Worldwide prevalence of Behçet’s disease [24].
\r\n\tThe purpose of this book is to provide the readers with an understanding of the characteristics of the crisis itself, recognize the wide range and multi-layer of the crisis from a real situation, give ideas on how to minimize the damage, and find ways to increase resilience in the future. To adapt to the rapidly and diversely changing world, the necessary experience and appropriate management for all kinds of crisis issues will be discussed as well. At the same time, it is intended to suggest elements such as verified scientific and empirical knowledge and applicable technologies; more effective risk management operation; modeling of the risks, manuals, management plans, and strategies.
\r\n\t
Behçet’s disease (BD) is described as a severely debilitating chronic, recurrent, multisystem vascular inflammatory disorder characterised by the triad of oral and genital ulceration and ocular lesions. This exemplary presentation would have been probably first identified by Hippocrates [1, 2]. Even though Behçet’s disease was first identified by the father of medicine in the fifth century BC, there were no literature representations for this entity till 1930, and then a Greek ophthalmologist Benediktos Adamantiades presented one of his case of relapsing eye lesions associated with genital ulceration and arthritis in a 20-year-old male; since then entity has been added with a synonym “Adamantiades-Behçet’s disease” [3, 4, 5, 6]. Further to its classic expression of orogenital ulceration and ocular lesions, the conditions seem to involve the musculoskeletal system, nervous system, gastrointestinal tract, vascular beds, urogenital tract and cardiopulmonary system, so Behçet’s disease have a high morbidity and mortality particularly in males with early age onset [7, 8]. The self-limiting inflammation and the relapsing episodes of clinical manifestations are the hallmark of Behçet’s disease [9]. Frequency and span of regression are uncertain and show no distinguishable pattern of onset.
\nAlthough Behçet’s disease has a worldwide distribution, it is more rampant in Turkish population, where the prevalence is about 421 cases per 100,000 and 13 to 20 cases per 100,000 population in China, Korea, Japan and the Middle East [10, 11]. Behçet’s disease is most commonly diagnosed in the second and third decades of life especially during the reproductive years and shows a female predilection among Europeans. Behçet’s disease rarely occurs prior to puberty and after the fifth decade of life. Behçet’s disease developing in early age has shown to have severe clinical manifestations and mortality. Familial occurrences have been reported in various literatures but are unusual, and the aetiology of Behçet’s disease remains cryptic [12, 13, 14, 15, 16, 17, 18]. The widely accepted hypothesis is that of an inappropriate inflammatory response provoked by an infectious agent in a genetically liable host [19].
\nDiagnosis of Behçet’s disease is based on the criteria developed by the International study group (ISG) in 1990 and International Criteria for Behçet’s Disease (ICBD) [20]. The ICBD was developed with the intention of bettering the ISG criteria that did not consist of nervous system, vascular and gastrointestinal involvement that are severe but rather infrequent complications of Behçet’s disease. A recent study conducted in the United Kingdom has compared the efficacy of ISG and ICBD diagnostic criteria among their patients with Behçet’s disease and concluded that the sensitivity was higher for ICBD than ISG criteria, but the specificity of ICBD was much lower than the ISG criteria [20, 21, 22].
\nManagement is aimed to alleviate symptoms, resolve inflammation, restrain tissue damage, dwindle frequency and severity and avoid lethal complications. A multitude of treatment modalities have been proposed for managing Behçet’s disease ranging from anti-inflammatory to immunomodulators and biologic monoclonal antibodies. Detrimental ramifications are a main concern since it requires long-term medication [8].
\nBehçet’s disease is observed to have a worldwide distribution. However, it is seen commonly among the inhabitants of the historic Silk Road, which was supposed to be an old trading route that linked Japan and China in the Far East to the Mediterranean Sea, including countries such as Turkey and Iran. Therefore, Behçet’s disease is also known by the synonym “Silk Road disease” [23]. Behçet’s disease has a highest prevalence rate in Turkey, where the estimated prevalence is about 421 per 100,000 population followed by Iran, Israel and Japan [24]. It is rarely reported in African countries and the USA [23] as well as Australia, where the prevalence remains unknown but with an annual incidence of 0.6% (Table 1) [25].
\nPrevalence per one lakh population | \nCountry | \n
---|---|
Turkey | \n421 | \n
Iran | \n80 | \n
Saudi Arabia | \n20 | \n
Iraq | \n17 | \n
Israel | \n15.2 | \n
Japan | \n13.5 | \n
France | \n7.1 | \n
USA | \n5.2 | \n
Sweden | \n4.9 | \n
Germany | \n2.26 | \n
Portugal | \n1.53 | \n
UK | \n0.64 | \n
Worldwide prevalence of Behçet’s disease [24].
Two studies conducted in Korea and Turkey in 2016 and 2017 reported the prevalence of Behçet’s disease. A study conducted in Korea estimated the prevalence of Behçet’s disease, and change in prevalence rate over time from the Korean healthcare big data that consists of medical institution claims data concerning diagnosis, prescription medicines and surgical treatment and represents the total population. The database was reviewed for patients diagnosed to have Behçet’s disease during the year 2011 and 2015. The diagnosis was based on the Korean Standard Classification of Diseases (KCD). The estimated prevalence was about 35.0 per 100,000 population which was a little more than the previously reported prevalence of 30.2 per 100,000 in Korea. The change in prevalence rate was also estimated during the time period of 2011 and 2015 and concluded that there is a creeping escalation in the annual prevalence rate between 2011 and 2015. The prevalence rate was 32.8 per 100,000 in 2011, 34.0 per 100,000 in 2012, 34.6 per 100,000 in 2013, 35.5 per 100,000 in 2014 and 35.7 per 100,000 in 2015. The prevalence would have been more since patients with milder form of the disease have not come for treatment. Females had a higher prevalence, with a female-to-male ratio of 1:0.54 in 2011 and 1:0.56 in 2015 [26].
\nAnother study conducted in Northern Turkey showed a prevalence of Behçet’s disease in 600/100,000 population who have crossed their second decade of life and is considered as the highest prevalence reported in the literature so far [27]. Nonetheless this conclusion seems to be biased since there are methodological errors. Patients were randomly selected from the 52 urban and 33 rural general practices of a city and are invited for an examination and interview by three dermatologists. As per the authors, the invited sample would well represent the whole population since all individuals are recorded in general practices. Eye examination and pathergy test were performed in suspected individuals. Individuals compatible to ISG criteria were diagnosed as Behçet’s disease. However, the total number of individuals who were invited for interview was not mentioned. Authors reported that 2325 of 2428 individuals interviewed were included in the study, of which 1290 were females and 1035 were males. Symptomatic individuals may have responded to the invitation, which might have led to a higher prevalence estimate. Authors have also reported increased prevalence of Behçet’s disease in females (860/100,000) compared to males (140/100,000) (p = 0.022) which does not correlate with the previous studies conducted in Turkey, since they concluded no significant gender predilections [27].
\nA recent meta-analysis that included 45 prevalence studies suggested that even though there was clearly a wide variation across countries, the overall prevalence of Behçet’s disease were 10.3/100,000. The estimated prevalence was 119.8/100,000 for Turkey, 31.8/100,000 for the Middle East, 4.5/100,000 for Asia and 3.3/100,000 for Europe [28]. A meta-regression analysis showed that classification criteria, study period or reference type had hardly any effect and study design was the deciding factor for Behçet’s disease prevalence in these studies. The authors have also suggested that true geographic variations and different study methods are the possible factors responsible for the large variation in Behçet’s disease prevalence across countries.
