) (Grant No. 19-12-00270) in the theoretical part.
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\\n"}]'},components:[{type:"htmlEditorComponent",content:'A significant number of working papers, early drafts, and similar work in progress are openly shared online between members of the scientific community. It has become common to announce one’s own research on a personal website or a blog to gather comments and suggestions from other researchers. Such works and online postings are, indeed, published in the sense that they are made publicly available. However, this does not mean that if submitted for publication by IntechOpen they are not original works. We differentiate between reviewed and non-reviewed works when determining whether a work is original and has been published in a scholarly sense or not.
\n\nThe significance of Peer Review cannot be overstated when it comes to defining, in our terms, what constitutes a published scientific work. Peer Review is widely considered to be the cornerstone of modern publishing processes and the key value-adding contribution to a scholarly manuscript that a publisher can make.
\n\nOther than the issue of originality, research misconduct is another major issue that all publishers have to address. IntechOpen’s Retraction & Correction Policy and various publication ethics guidelines identify both redundant publication and (self)plagiarism to fall within the definition of research misconduct, thus constituting grounds for rejection or the issue of a Retraction if the work has already been published.
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\n\nSome basic information about the editorial treatment of different varieties of prior publication is laid out below:
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\n\nAll submitted manuscripts originating from a previously published conference paper must contain at least 50% of new original content to be accepted for review and considered for publication.
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An Overview of Studies in Hematology"},signatures:"Youngchan Kim, Kyoohyun Kim and YongKeun Park",authors:[{id:"143622",title:"Prof.",name:"YongKeun",middleName:null,surname:"Park",slug:"yongkeun-park",fullName:"YongKeun Park"},{id:"143623",title:"Mr.",name:"Kyoohyun",middleName:null,surname:"Kim",slug:"kyoohyun-kim",fullName:"Kyoohyun Kim"},{id:"143624",title:"Mr.",name:"Sangyeon",middleName:null,surname:"Cho",slug:"sangyeon-cho",fullName:"Sangyeon Cho"}]},{id:"31178",doi:"10.5772/38961",title:"Physiological Factors in the Interpretation of Equine Hematological Profile",slug:"haematological-profile-of-the-horse-phisiological-factors-influencing-equine-haematology",totalDownloads:10715,totalCrossrefCites:15,totalDimensionsCites:35,abstract:null,book:{id:"1830",slug:"hematology-science-and-practice",title:"Hematology",fullTitle:"Hematology - Science and Practice"},signatures:"K. Satué, A. Hernández and A. Muñoz",authors:[{id:"125292",title:"Dr.",name:"Katy",middleName:null,surname:"Satué Ambrojo",slug:"katy-satue-ambrojo",fullName:"Katy Satué Ambrojo"}]},{id:"55356",doi:"10.5772/intechopen.68617",title:"Neutrophils in Rheumatoid Arthritis: A Target for Discovering New Therapies Based on Natural Products",slug:"neutrophils-in-rheumatoid-arthritis-a-target-for-discovering-new-therapies-based-on-natural-products",totalDownloads:2040,totalCrossrefCites:9,totalDimensionsCites:12,abstract:"Rheumatoid arthritis (RA) is a systemic autoimmune disorder with an important inflammatory component in joints. Neutrophils are the most abundant leukocytes in inflamed joints, and play an essential role in the initiation and progression of RA. Neutrophil effector mechanisms include the release of proinflammatory cytokines, reactive oxygen and nitrogen species (ROS and RNS), and granules containing degradative enzymes, which can cause further damage to the tissue and amplify the neutrophil response. Therefore, the modulation of neutrophil migration and functions is a potential target for pharmacological intervention in arthritis. The pharmacologic treatment options for RA are diverse. The current treatments are mostly symptomatic and have side effects, high costs, and an increased risk of malignancies. Because of these limitations, there is a growing interest in the use of natural products as therapies or adjunct therapies. Herbal products have attracted considerable interest over the past decade because of their multiple beneficial effects such as their antioxidant, anti-inflammatory, antiproliferative, and immunomodulatory properties. This chapter focuses on the role of neutrophils in the pathogenesis of arthritis and the action of substances from natural products as putative antirheumatic therapies.",book:{id:"5834",slug:"role-of-neutrophils-in-disease-pathogenesis",title:"Role of Neutrophils in Disease Pathogenesis",fullTitle:"Role of Neutrophils in Disease Pathogenesis"},signatures:"Elaine Cruz Rosas, Luana Barbosa Correa and Maria das Graças\nHenriques",authors:[{id:"64332",title:"Dr.",name:"Maria Das Graças",middleName:null,surname:"Henriques",slug:"maria-das-gracas-henriques",fullName:"Maria Das Graças Henriques"},{id:"197932",title:"Dr.",name:"Elaine",middleName:"Cruz",surname:"Rosas",slug:"elaine-rosas",fullName:"Elaine Rosas"},{id:"199677",title:"MSc.",name:"Luana",middleName:null,surname:"Correa",slug:"luana-correa",fullName:"Luana Correa"}]},{id:"46041",doi:"10.5772/57335",title:"An Insight into the Abnormal Fibrin Clots — Its Pathophysiological Roles",slug:"an-insight-into-the-abnormal-fibrin-clots-its-pathophysiological-roles",totalDownloads:3862,totalCrossrefCites:4,totalDimensionsCites:11,abstract:null,book:{id:"3836",slug:"fibrinolysis-and-thrombolysis",title:"Fibrinolysis and Thrombolysis",fullTitle:"Fibrinolysis and Thrombolysis"},signatures:"Payel Bhattacharjee and Debasish Bhattacharyya",authors:[{id:"88185",title:"Prof.",name:"Debasish",middleName:null,surname:"Bhattacharyya",slug:"debasish-bhattacharyya",fullName:"Debasish Bhattacharyya"},{id:"170045",title:"Ms.",name:"Payel",middleName:null,surname:"Bhattacharjee",slug:"payel-bhattacharjee",fullName:"Payel Bhattacharjee"}]},{id:"64230",doi:"10.5772/intechopen.81758",title:"The Biology and Therapeutic Applications of Red Blood Cell Extracellular Vesicles",slug:"the-biology-and-therapeutic-applications-of-red-blood-cell-extracellular-vesicles",totalDownloads:1367,totalCrossrefCites:6,totalDimensionsCites:10,abstract:"This chapter focuses on the biology of red blood cell extracellular vesicles (RBCEVs) in normal and diseased conditions, and the potential application of RBCEVs in treatment. Extracellular vesicles (EVs) refer to membranous vesicles secreted by cells into the extracellular environment. EV biology belongs to a rapidly developing field in biomedical sciences. EVs represent a natural mode of cell-to-cell communication, which makes them suitable for delivery of therapeutic agents, such as nucleic acids and proteins, in the body. In particular, RBCEVs feature a wide range of benefits in drug delivery as compared to extracellular vesicles derived from other cell types. In comparison to other delivery systems currently available, RBCEVs are nontoxic, low immunogenic, conveniently obtainable, and easy to use and store. Therefore, RBCEVs boast promising and exceptional advantages in overcoming various limitations of conventional therapeutics.",book:{id:"7181",slug:"erythrocyte",title:"Erythrocyte",fullTitle:"Erythrocyte"},signatures:"Daniel Xin Zhang, Theodoros Kiomourtzis, Chun Kuen Lam and Minh T.N. Le",authors:[{id:"267051",title:"Dr.",name:"Minh",middleName:null,surname:"Le",slug:"minh-le",fullName:"Minh Le"},{id:"276896",title:"Dr.",name:"Daniel Xin",middleName:null,surname:"Zhang",slug:"daniel-xin-zhang",fullName:"Daniel Xin Zhang"},{id:"276897",title:"Mr.",name:"Theodoros",middleName:null,surname:"Kiomourtzis",slug:"theodoros-kiomourtzis",fullName:"Theodoros Kiomourtzis"},{id:"276898",title:"Mr.",name:"Chun Kuen",middleName:null,surname:"Lam",slug:"chun-kuen-lam",fullName:"Chun Kuen Lam"}]}],mostDownloadedChaptersLast30Days:[{id:"66797",title:"Blood