\nTwo studies conducted in Korea reported on the clinical manifestations of Behçet’s disease patients according to gender [29, 30]. The first study was carried out by a rheumatology department of a university hospital in Turkey, which assessed the prevalence between male and female with Behçet’s disease in a retrospective chart review of 329 patients [29]. The study included patients who fulfilled the ISG criteria. Data on demographic features of the patients, family history, age of onset, manifestations of Behçet’s, positive pathergy test and HLA-B51 were retrieved from patient charts. Among the 329 patients, 199 (60.4%) were males. A family history of Behçet’s disease was reported by 9.7% of the patients and a family history of oral ulcers by 22.5%. Early onset was observed in patients with a positive family history; this phenomenon is termed as genetic anticipation which had already been seen in previous studies [31]. Female patients had an early onset compared to males (23.0 vs. 25.2 years, p < 0.05). Eye lesions were more common among males (42.2 vs. 29.2%, p = 0.014). Vascular involvement was also more common among in males (44.7 vs. 15.3%, p < 0.001), whereas joint involvement and headache were common among women (70.0 vs. 49.2%, p < 0.001 for joint involvement and 60.0 vs. 36.2%, p < 0.001 for headache). Frequency of genital ulcers, nodular lesions, papulopustular lesions and nervous system involvement was similar among males and females. Pathergy test was positive in 48.7% of the patients (52.4% among male and 43.4% among female, p = 0.316). HLA-B51 was positive in 44.1% of Behçet’s disease patients, and the frequency was lower among men, but the difference was not that significant (38.8 vs. 50.6%, p = 0.106). The second study was conducted in Korea, which was a retrospective chart review of 193 patients, which analysed gender, age of onset of Behçet’s disease and HLA-B51 [30]. The study showed that there is an increased prevalence in females (67%), whereas other parameters like the mean age at onset, the mean disease duration, positive pathergy test and positive HLA-B51 were similar in both males and females. Genital ulcers, peripheral joint involvement and inflammatory back pain were more common in females, while skin lesions were more frequent in males. In total, major organ involvement was present in 39% of the patients (uveitis, 27%; nervous system involvement, 7%; vascular involvement, 4% and gastrointestinal involvement, 11%), with similar frequency in both the genders. When clinical findings were compared based on onset of disease, patients with late onset (>40 years) had more nervous system involvement than those with an early onset (15.9 vs. 4.2%, p = 0.007).
\nLike the previous study, HLA-B51 positive patients had a history of early disease onset, but less nervous system (17.2 vs. 2.5%, p = 0.02) and gastrointestinal system (20.7 vs. 2.5%, p = 0.01) involvement than patients with negative HLA-B51 [32, 33].
\nA Japanese study conducted in 2015 analysed the change in disease phenotype over time among Behçet’s disease patients treated in seven hospitals in a district in mid-Japan between 1991 and 2015. Patients fulfilled the 1987 revised diagnostic criteria of the Behçet’s disease research committee; the Ministry of Health, Labour and Welfare of Japan was included in the study [34, 35]. This criterion classified the manifestations of Behçet’s disease into major and minor symptoms. Major symptoms include recurrent aphthous oral ulcers, skin lesions, ocular inflammation and genital ulcers, and minor symptoms include arthritis, intestinal ulcers, epididymitis, vascular lesions and neuropsychiatric disease.
\nThose who have all four major symptoms during the clinical course are classified as complete, whereas those who have three major symptoms, two major and two minor symptoms, typical recurrent ocular inflammation and one or more major symptoms or typical recurrent ocular inflammation and two minor symptoms are classified as incomplete Behçet’s disease. Patients were divided into three groups as group A, diagnosed before 2000; group B, diagnosed between 2000 and 2007; and group C, diagnosed after 2008. Authors observed a decrease in the number of patients with complete disease over time, suggesting a trend for milder disease in more recent years which could be due to usage of newer medicaments and awareness about the disease. The male-to-female ratio and the age of onset of disease were not changed over time, whereas the frequency of genital ulcers and HLA-B51 positivity decreased and gastrointestinal involvement frequency increased [34, 35].
\nAdditionally, individuals migrated from countries with high prevalence of Behçet’s disease to countries with less prevalence rate were shown to have less risk of developing disease [36, 37]. Prevalence of Behçet’s disease among Turkish individuals in Germany is about 21/100,000, which, although higher than that of the German population, remains inferior to prevalence in Turkey [38].
\nAlthough Behçet’s disease is rare in Africans, two series have been published recently based on studies conducted in Nigeria and Dakar from the year 2007 to 2011. Based on the observation by Italian authors, the prevalence of Behçet’s disease was found to be higher among immigrants when they analysed its prevalence among patients of Italian and non-Italian origin living in these areas.
\nA study conducted in the Netherlands estimated the prevalence of Behçet’s disease in patients with diverse ethnic origins residing in the Rotterdam area showed a prevalence of 1/100,000 population among Dutch Caucasians, 39/100,000 among Moroccans and 71/100,000 among Turks, suggesting that the prevalence among Moroccans is the same as in their countries of origin [39, 40].
\nPeculiar geographical distribution, familial aggregation, polymorphisms in genes that control immune responses and correlation with HLA-B51 class I antigen are the four factors that are considered to contribute to Behçet’s disease susceptibility. Ohno in 1973 described the association of BD with HLA-B5 [39]. They demonstrated that HLA-B5 includes HLA-B51 and HLA-B52 as it has a heterogeneous composition. In major histocompatibility locus, HLA-B51 and HLA-B5701 were associated with the pathogenesis of the disease, mainly among populace alongside of ancient Silk Road. Although associations with HLA-A and HLA-C have been described, they are non-specific and require confirmation. Other MHC genes such as TNF and MHC class I genes (MICA) are under study; the exact mechanism has not been fully understood. The association with HLA-B51 appears to be important in neutrophil activation. However, the presence of HLA-B51 alone is not ample to explain the manifestations of Behçet’s disease. A case series of Iranian patients showed association with HLA-B35, HLA-B51, HLA-B52 and HLA-Bw4. Supplementary studies suggest associations with HLA-B15, HLA-B27, HLA-B57 and HLA-A26 [40].
\nResearches focused on single-nucleotide polymorphisms (SNPs) revealed that SNP which is in the HLA-B region between HLA-B and MICA genes is responsible for the relationship between HLA-B51 and Behçet’s disease. The epistatic interactions with endoplasmic reticulum-associated aminopeptidase 1 (ERAP-1) has also been studied, and the authors suggested that the interaction of ERAP-1 and HLA-B has also been consistent, and these cytokines were apparently high in the peripheral blood mononuclear cells of patients with Behçet’s disease compared to the control group. Another conclusion was the unbalanced suppressor of cytokine signalling expression in patients with Behçet’s disease compared to controls [41].
\nA Chinese study stated that the polymorphisms of NOS3/rs1799983, a nitric oxide synthase gene, were found to be associated with the disease and the involvement of CD16 and CD11c in Behçet’s disease susceptibility. Mutations in the familial Mediterranean fever (MEFV) gene were suggested by a meta-analysis of 8 studies which analysed 2538 patients and 2792 healthy controls. Researches also suggested the associations of Toll-like receptors 7 (TLR7) and other nucleic acid-sensing genes of innate immunity-like inflammatory pathways such as IFI16 (a dsDNA cytosolic sensor and mediator of the AIM2-dependent inflammatory pathway) found to influence Behçet’s disease susceptibility [39]. Epigenetic studies with inverted repeat sequences (IRS) demonstrated that methylation level of IRS elements may influence the pathogenesis of the Behçet’s disease. Researches were done on genes related to apoptosis, but the results were not conclusive [41].
\nA multitude of factors that indicate the interaction between environmental, innate and adaptive immunity in the development of the disease has been already discussed in the Genetics section. Various researches have studied about the role of bacterial and viral agents in the development of Behçet’s disease, but the results were inconclusive.
Matzinger suggested the danger model, which occurs due to a continuous autoimmune cascade resulting from signals emitted by the affected cells of the host which will override the external stimulus. T cells and other antigen-presenting cells (APC) would command the process, which would be perpetuated on a favourable genetic terrain. Damage by a non-self-entity would trigger permanent aggression by activating an uncontrolled adaptive response. Because of their similarity to other pathogenic proteins, heat shock proteins (HSP60) could be involved. This adaptive reaction to external stimuli would persist in the permanent pathogenic presence via autoantigens that would activate dendritic T cells and B cells [40]. Thus, overexpression of proinflammatory cytokines especially Th1 and Th17 and probably association with genetic susceptibility may be the contributing factor for the increased inflammatory reaction in Behçet’s disease. Stimulated lymphocytes would activate neutrophils and endothelial cells, and HSPs would probably trigger innate and adaptive immune responses. Hypersensitivity to
Many studies have demonstrated the presence of IFN-gamma and IL-12 in peripheral blood of Behçet’s disease patients suggesting involvement of TH1 cells. Elevated IL-1, IL-6, IL-18, TNF-alpha and chemokines would reflect the activation of innate and adaptive immune systems. Neutrophils are hyperactivated with increased phagocytosis, chemotaxis, superoxide and lysosomal enzyme production. Lymphocytes have also shown abnormal functions such as clonal expansion of autoreactive T cells specific for heat shock protein 60 peptides. In addition, gamma-delta T cells are abundant in the blood and mucosal lesions of the affected individuals. Researchers have concluded that the interaction between T cells, neutrophils and antigen-presenting cells probably contributes to the pathogenesis of Behçet’s disease [40].
\nBehçet’s disease is a form of systemic vasculitis which affect almost all vascularized systems (Table 2) and is characterised by episodes of relapses and remissions [9, 43, 44].
\nManifestation | \nPrevalence | \nPrognosis | \nComments | \n
---|---|---|---|
Oral ulcers | \n47–83% | \nFavourable | \nAppear in all patients during the disease course | \n
Genital ulcers | \n57–93% | \nFavourable | \nLesion will leave a scar | \n
Ocular lesions | \n30–70% | \nPoor | \nMore frequent in males. Has high morbidity | \n
Cutaneous lesions | \n38–99% | \nFavourable | \nErythema nodosum more frequent in females | \n
Joint involvement | \n45–60% | \nFavourable | \nNondeforming and nonerosive | \n
Cardiovascular involvement | \n7–49% | \nPoor | \nMore frequent in males, high morbidity and mortality | \n
Neurological involvement | \n5–10% | \nPoor | \nMore frequent in males, high morbidity and mortality | \n
Gastrointestinal involvement | \n3–26% | \nPoor | \nMore frequent among Japanese | \n
Manifestations of Behçet’s disease.
The triad of oral aphthae, genital ulcers and ocular lesions specifies the disease pattern even though Behçet’s disease has other multisystem involvement and several clinical manifestations.
\nChildren exhibit more frequent perianal ulceration and more severe course of chorioretinitis and less frequent genital ulcers and vascular involvement [44, 45].
\nA meta-analysis of 18 articles which was performed by Horie et al. to assess the association between HLA-B51 and the ocular manifestations of Behçet’s disease among various ethnic group studies from Middle and Far East suggested that there was a strong association between HLA-B51 expression and ocular involvement, whereas studies from North Africa and Europe showed no association [46].
\nAccorinti et al. investigated demographic and clinical trends of 385 Behçet’s disease patients with uveitis seen over 44 years in a referral unit at Sapienza University in Rome, Italy. The cohort was divided into cohort 1, which included the patients seen from 1968 to 1992, and cohort 2 included the patients seen during 1993 and 2011. Compared to the cohort 1, the cohort 2 has more female patients, more patients with milder disease (more frequent isolated anterior uveitis, less frequent hypopyon) and more immunosuppressive use. Ocular complications such as optic atrophy, maculopathy and retinal neovascularisation and retinal detachment were significantly more common in cohort 1. The visual acuity at final evaluation was better in the second cohort. When considered both the cohorts, more severe findings were observed in males. From the above findings, the authors concluded that timely and aggressive management reduces ocular complications and facilitates better prognosis [47].
\nEven though uveitis is the common ocular pathology in Behçet’s disease, it is not a common cause of uveitis. The highest incidence of uveitis is reported by Mishima S from Japan [48], where it constitutes about 25%, but it is much rarer in other countries such as Brazil, where the incidence is 2% [49], and India, where the incidence is 1% reported by Sen DK from a study conducted in 94 Indian children [50]. The classical feature of Behçet’s disease is recurrent, acute anterior uveitis associated with hypopyon. Other ocular manifestations seen in Behçet’s disease include necrotizing vascular lesions involving the retina and the optic nerve. These manifestations may be unnoticed because of severity of the anterior segment reaction and commonly include macular oedema, retinal periphlebitis and periarteritis, thrombosis of the vessels and retinal or vitreous haemorrhages which are frequently observed in males with Behçet’s disease [51, 52].
\nRecurrent oral ulcers are one of the earliest manifestations of Behçet’s disease in around 47–86% of patients and are seen in almost all patients during their clinical course [53]. Other symptoms may at times take years to appear after the onset of disease. Oral ulcerative lesions usually manifest as a round- or oval-shaped ulcer with discrete erythematous border with a greyish-white pseudomembrane or a central yellowish fibrinous floor and grow rapidly from a flat ulcer to a deep sore [9]. They may occur as single ulcers or as numerous [9, 53]. Oral ulcers most commonly affect the gingival and buccal mucosa, tongue and lips yet may also appear in the soft and hard palates, pharynx and tonsils [9]. Minor ulcers which are less than 1 cm in diameter heal without scarring over a period of 1 to 2 weeks, whereas major ulcers which are more than 1 cm in diameter are more painful and heal within 2–6 weeks. Herpetiform ulcers occurring in recurrent crops of small ulcers that are 0.2–0.3 cm in diameter are painful and may coalesce to form large ulcers. Treatment is usually symptomatic, and prognosis of oral ulcerations is favourable [18, 53].
\nThe most commonly seen cutaneous manifestations are erythema nodosum and pseudofolliculitis, in which erythema nodosum is manifested as painful multiple subcutaneous nodules that vary in size and colour, whereas pseudofolliculitis (pustulosis) appears as a dome-shaped sterile pustule on a round reddish edematous base that looks like acne vulgaris [54]. Although these are commonly seen on the lower extremities, it can be seen throughout the body [55]. The pathergy reaction is included in the criteria for the diagnosis of Behçet’s disease. Although more than 50% of patients from Turkey and Japan had a positive pathergy test, it is rarely observed in patients from Northern Europe, the USA and Australia [56, 57]. It used to be an important diagnostic criterion for Behçet’s disease; however, the frequency of the pathergy phenomenon was reported to decrease during the recent years [58]. Subcutaneous thrombophlebitis is often confused with lesions of erythema nodosum; the former is manifested as tender erythematous nodules with a linear arrangement in most case. The lesions may relocate depending on the vascular segment involved [59].
\nCardiac involvement is a rare finding in patients with Behçet’s disease. Behçet’s disease affects arteries, veins as well as the heart. Cardiovascular features have been reported to affect 7–49% of patients, more frequently in males. They occur 3–16 years after the onset of Behçet’s disease. Cardiac involvement in Behçet’s disease patients was first described by Mirone et al. in 1958 as a case of paroxysmal fibrillation and heart block. In 1963, Oshima et al. described a case of myocardial infarction complicated by incomplete right bundle-branch block [60]. Since then different types of cardiovascular lesions, including pericarditis, atrial thrombus, complex ventricular arrhythmia, myocardial infarction, heart block and sudden death, have been reported in association with Behçet’s disease [61]. Dong Soo et al. in 1998 reported a case of superior vena cava syndrome caused by Behçet’s disease in a 40-year-old man with recurrent oral aphthous ulcers and skin rashes on the anterior chest wall [62].
\nNeurological involvement in Behçet’s disease, the neuro-Behçet’s disease, occurs very rarely and only in 5–10% of patients. It is frequently seen in males [63]. It usually occurs around 5 years after the onset of the disease and is associated with long-term morbidity and mortality [9]. Neuro-Behçet’s disease can be parenchymal, nonparenchymal or mixed brain disease, in which the parenchymal brain disease affects the brainstem and/or basal ganglia and is correlated with a poor prognosis, whereas nonparenchymal also known as vasculo-Behçet’s disease or angio-Behçet’s disease is characterised by subsets of cerebral venous thromboses, dural venous sinus thrombosis, arterial vasculitis and aseptic meningitis and comprises the most devastating symptom category of Behçet’s disease with high mortality [63, 64]. A mixed parenchymal and nonparenchymal disease has also been reported but is very rare. Infrequent clinical manifestations like epilepsy, stroke, brain tumour-like neuro-Behçet’s disease, acute meningeal syndrome, movement disorders, optic neuropathy, spinal cord involvement and asymptomatic and subclinical neurological involvement have also been reported [65, 66]. Meningitis, neurological deficits including motor disturbances and brainstem symptoms and psychiatric symptoms including personality changes develop in patients with neuro-Behçet’s disease are considered as a classic finding [18, 63]. These symptoms are associated with disease exacerbations and gradually cause disability and unfortunately are irreversible [18]. At late stages, dementia develops in approximately one-third of patients with neuro-Behçet’s disease.
\nGastrointestinal involvement was observed in 3–26% of patients and varies among different populations [38, 39]. It is much more frequent in Japan than in the Middle East and the Mediterranean region [1, 2, 3]. Mucosal inflammation and ulceration can occur anywhere in the gastrointestinal tract but typically in the ileocecal region. Other rarely involved sites include the oesophagus, ascending colon and transverse colon [18, 19, 67]. Clinical symptoms include anorexia, vomiting, dyspepsia, diarrhoea, melena, abdominal pain and, less frequently, perforation requiring surgical intervention [68]. Due to the similarity in intestinal and extraintestinal symptoms, it is tough to differentiate Behçet’s disease from inflammatory bowel disease; however, the presence of granulomata can be used to confirm inflammatory bowel disease [66].