Transfusion Reactions",slug:"blood-transfusion-reactions",totalDownloads:2552,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Blood transfusion reaction/adverse transfusion reactions could be fatal/severe or mild, immediate or delayed, immunological or nonimmunological, and infectious or noninfectious, and attention is paid particularly to the incidence, possible causes and pathophysiology, clinical features, and management of each type with the aim of improving awareness and raising consciousness towards improving blood safety and judicious use of blood so as to forestall these blood transfusion reactions as much as possible. This chapter serves as a synopsis to adverse blood reactions, which are very common but apparently more often under-recognized and/or under-reported particularly in developing countries. This should sharpen the consciousness of all health practitioners involved in blood transfusion services towards taking measures at preventing transfusion reactions right from donor selection up to the infusion of blood into the recipients.",book:{id:"6905",slug:"blood-groups",title:"Blood Groups",fullTitle:"Blood Groups"},signatures:"John Ayodele Olaniyi",authors:[{id:"202764",title:"Dr.",name:"John",middleName:null,surname:"Olaniyi",slug:"john-olaniyi",fullName:"John Olaniyi"}]},{id:"49387",title:"Thalassemia — From Genotype to Phenotype",slug:"thalassemia-from-genotype-to-phenotype",totalDownloads:4802,totalCrossrefCites:2,totalDimensionsCites:3,abstract:"Thalassemia encompasses serious diseases with complex pathophysiology that is difficult to explain since it is considered a group of defects with similar clinical effects, still not a single disorder.",book:{id:"4729",slug:"inherited-hemoglobin-disorders",title:"Inherited Hemoglobin Disorders",fullTitle:"Inherited Hemoglobin Disorders"},signatures:"Ghada Y. El-Kamah and Khalda S. Amr",authors:[{id:"58735",title:"Prof.",name:"Ghada",middleName:null,surname:"El-Kamah",slug:"ghada-el-kamah",fullName:"Ghada El-Kamah"},{id:"176872",title:"Prof.",name:"Khalda",middleName:null,surname:"Amr",slug:"khalda-amr",fullName:"Khalda Amr"}]},{id:"51831",title:"Disorders Mimicking Myelodysplastic Syndrome and Difficulties in its Diagnosis",slug:"disorders-mimicking-myelodysplastic-syndrome-and-difficulties-in-its-diagnosis",totalDownloads:4475,totalCrossrefCites:1,totalDimensionsCites:6,abstract:"Myelodysplastic morphology of blood cells can be encountered not only in myelodysplastic syndrome (MDS) but also in nonclonal disorders like viral, bacterial, parasitic infections, juvenile rheumatoid arthritis, polyarteritis nodosa, immune thrombocytopenic purpura (ITP), iron deficiency anemia, megaloblastic anemia, dysgranulopoietic neutropenia, congenital neutropenia, cases with microdeletion 22q11.2, malignant lymphoma, after administration of granulocyte colony stimulating factor, chemotherapy, steroids, smoking, alcohol, posttransplantation, copper deficiency also, together with or without cytopenia. Absence of cytogenetic abnormality in 50–70% of cases with MDS, some overlapping morphological and/or pathophysiological features make it challenging to differentiate between MDS and other diseases/disorders like aplastic anemia, refractory ITP, copper deficiency. Transient genetic abnormalities including monosomy 7 in megaloblastic anemia; increased immature myeloid cells in bone marrow of cases with copper, vitamin B12, or folic acid deficiency in the setting of cytopenia and dysmorphism may also lead to the misdiagnosis of MDS. On the other hand, there are also cases of transient MDS. In this chapter, a literature is be presented to draw attention of the readers on the disorders that mimic MDS. Additionally, our personal experiences are also be shared. Awareness of disorders mimicking MDS may prevent over- or underdiagnosis of MDS.",book:{id:"5276",slug:"myelodysplastic-syndromes",title:"Myelodysplastic Syndromes",fullTitle:"Myelodysplastic Syndromes"},signatures:"Lale Olcay and Sevgi