\nJoint involvement is common in patients with Behçet’s disease seen in almost half of patients. It presents as an initial manifestation seen long before the commencement of other features of BD [55]. Erosive, non-deforming oligoarthritis typically involving the knees, ankles and wrists is seen in most of the Behçet’s disease patients. Rarely, it can present as sacroiliitis or erosive arthritis. Myopathy has also been reported by Arkin in 1980 [69, 70, 71, 72].
\nVasculitis is one of the classic signs in Behçet’s disease, and the typical finding is deep vein thrombosis. Thrombophlebitis occurs generally in the first year after onset of Behçet’s disease, and relapses are frequent. Vasculitis can affect both the veins and arteries and capillaries although venous involvement is more common [55]. Venous thrombosis may occur at any site and can even involve large vessels like the inferior vena cava, the superior vena cava and the pulmonary artery. [55]. Arterial involvement is seen in 3–5% of cases [73]. Aneurysm formation is found to be the foremost manifestation, and the affected patients can be asymptomatic [74]. Vascular surgery is mandatory, but relapse is a frequent concern [55].
\nPulmonary manifestations are rare in patients with Behçet’s disease. Haemoptysis is the only reported manifestation, but it can be massive and fatal [74].
\nThe diagnosis of Behçet’s disease relies purely on its clinical manifestation since it lacks specific biological test, so diagnosis with clinical symptoms is challenging, especially due to non-concomitant symptoms. Hence different diagnostic criteria have been developed for the determination of Behçet’s disease. In 1990, an ISG for Behçet’s disease was formed by a group of researchers [21]. The International Study Group developed a set of classification criteria which is designed for research studies, which in many instances is used for diagnosing. The features were defined as the presence of specific symptoms as seen in Table 3. Oral ulceration along with any other two symptoms is said to be diagnostic [75]. The capability of the ISG criteria as a diagnostic tool has been questioned [56]. An international team which includes 27 countries was formed to evaluate and reassess the ISG criteria, and a new ICBD was developed that include the major criteria consisting of oral aphthosis, genital aphthosis and ocular lesions which were each given 2 points, whereas 1 point was assigned to the skin lesion, neurological manifestation, vascular manifestation and positive pathergy test (which is optional and not included in the primary criteria due to geographic variation and its declining sensitivity and increased specificity) [58, 75]. Higher sensitivity of the ICBD was reported as it aided in earlier diagnosis and hence earlier treatment and thereby better prognosis [75]. However, the delay between the onsets of major manifestations may be decades needs to be considered [76]. Inflammatory markers such erythrocyte sedimentation rate (ESR) and C-reactive protein have no longer been recognised as accurate or specific for the disease activity (Table 4).
\nRecurrent oral ulcerations | \nMinor aphthous, major aphthous or herpetiform ulceration observed by physician or patient, which recurred at least three times in one 12-month period | \n
Plus any two of the following | \n|
Recurrent genital ulceration | \nAphthous ulceration or scarring observed by physician or patient | \n
Eye lesion | \nAnterior uveitis, posterior uveitis or cells in vitreous on slit lamp examination or retinal vasculitis observed by ophthalmologist | \n
Skin lesions | \nErythema nodosum observed by physician or patient, pseudofolliculitis or papulopustular lesions or acneiform nodules observed by physician in post adolescent patients not on corticosteroid treatment | \n
Positive pathergy test | \nRead by a physician at 24–48 hours | \n
The international study group criteria for Behçet’s disease [21].
Symptoms | \nPoints | \n
---|---|
Oral aphthosis | \n2 | \n
Genital aphthosis | \n2 | \n
Ocular lesion | \n2 | \n
Skin lesion | \n1 | \n
Neurological manifestation | \n1 | \n
Vascular manifestation | \n1 | \n
Positive pathergy test | \n1b | \n
International criteria for Behçet’s disease [75].
Investigations for Behçet’s disease include routine total blood count; renal, liver and bone profile; inflammatory markers, including C-reactive protein and erythrocyte sedimentation rate; urine analysis; chest X-ray; coeliac screen; stool sample; autoimmune screen; coagulation profile and antiphospholipid antibodies; mouth and genital ulcer swab and culture; and occasionally eye swab. Other investigations that may be required include oral biopsy and direct immunofluorescence to exclude orofacial granulomatosis and bullous dermatosis. Vulval biopsy is indicated to exclude lichen sclerosis).
\nDoppler studies, CT or MRI brain and spinal cord, magnetic resonance venography, computerised tomographic venography, magnetic resonance angiography, computerised tomography angiography to evaluate neurologic and vascular disease; CSF studies, electro encephalogram, electromyography, nerve conduction study, 18 F fluoro2-deoxyglucose positron emission tomography, with CT/MRI localisation (for early inflammation in large vessel vasculitis). Musculoskeletal BD—synovial fluid analysis, X-ray, ultrasound or MRI to evaluate joints. Skin biopsy and immunofluorescence for cutaneous involvement. Cardiac BD—electrocardiogram, echocardiogram in case of cardio vascular involvement chest CT to assess mediastinal diseases, fibrosing mediastinitis, aneurysms, pleural effusions, complications of venous thrombosis and collaterals. Stool sample for faecal calprotectin, endoscopy and biopsy if there is Gastrointestinal involvement. Ocular BD—optical coherence tomography, visual evoked potentials, fluorescein angiogram, Schirmer’s test, intraocular fluid culture to exclude infections in Behçets patients with ocular involvement. Cystoscopy and kidney, urinary bladder CT for urological disease [7].
\nThe multisystem involvement in Behçet’s systems alarms the requirement of a teamwork from different medical specialties such as oral medicine, ophthalmology, dermatology, rheumatology, neurology, cardiology and gastroenterology for its management. The main objective of management of Behçet’s disease is to induce and maintain remission and improve the patient’s quality of life, preventing irreversible damage and exacerbation of mucocutaneous and articular disease [77, 78]. Since Behçet’s disease has plethoric expressions, treatment plan may vary depending on severity, organ affected, age of disease onset, disease duration and frequency of recurrences [59].
\nThe European League Against Rheumatism (EULAR) formed a committee in 2008 to develop an evidence-based recommendation for the treatment modalities of Behçet’s disease [78]. Suggestions regarding ocular and mucocutaneous diseases and arthritis are primarily evidence-based, but recommendations on neurological, vascular and gastrointestinal involvement relied on observational studies, retrospective analyses and expert opinion [78].
\nTreatment of Behçet’s disease is mainly based on the suppression of the inflammatory attack using immunomodulatory agents such as corticosteroids, azathioprine or interferon 𝛼 [78]. The primary line of management of mucocutaneous lesions in Behçet’s disease is colchicine (1 mg/day). NSAID is usually sufficient for joint manifestations [54]. Clinicians should keep in mind the neurotoxicity of cyclosporine A while prescribing it to any patient with neurologic problems for treating vascular involvement and refractory eye disease [54]. Biologic agents are the only option if the disease seems to be resistant to treatments [78]. Suggested management options are summarised in Tables 5 and 6.
\nManifestations | \nTreatments | \n
---|---|
Mild mucocutaneous lesions | \nTopical steroids | \n
Moderate to severe mucocutaneous lesions | \nInitial: systemic steroid, colchicine | \n
Refractory case: azathioprine, interferon𝛼 | \n|
Ocular lesions | \nInitial: systemic steroid + azathioprine | \n
Refractory case: first cyclosporine A + steroid + azathioprine Second interferon 𝛼+/− systemic steroid | \n|
Arthritis | \n(First) colchicine nonsteroidal anti-inflammatory drug, (second) azathioprine, interferon 𝛼 | \n
Vascular: deep venous thrombosis | \nAzathioprine, cyclosporine A, cyclophosphamide (larger vessels) | \n
Vascular: arterial aneurysm | \nCyclophosphamide + systemic steroid | \n
Neurological | \nCyclophosphamide (drug of choice) | \n
Gastrointestinal | \nSystemic steroid, sulfasalazine, azathioprine | \n
Disease-modifying drugs (DMDs) | \nDosage | \n
---|---|
Azathioprine | \n2–3 mg/kg/day | \n
Mycophenolate mofetil | \n2–3 g/day | \n
Methotrexate | \n20–25 mg/week | \n
Tacrolimus | \n4–8 mg/day | \n
Ciclosporin | \n2–5 mg/kg/day | \n
Sulfasalazine | \n2–3 g/day | \n
Dapsone | \n2–3 mg/kg/day | \n
Thalidomide (exceptional use) | \n50–300 mg/day | \n
Colchicine | \n0.5–2 mg/day | \n
Prednisolone | \nVariable dose (depending on indication and stage of treatment) | \n
Cyclophosphamide | \n15 mg/kg (vasculitis regimens) | \n
Infliximab | \n5 mg/kg at 0, 2 and 6 weeks then once every 8 weeks | \n
Adalimumab | \n40 mg every 2 weeks | \n
Etanercept | \n50 mg/week | \n
Certolizumab | \n400 mg at 0, 2 and 4 weeks then once every 4 week | \n
Rituximab | \n1 g at 0 and 2 weeks | \n
Interferon α | \nVarious regimens for Roferon A and pegylated interferon α 2b | \n
Alemtuzumab | \n3 mg (day 1), 10 mg (day 3), 30 mg (day 5), 30 mg (day 8), 30 mg (day 10) and 30 mg (day 12) | \n
Disease-modifying drugs used in Behçet’s disease [7].
Behçet’s disease is a chronic, relapsing vasculitis with multisystem involvement with considerable morbidity and mortality. There exists a delay in the diagnosis of Behçet’s disease since it lacks a specific diagnostic test and biomarkers. Another area to be focussed on is to develop a more effective disease activity score. Researches are on the go to explore more about the disease’s pathophysiology which may aid in early diagnosing and effective treatment planning.
\nWe thank Prof Dr. Sobha Kuriakose, Dr. Sarika S. Kamal, Dr. Sumal V. Raj, Dr. Nithin V. S and Dr. Deena C. Thomas, Dr. Alaka Subodh and Adithi S. A for critically analysing this manuscript.
\nAs early as the 1970s, Maxwell revealed that electromagnetic waves can carry momentum in his famous electromagnetic field theory. When electromagnetic waves are applied to objects, they will transmit momentum. Therefore, electromagnetic waves can exert force on objects, and then the concept of electromagnetic force is proposed [1]. Until the beginning of the twentieth century, Einstein proposed the concept of photonic quantum, which believes that light is composed of a group of photons with both mass and momentum. When light is irradiated on the surface of the object, it can cause changes in the photon momentum to produce radiation pressure on the object due to the scattering and absorption of light. Subsequently, Lebedev, Nichol, and Hull first demonstrated the existence of radiation pressure experimentally. The experiment used arc lamps and torsion scales to observe the effect of light in the macroscopic physical world. However, the light produced by the arc lamp is very weak and difficult to practically apply. Until 1960, the invention of the laser provided a high-intensity optical source for studying optical force, which greatly promoted the application of optical manipulation. Arthur Ashkin, a scientist at Bell Experiments in the United States, first used the radiation pressure generated by the laser beam to push tiny particles in the liquid environment [2] and then used two opposing laser beams to capture microparticles and even atoms. However, the experimental setup used in the dual-beam capture method is too complex and can only limit microparticles in a two-dimensional plane. Scientists hope to use a single laser to achieve three-dimensional trapping of microparticles. To this end, in 1986, Ashkin et al. used a high-numerical-aperture objective to focus a single laser to trap microparticles and named the technology “single beam gradient force trap” [3]. A year later, Ashkin et al. continued to improve this technology and achieved optical trapping and manipulation of tiny bacteria and viruses. They officially named the technology “optical tweezers” [3]. Compared with traditional macro-mechanical tweezers, the optical tweezers have the advantages of noncontact and no damage and can perform high-precision manipulation of microscopic particles. Therefore, since the birth of the optical tweezer technology, it has played an important role in the fields of biomedicine and physical chemistry.
\nThe core component of the traditional optical tweezers is a highly focused beam, as shown in \nFigure 1a\n [4]. When the incident laser (usually a near-infrared laser with a wavelength of 1064 nm) is focused by a high-numerical-aperture objective lens, the microparticles in the liquid environment will be exposed to optical force near the focus. This force is derived from the momentum transfer effect between light and particles. Specifically, the optical forces are divided into two components: one component along the direction of the optical gradient, called the optical gradient force, which is caused by the microparticles being in a nonuniform optical field, and the optical gradient force, which drives the particles to the area where the optical intensity is greatest; another component along the direction of optical propagation, called optical scattering force, is caused by the scattering and absorption of particles, and the optical scattering force causes the microparticles to move along the direction of optical propagation. By modulating the focused beam, the magnitude of two forces can be varied to achieve different functions such as capture, acceleration, and rotation of the microparticles. For traditional optical tweezers to construct a stable trap, it is necessary to focus the incident laser with a high-numerical-aperture (generally NA = 1.0~1.4) objective lens. The resulting optical gradient force is greater than the optical scattering force, so the microparticles or the cells can be stably trapped in the focus of light [5].
\nSchematic diagram of the traditional optical tweezers. (a) A single microparticle is trapped to the focused spot of a laser beam by gradient force and scattering force to [
The model in which the object is trapped by the optical tweezers can be equivalent to a simple oscillator, as shown in \nFigure 1b\n. The magnitude of the object’s received optical force (
where the constant
We first analyze the Rayleigh nanoparticle (
where α is the polarizability of the dipole,
where
The radiation pressure (
where
The
where \n
The dipole approximation model is only applicable to spherical nanoparticles. When the shape of the captured object is irregular or the size is the same magnitude as the wavelength, it needs to be solved from the most basic Maxwell equations using simulation software. This method is based on the Maxwell stress tensor integral of the surface
where
where \n
where \n
Professor Ashkin, the pioneer of optical tweezers, predicted that optical tweezers as the manipulation technology of tiny particles will be widely used in the research of molecular biology, cell biology, and mesoscopic physics, especially to promote the development of many interdisciplinary subjects [9]. As an example, we will introduce some of the applications of the optical tweezers in the following aspects:
\nThe invention of optical tweezers was used to capture and manipulate tiny particles such as polystyrene microspheres, biological cells, viruses, and bacteria [12]. By capturing these tiny particles, the Brownian motion of particles can be overcome and fixed in the field of the microscope for the researcher to observe and detect. When the particles are stably captured, they can be moved to a specific position and arranged in a regular pattern, which is applied to the ordered assembly of particles and cell arrays (as shown in \nFigure 2a\n), giving it a specific function. Further, by measuring the mechanical properties of particles and cell array, the interaction between the particles or cells can be studied. In addition, since different types of particles and cells are affected by the magnitude and direction of optical force, separation and screening of particles and cells can be achieved. With the maturity of optical tweezer technology, the system of optical tweezers is gradually combined with Raman technology, fluorescence technology [13], confocal technology, and femtosecond laser technology and achieves real-time detection of captured targets, which will enrich the applications of optical tweezers in cell biology and colloidal physics.
\nSeveral application examples of traditional optical tweezers. (a) Order and assemble microparticles and cells. (b) Study the interaction of nucleic acid molecules using micron media balls as handles [
The optical technology has a high mechanical resolution (10−12–10−15 N), which is sufficient for the study of individual biomacromolecules. For example, the basic laws of life movement are explained by measuring the physical forces such as the tiny force of biological single molecule and the motion step size. Optical tweezer technology has become an indispensable tool for quantitatively studying life processes and transforming life activities. Since the diameter of biomolecules is generally between 1 and 10 nanometers, the optical tweezer system cannot directly observe and manipulate. In order to see a single molecule, it is necessary to combine fluorescence imaging technology; in order to manipulate a single molecule, it is necessary to connect the molecule to the microsphere and indirectly manipulate and measure by using the small microsphere as the “handle” of the manipulation. For example, the two ends of the DNA molecular chain are, respectively, connected to two microspheres, and the microspheres are manipulated by a double-beam tweezers to stretch the DNA molecular chain and measure its elastic properties (as shown in \nFigure 2b\n) [10]. By rotating the two microspheres in the opposite direction, the binding force of the DNA molecular chain can be calculated. Using similar methods, researchers can also study the properties of various biomacromolecules: RNA transcription, kinesin movement, the role of polymerases, etc. These are the basic processes of life activities. Its high-precision measurement can reveal the basic laws of life activities and lay the foundation for the research and application of biomedicine.
\nThe optical rotator is a branch of the optical tweezers that not only captures the microparticles but also allows the angular rotation of the microparticles as shown in \nFigure 2c\n [11]. This technique is based on the moment applied by the angular momentum of the light to the object. In order to achieve the rotation of the particles, the optical rotator requires a special beam of angular momentum, such as a Laguerre-Gauss beam [14]. Rotating particles or cells are used in many fields, such as rotating a tiny mechanical motor in a liquid environment to control the movement of local water flow. In addition, by rotating living cells, it can be imaged at various angles, which is beneficial to observe the full three-dimensional appearance of cells.