Yetgin",authors:[{id:"184156",title:"Prof.",name:"Lale",middleName:null,surname:"Olcay",slug:"lale-olcay",fullName:"Lale Olcay"}]},{id:"64871",title:"Diagnosis and Classification of Myelodysplastic Syndrome",slug:"diagnosis-and-classification-of-myelodysplastic-syndrome",totalDownloads:3165,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disorder characterized by morphological dysplastic changes in one or more of the major hematopoietic cell lines. MDS can present with varying degrees of single or multiple cytopenias including neutropenia, anemia and thrombocytopenia. Presentation of MDS can range from asymptomatic to life threatening. MDS diagnosis and classification present important challenges, particularly in the distinction from benign conditions. French-American-British (FAB) classification proposed a classification based on easily obtainable laboratory information and was recommended in early and as modified by guidelines of new classification of World Health Organization (WHO). The strategy of diagnostic laboratory in MDS depends on morphological changes and is based on existence of dysplastic changes in the peripheral blood and bone marrow including peripheral blood smear, bone marrow aspirate smear and bone marrow trephine biopsy. The correct morphological interpretation and the use of cytogenetics, immunophenotyping, immunohistochemistry and molecular analysis will give valuable information on diagnosis and prognosis.",book:{id:"7138",slug:"recent-developments-in-myelodysplastic-syndromes",title:"Recent Developments in Myelodysplastic Syndromes",fullTitle:"Recent Developments in Myelodysplastic Syndromes"},signatures:"Gamal Abdul Hamid, Abdul Wahab Al-Nehmi and Safa Shukry",authors:[{id:"36487",title:"Prof.",name:"Gamal",middleName:null,surname:"Abdul Hamid",slug:"gamal-abdul-hamid",fullName:"Gamal Abdul Hamid"},{id:"273724",title:"Dr.",name:"Safa",middleName:null,surname:"Shukry",slug:"safa-shukry",fullName:"Safa Shukry"},{id:"277511",title:"Dr.",name:"Abdulwahab",middleName:null,surname:"Al-Nehmi",slug:"abdulwahab-al-nehmi",fullName:"Abdulwahab Al-Nehmi"}]},{id:"70780",title:"Laboratory Diagnosis of β-Thalassemia and HbE",slug:"laboratory-diagnosis-of-thalassemia-and-hbe",totalDownloads:1338,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"β-Thalassemia and HbE, each, is a syndrome resulted from quantitative and qualitative defects of β-globin chain, respectively. In addition to history retrieve and physical examination, diagnosis of these disorders requires laboratory information. Laboratory tests that are conventionally performed to diagnose the β-thalassemia and HbE are classified into two groups, based on the purposes, including the screening tests and confirmatory tests. The screening tests are aimed to screen for carriers of the β-thalassemia and HbE, while confirmatory tests are the tests performed to definitely diagnose these disorders. This chapter will explain all of these tests, the information of which will be useful for those who are working and interested in the β-thalassemia and HbE.",book:{id:"8450",slug:"beta-thalassemia",title:"Beta Thalassemia",fullTitle:"Beta Thalassemia"},signatures:"Thanusak Tatu",authors:null}],onlineFirstChaptersFilter:{topicId:"183",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:87,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:98,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:27,numberOfPublishedChapters:287,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:139,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:0,numberOfUpcomingTopics:2,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!1},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:10,numberOfPublishedChapters:103,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:0,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!1},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,numberOfOpenTopics:4,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"7",title:"Biomedical Engineering",doi:"10.5772/intechopen.71985",issn:"2631-5343",scope:"Biomedical Engineering is one of the fastest-growing interdisciplinary branches of science and industry. The combination of electronics and computer science with biology and medicine has improved patient diagnosis, reduced rehabilitation time, and helped to facilitate a better quality of life. Nowadays, all medical imaging devices, medical instruments, or new laboratory techniques result from the cooperation of specialists in various fields. The series of Biomedical Engineering books covers such areas of knowledge as chemistry, physics, electronics, medicine, and biology. 