\nStretching cells can study the elasticity of cell membranes, and the elasticity of cell membranes is closely related to many cellular diseases and can be used to reflect the activity of cells and even the health of the human body. There are many optical stretching methods based on optical tweezers, such as direct stretching of double-beam tweezers, stretching by microsphere handle, time-division multiplexed stretching, and so on. The method based on the microsphere handle-stretching method is more commonly used because of the high measurement precision. The method is shown in \nFigure 2d\n: two microspheres are adhered to the cell surface by chemical coupling, and then the microspheres are controlled to move in opposite directions by the tweezers. At this time, the cell membrane is stretched by shearing force. By recording the shape variables of the cells and measuring the force of stretching the microspheres, physical parameters such as the elastic modulus of the cell membrane can be calculated.
\nTraditional optical tweezers based on single beam can only capture and manipulate one or a few particles at a time. However, researchers want to improve the efficiency of capture, such as controlling multiple particles at the same time. Based on this goal, scientists invented holographic optical tweezers. The core component of holographic optical tweezers is a hologram element: an interference pattern formed by recording the object light and reference light through the film. The wave front can be adjusted by holographic elements to construct a light field with a specific function. The holographic optical tweezers were firstly invented in 1998 by Professor Grier of the University of Chicago and his collaborators [15]. They used a holographic element (diffraction grating) to split the collimated single laser beam into multiple independent beams, and then an array of grating is formed by focusing the lens to capture a large number of microparticles. The earliest holographic elements were prepared by coherent-optical interferometry, but the holographic elements obtained by this method have low diffraction efficiency and poor versatility, and thus this method has not been widely used. In order to improve diffraction efficiency and applicability, conventional holographic elements are often composed of spatial light modulators. The spatial light modulators include liquid crystal spatial light modulators, acousto-optic modulators, and digital microlens arrays. The spatial light modulator is controlled by a computer, and each focused beam can be individually controlled by changing the hologram element so that the formed trap well can be dynamically changed. Such holographic optical tweezers not only capture a plurality of microparticles at the same time but also control the movement of each microparticle to be arranged in different shapes, thereby achieving ordered assembly of the microparticles.
\nAs an emerging optical technology, holographic optical tweezers can trap and manipulate a large number of particles, showing great application prospects in the fields of particle assembly and construction of three-dimensional cell microstructure (\nFigure 3\n). For example, Glen R. Kirkham et al. of the United Kingdom used holographic optical tweezers to assemble one-, two-, and three-dimensional embryonic stem cell array structures (as shown in \nFigure 4\n) to provide a new means to study the directed differentiation of stem cells [16]. Moreover, Jesacher and his colleagues from Austria regulated the amplitude and phase of the incident light field through a liquid crystal spatial light modulator, which not only realized trapping potential wells of special shapes such as line, cross, circle, and rectangle but also controlled the microparticle movement along a specific path. In addition, holographic optical tweezer technology can also produce beams with special modes, such as Bessel beams, Laguerre-Gauss beams, and Airy beams [18]. These special-mode beams have peculiar phase distribution and propagation characteristics and can generate trapped potential wells with special functions, such as rotating particles with a Laguerre-Gauss beam, which can be used to construct micro- and nano-motors and study the transfer of orbital angular momentum; Airy beam or Bessel beam can be used to transport particles for sorting different types of particles and cells.
\nBright-field optical micrographs and confocal fluorescence micrographs of one-, two-, and three-dimensional microarray structures of embryonic stem cells assembled by holographic optical tweezers [
The basic principle of the fiber-based optical tweezers. (a) Schematic diagram of the optical gradient force (Fg) and scattering force (Fs) applied to the microparticles by the fiber-based optical tweezers. (b) Simulation of electric field intensity distribution of the fiber-based optical tweezers. (c) A chain of yeast cells was trapped by the fiber-based optical tweezers [
Due to the low integration of conventional optical tweezer systems, it is difficult to manipulate particles located in a narrow position, such as particles inside a microfluidic channel or red blood cells in a blood vessel. The newly developed fiber-based optical tweezers are promising candidates because of its compact structure and flexible operation, which can overcome the problems of traditional optical tweezers [19]. Fiber-based optical tweezers use the output light from the end face of the fiber to achieve particle capture and manipulation, as shown in \nFigure 5a\n. When the laser beam passes into the fiber, it converges through the end of fiber and form a highly focused beam. The microparticles located near the tip of the fiber will be captured by the longitudinal gradient force onto the optical axis of the fiber and then captured by the lateral gradient force at the focus of the emitted light or move along the optical axis under the action of optical scattering force. For fiber-based optical tweezers, the distribution of the exiting light field depends on the shape of the fiber tip, which is a highly focused beam, to create a three-dimensional trapping potential. Currently, the tip of the fiber-based optical tweezers is generally designed as a parabolic, spherical, or conical structure. Different shapes of fiber tip can be prepared by physical polishing, heating stretching, chemical etching, and femtosecond laser processing. By changing the physical parameters of the preparation method, such as temperature, speed, time, etc., the shape and size of the fiber tip can be controlled to achieve different functions. \nFigure 5b\n shows the output light field distribution of a typical tapered fiber. It can be seen that the light is concentrated at the front end of fiber so that the cells can be trapped on the axis of the front end of the fiber and arranged into an ordered structure, as shown in \nFigure 5c\n [17].
\nThis schematic shows a versatile fiber-based optical tweezers: number 1 indicates the capture, transport, and sorting of cells, number 2 indicates the optical stretching and deformation of cells, and numbers 3 indicates the optical rotation of cells.
Since the fiber-based optical tweezers have the advantages of simple fabrication, flexible operation, compact structure, and easy integration, it has applications in many fields. For example, Xin et al. used a flame heating and melting taper to prepare a fiber-based optical tweezers with a tapered tip, which enables the capture of submicron-sized polystyrene particles and
Slot waveguide optical tweezers. (a) Schematic diagram of the optical gradient force and scattering force of nanoparticles in the slot waveguide. (b) A simulation result of the light intensity distribution of the slot waveguide in an aqueous environment. (c) An electron scanning micrograph of a waveguide having a slit of 100 nm. (d) The slot waveguide captures a large number of polystyrene particles of 75 nm in diameter in the water flow [
When the light is transmitted in the waveguide, an evanescent wave is generated on the surface of the waveguide due to the total reflection. The evanescent wave is limited to a near-field range of 100 nanometers from the surface of the waveguide. When a nanoparticle enters the evanescent wave, the gradient of the light intensity changes greatly in the direction perpendicular to the waveguide, so the nanoparticles will be trapped on the surface of the waveguide by a strong optical gradient force. In the direction of light propagation, the evanescent wave can be considered to be uniformly distributed. Therefore, there is no optical gravity force in this direction. Only the optical scattering force exists. The nanoparticles move along the direction of light propagation due to the optical scattering force. Therefore, planar waveguide optical tweezers are often used for the transport of nanoparticles. Moreover, since the optical waveguide device is easily integrated into the microfluidic chip, the planar waveguide optical tweezers play an important role in the field of microfluidics. Current planar waveguide optical tweezers can be classified into three types: rectangular waveguide optical tweezers, slot waveguide optical tweezers, and nanofiber waveguide optical tweezers.
\nThe manipulation of microparticles by a rectangular waveguide optical tweezers was first implemented by Kawata et al. [5]. They use rectangular waveguides to perform noncontact optical transport of different sizes of microparticles. This method can deliver cells or drugs over long distances. After this groundbreaking work, more and more researchers have entered this field and designed rectangular waveguides with different structures for transporting metal particles, media particles, microbial cells, etc. [5].
\nSince the evanescent wave of the rectangular waveguide has limited light confinement, it is challenging for the rectangular waveguide to capture particles and biomolecules below 100 nm. To solve this limitation, the researchers developed slot waveguide nanotweezers [23]. The slot waveguide is an air slit having a width of nanometers by photolithography or electron beam etching. The large refractive index contrast between low refractive index slot and high refractive index waveguide material makes the light energy highly confined in the slot region, which produces a strong optical gradient force and scattering force on the nanoparticles entering the slot. Using this property, Yang et al. achieved capture and transport of polystyrene particles and DNA molecules with sizes below 100 nanometers (as shown in \nFigure 7\n) [23].
\nPhotonic crystal optical tweezers. (a) Schematic representation of a single-dimensional photonic crystal resonator capturing a single nanoparticle [
A common problem with rectangular waveguide optical tweezers and slot waveguide optical tweezers is that they must be fixed on the substrate, making it difficult to operate. The emerging nanofiber waveguide optical tweezers can solve this problem. Li et al. used fibers with a diameter of 500–700 nm to achieve stable trap, bidirectional transport, optical separation, and controlled release of nanoparticles and micro-pathogens in microfluidics [26, 27]. The nanofiber waveguide optical tweezers have the advantages of low cost, production, and large control range and have important research value and application prospects in cell transportation, drug delivery, and particle collection.
\nOptical tweezers based on rectangular waveguides, slot waveguides, and nanofiber waveguides can only move particles along the waveguide surface but cannot be used to stably trap nanoparticles. In order to stably capture the nanoparticles, a photonic crystal optical tweezers were developed. The photonic crystal optical tweezers are based on one- or two-dimensional photonic crystal resonator structures (as shown in \nFigure 8\n) [24, 25]. When the laser that satisfies the wavelength matching condition is coupled into the photonic crystal resonator, static interference will occur in the cavity. With the resonance effect, the intensity of the light is greatly enhanced, and the size of the light spot is strongly suppressed, thereby enhancing the optical force of nanoparticles. Based on this principle, Erickson and Mandal et al. achieved stable capture and controlled release of nano-objects such as polystyrene particles, semiconductor quantum dots, and serum protein molecules in a liquid environment [30]. In addition, this method can also be used to study the angular rotation of silver nanowires or carbon nanotubes [31].
\nPlasmon optical tweezers. (a) Schematic diagram of a metal film having nanopores. (b) Schematic diagram of magnified metal nanopore capture nanoparticles. (c) SEM image of the metal nano-antenna structure and motion trajectory after the nanoparticles are captured. (d) Schematic representation of metal nano-antenna structures [
Plasmon is a near-field electromagnetic wave formed by the resonance of free electrons on a metal surface and incident photons. Under such resonance conditions, the energy of the electromagnetic field will be converted into the collective vibrational energy of the free electrons on the metal surface, thereby forming a special electromagnetic field: the light is confined to the sub-wavelength of the metal surface and greatly enhanced. The effect is called the plasmon effect. Since the plasmon effect localizes the light in the near-field range of the nanometer order, it is widely used in the fields of fluorescence signal enhancement, near-field super-resolution imaging, high-density optical storage, integrated optical circuits, etc. [32]. In recent years, the plasmon effect has also been applied in the field of optical trapping and manipulation. The plasmon effect is divided into two types: surface plasmon resonance (SPR) and local surface plasmon resonance (LSPR), both of which can be used to enhance optical force. Researchers used a prismatic total internal reflection to couple incident light into a metal micro-disk on the substrate, which will increase the optical force of the particle by two orders of magnitude and realize the capture of the microparticle. However, the SPR-based optical tweezers can only enhance the optical force of the particle in a two-dimensional plane. Therefore, researchers have proposed an LSPR-based nano-optical tweezers to enhance the optical force of the nanoparticle in three dimensions, including metal nanopores (\nFigure 8a\n,\nb\n), metal nano-antennas (\nFigure 8c\n,\nd\n) [28], metal nano-bows (\nFigure 8e\n,\nf\n) [29], and metal nano-double holes [33]. By using these nano-optical tweezers to achieve trapping of various nanoparticles, such as polystyrene particles, protein molecules, gold particles, micro-pathogenic bacteria, and so on.
\nThe noncontact and noninvasive optical trapping and manipulation of microparticles, cells, and biomolecules in liquid environments has broad application prospect in the fields of biomedicine and nanomaterial science [34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47]. Traditional optical tweezers and holographic optical tweezers play an important role in the study of microscale optical manipulation. However, in the rapid development of nanoscience, traditional optical tweezers and holographic optical tweezers are difficult to adapt integration and nano-precision requirements due to the large volume and diffraction limitations. The developed nano-optical manipulation techniques, such as planar waveguides, plasmon optical tweezers, and photonic crystal resonators, can overcome the problem of difficult integration and diffraction limitations of conventional optical tweezers and holographic optical tweezers, which hold great promise in biophotonic and biomedical applications.
\nThis work was supported by the National Natural Science Foundation of China (No. 11774135, 11874183, and 61827822).
\nThe authors declare no competing financial interests.
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Bandyopadhyay",authors:[{id:"27050",title:"Prof.",name:"Sri",middleName:null,surname:"Bandyopadhyay",slug:"sri-bandyopadhyay",fullName:"Sri Bandyopadhyay"},{id:"44992",title:"Prof.",name:"Anandhan",middleName:null,surname:"Srinivasan",slug:"anandhan-srinivasan",fullName:"Anandhan Srinivasan"}]},{id:"9725",doi:"10.5772/8508",title:"Biosynthesis and Application of Silver and Gold Nanoparticles",slug:"biosynthesis-and-application-of-silver-and-gold-nanoparticles",totalDownloads:27927,totalCrossrefCites:23,totalDimensionsCites:58,abstract:null,book:{id:"3621",slug:"silver-nanoparticles",title:"Silver Nanoparticles",fullTitle:"Silver Nanoparticles"},signatures:"Zygmunt Sadowski",authors:null},{id:"17194",doi:"10.5772/21694",title:"Properties of Nanofillers in Polymer",slug:"properties-of-nanofillers-in-polymer",totalDownloads:20385,totalCrossrefCites:9,totalDimensionsCites:56,abstract:null,book:{id:"1045",slug:"nanocomposites-and-polymers-with-analytical-methods",title:"Nanocomposites and Polymers with Analytical Methods",fullTitle:"Nanocomposites and Polymers with Analytical Methods"},signatures:"Damien M. Marquis, Éric Guillaume and Carine Chivas-Joly",authors:[{id:"44307",title:"Dr",name:"Damien",middleName:"Michel",surname:"Marquis",slug:"damien-marquis",fullName:"Damien Marquis"},{id:"44317",title:"Prof.",name:"Carine",middleName:null,surname:"Chivas-Joly",slug:"carine-chivas-joly",fullName:"Carine Chivas-Joly"}]},{id:"52860",doi:"10.5772/65937",title:"Cerium Oxide Nanostructures and their Applications",slug:"cerium-oxide-nanostructures-and-their-applications",totalDownloads:5365,totalCrossrefCites:23,totalDimensionsCites:55,abstract:"Due to excellent physical and chemical properties, cerium oxide (ceria, CeO2) has attracted much attention in recent years. This chapter aimed at providing some basic and fundamental properties of ceria, the importance of oxygen vacancies in this material, nano‐size effects and various synthesis strategies to form diverse structural morphologies. Finally, some key applications of ceria‐based nanostructures are reviewed. We conclude this chapter by expressing personal perspective on the probable challenges and developments of the controllable synthesis of CeO2 nanomaterials for various applications.",book:{id:"5510",slug:"functionalized-nanomaterials",title:"Functionalized Nanomaterials",fullTitle:"Functionalized Nanomaterials"},signatures:"Adnan Younis, Dewei Chu and Sean Li",authors:[{id:"191574",title:"Dr.",name:"Adnan",middleName:null,surname:"Younis",slug:"adnan-younis",fullName:"Adnan Younis"}]}],mostDownloadedChaptersLast30Days:[{id:"71103",title:"Preparation of Nanoparticles",slug:"preparation-of-nanoparticles",totalDownloads:3140,totalCrossrefCites:11,totalDimensionsCites:25,abstract:"Innovative developments of science and engineering have progressed very fast toward the synthesis of nanomaterials to achieve unique properties that are not the same as the properties of the bulk materials. The particle reveals interesting properties at the dimension below 100 nm, mostly from two physical effects. The two physical effects are the quantization of electronic states apparent leading to very sensitive size-dependent effects such as optical and magnetic properties and the high surface-to-volume ratio modifies the thermal, mechanical, and chemical properties of materials. The nanoparticles’ unique physical and chemical properties render them most appropriate for a number of specialist applications.",book:{id:"9109",slug:"engineered-nanomaterials-health-and-safety",title:"Engineered Nanomaterials",fullTitle:"Engineered Nanomaterials - Health and Safety"},signatures:"Takalani Cele",authors:[{id:"305934",title:"Dr.",name:"Takalani",middleName:null,surname:"Cele",slug:"takalani-cele",fullName:"Takalani Cele"}]},{id:"72636",title:"Nanocomposite Materials",slug:"nanocomposite-materials",totalDownloads:2139,totalCrossrefCites:5,totalDimensionsCites:11,abstract:"Nanocomposites are the heterogeneous/hybrid materials that are produced by the mixtures of polymers with inorganic solids (clays to oxides) at the nanometric scale. Their structures are found to be more complicated than that of microcomposites. They