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Dr. Koprowski has authored more than a hundred research papers with dozens in impact factor (IF) journals and has authored or co-authored six books. Additionally, he is the author of several national and international patents in the field of biomedical devices and imaging. Since 2011, he has been a reviewer of grants and projects (including EU projects) in biomedical engineering.",institutionString:null,institution:{name:"University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:3,paginationItems:[{id:"7",title:"Bioinformatics and Medical Informatics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/7.jpg",isOpenForSubmission:!0,editor:{id:"351533",title:"Dr.",name:"Slawomir",middleName:null,surname:"Wilczynski",slug:"slawomir-wilczynski",fullName:"Slawomir Wilczynski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035U1loQAC/Profile_Picture_1630074514792",biography:"Professor Sławomir Wilczyński, Head of the Chair of Department of Basic Biomedical Sciences, Faculty of Pharmaceutical Sciences, Medical University of Silesia in Katowice, Poland. His research interests are focused on modern imaging methods used in medicine and pharmacy, including in particular hyperspectral imaging, dynamic thermovision analysis, high-resolution ultrasound, as well as other techniques such as EPR, NMR and hemispheric directional reflectance. Author of over 100 scientific works, patents and industrial designs. Expert of the Polish National Center for Research and Development, Member of the Investment Committee in the Bridge Alfa NCBiR program, expert of the Polish Ministry of Funds and Regional Policy, Polish Medical Research Agency. Editor-in-chief of the journal in the field of aesthetic medicine and dermatology - Aesthetica.",institutionString:null,institution:{name:"Medical University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null},{id:"8",title:"Bioinspired Technology and Biomechanics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/8.jpg",isOpenForSubmission:!0,editor:{id:"144937",title:"Prof.",name:"Adriano",middleName:"De Oliveira",surname:"Andrade",slug:"adriano-andrade",fullName:"Adriano Andrade",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRC8QQAW/Profile_Picture_1625219101815",biography:"Dr. Adriano de Oliveira Andrade graduated in Electrical Engineering at the Federal University of Goiás (Brazil) in 1997. He received his MSc and PhD in Biomedical Engineering respectively from the Federal University of Uberlândia (UFU, Brazil) in 2000 and from the University of Reading (UK) in 2005. He completed a one-year Post-Doctoral Fellowship awarded by the DFAIT (Foreign Affairs and International Trade Canada) at the Institute of Biomedical Engineering of the University of New Brunswick (Canada) in 2010. Currently, he is Professor in the Faculty of Electrical Engineering (UFU). He has authored and co-authored more than 200 peer-reviewed publications in Biomedical Engineering. He has been a researcher of The National Council for Scientific and Technological Development (CNPq-Brazil) since 2009. He has served as an ad-hoc consultant for CNPq, CAPES (Coordination for the Improvement of Higher Education Personnel), FINEP (Brazilian Innovation Agency), and other funding bodies on several occasions. He was the Secretary of the Brazilian Society of Biomedical Engineering (SBEB) from 2015 to 2016, President of SBEB (2017-2018) and Vice-President of SBEB (2019-2020). 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