are highly influenced by the structure, composition, interfacial interactions, and components of individual property. Most popularly, nanocomposites are prepared by the process within in situ growth and polymerization of biopolymer and inorganic matrix. With the rapid estimated demand of these striking potentially advanced materials, make them very much useful in various industries ranging from small scale to large to very large manufacturing units. With a great deal to mankind with environmental friendly, these offer advanced technologies in addition to the enhanced business opportunities to several industrial sectors like automobile, construction, electronics and electrical, food packaging, and technology transfer.",book:{id:"10072",slug:"nanotechnology-and-the-environment",title:"Nanotechnology and the Environment",fullTitle:"Nanotechnology and the Environment"},signatures:"Mousumi Sen",authors:[{id:"310218",title:"Dr.",name:"Mousumi",middleName:null,surname:"Sen",slug:"mousumi-sen",fullName:"Mousumi Sen"}]},{id:"38951",title:"Carbon Nanotube Transparent Electrode",slug:"carbon-nanotube-transparent-electrode",totalDownloads:3985,totalCrossrefCites:3,totalDimensionsCites:5,abstract:null,book:{id:"3077",slug:"syntheses-and-applications-of-carbon-nanotubes-and-their-composites",title:"Syntheses and Applications of Carbon Nanotubes and Their Composites",fullTitle:"Syntheses and Applications of Carbon Nanotubes and Their Composites"},signatures:"Jing Sun and Ranran Wang",authors:[{id:"153508",title:"Prof.",name:"Jing",middleName:null,surname:"Sun",slug:"jing-sun",fullName:"Jing Sun"},{id:"153596",title:"Ms.",name:"Ranran",middleName:null,surname:"Wang",slug:"ranran-wang",fullName:"Ranran Wang"}]},{id:"49413",title:"Electrodeposition of Nanostructure Materials",slug:"electrodeposition-of-nanostructure-materials",totalDownloads:3732,totalCrossrefCites:1,totalDimensionsCites:7,abstract:"We are conducting a multi-disciplinary research work that involves development of nanostructured thin films of semiconductors for different applications. Nanotechnology is widely considered to constitute the basis of the next technological revolution, following on from the first Industrial Revolution, which began around 1750 with the introduction of the steam engine and steelmaking. Nanotechnology is defined as the design, characterization, production, and application of materials, devices and systems by controlling shape and size of the nanoscale. The nanoscale itself is at present considered to cover the range from 1 to 100 nm. All samples prepared in thin film forms and the characterization revealed their nanostructure. The major exploitation of thin films has been in microelectronics, there are numerous and growing applications in communications, optical electronics, coatings of all kinds, and in energy generation. A great many sophisticated analytical instruments and techniques, largely developed to characterize thin films, have already become indispensable in virtually every scientific endeavor irrespective of discipline. Among all these techniques, electrodeposition is the most suitable technique for nanostructured thin films from aqueous solution served as samples under investigation. The electrodeposition of metallic layers from aqueous solution is based on the discharge of metal ions present in the electrolyte at a cathodic surface (the substrate or component.) The metal ions accept an electron from the electrically conducting material at the solid- electrolyte interface and then deposit as metal atoms onto the surface. The electrons necessary for this to occur are either supplied from an externally applied potential source or are surrendered by a reducing agent present in solution (electroless reduction). The metal ions themselves derive either from metal salts added to solution, or by the anodic dissolution of the so-called sacrificial anodes, made of the same metal that is to be deposited at the cathode.",book:{id:"4718",slug:"electroplating-of-nanostructures",title:"Electroplating of Nanostructures",fullTitle:"Electroplating of Nanostructures"},signatures:"Souad A. M. Al-Bat’hi",authors:[{id:"174793",title:"Dr.",name:"Mohamad",middleName:null,surname:"Souad",slug:"mohamad-souad",fullName:"Mohamad Souad"}]},{id:"71346",title:"Application of Nanomaterials in Environmental Improvement",slug:"application-of-nanomaterials-in-environmental-improvement",totalDownloads:1691,totalCrossrefCites:0,totalDimensionsCites:13,abstract:"In recent years, researchers used many scientific studies to improve modern technologies in the field of reducing the phenomenon of pollution resulting from them. In this chapter, methods to prepare nanomaterials are described, and the main properties such as mechanical, electrical, and optical properties and their relations are determined. The investigation of nanomaterials needed high technologies that depend on a range of nanomaterials from 1 to 100 nm; these are scanning electron microscopy (SEM), transmission electron microscopy (TEM), and X-ray diffractions (XRD). The applications of nanomaterials in environmental improvement are different from one another depending on the type of devices used, for example, solar cells for producing clean energy, nanotechnologies in coatings for building exterior surfaces, and sonochemical decolorization of dyes by the effect of nanocomposite.",book:{id:"10072",slug:"nanotechnology-and-the-environment",title:"Nanotechnology and the Environment",fullTitle:"Nanotechnology and the Environment"},signatures:"Ali Salman Ali",authors:[{id:"313275",title:"Associate Prof.",name:"Ali",middleName:null,surname:"Salman",slug:"ali-salman",fullName:"Ali Salman"}]}],onlineFirstChaptersFilter:{topicId:"208",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"81438",title:"Research Progress of Ionic Thermoelectric Materials for Energy Harvesting",slug:"research-progress-of-ionic-thermoelectric-materials-for-energy-harvesting",totalDownloads:24,totalDimensionsCites:0,doi:"10.5772/intechopen.101771",abstract:"Thermoelectric material is a kind of functional material that can mutually convert heat energy and electric energy. It can convert low-grade heat energy (less than 130°C) into electric energy. Compared with traditional electronic thermoelectric materials, ionic thermoelectric materials have higher performance. The Seebeck coefficient can generate 2–3 orders of magnitude higher ionic thermoelectric potential than electronic thermoelectric materials, so it has good application prospects in small thermoelectric generators and solar power generation. According to the thermoelectric conversion mechanism, ionic thermoelectric materials can be divided into ionic thermoelectric materials based on the Soret effect and thermocouple effect. They are widely used in pyrogen batteries and ionic thermoelectric capacitors. The latest two types of ionic thermoelectric materials are in this article. The research progress is explained, and the problems and challenges of ionic thermoelectric materials and the future development direction are also put forward.",book:{id:"10037",title:"Thermoelectricity - Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10037.jpg"},signatures:"Jianwei Zhang, Ying Xiao, Bowei Lei, Gengyuan Liang and Wenshu Zhao"},{id:"77670",title:"Thermoelectric Elements with Negative Temperature Factor of Resistance",slug:"thermoelectric-elements-with-negative-temperature-factor-of-resistance",totalDownloads:71,totalDimensionsCites:0,doi:"10.5772/intechopen.98860",abstract:"The method of manufacturing of ceramic materials on the basis of ferrites of nickel and cobalt by synthesis and sintering in controllable regenerative atmosphere is presented. As the generator of regenerative atmosphere the method of conversion of carbonic gas is offered. Calculation of regenerative atmosphere for simultaneous sintering of ceramic ferrites of nickel and cobalt is carried out. It is offered, methods of the dilated nonequilibrium thermodynamics to view process of distribution of a charge and heat along a thermoelement branch. The model of a thermoelement taking into account various relaxation times of a charge and warmth is constructed.",book:{id:"10037",title:"Thermoelectricity - Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10037.jpg"},signatures:"Yuri Bokhan"},{id:"79236",title:"Processing Techniques with Heating Conditions for Multiferroic Systems of BiFeO3, BaTiO3, PbTiO3, CaTiO3 Thin Films",slug:"processing-techniques-with-heating-conditions-for-multiferroic-systems-of-bifeo3-batio3-pbtio3-catio",totalDownloads:96,totalDimensionsCites:0,doi:"10.5772/intechopen.101122",abstract:"In this chapter, we have report a list of synthesis methods (including both synthesis steps & heating conditions) used for thin film fabrication of perovskite ABO3 (BiFeO3, BaTiO3, PbTiO3 and CaTiO3) based multiferroics (in both single-phase and composite materials). The processing of high quality multiferroic thin film have some features like epitaxial strain, physical phenomenon at atomic-level, interfacial coupling parameters to enhance device performance. Since these multiferroic thin films have ME properties such as electrical (dielectric, magnetoelectric coefficient & MC) and magnetic (ferromagnetic, magnetic susceptibility etc.) are heat sensitive, i.e. ME response at low as well as higher temperature might to enhance the device performance respect with long range ordering. The magnetoelectric coupling between ferromagnetism and ferroelectricity in multiferroic becomes suitable in the application of spintronics, memory and logic devices, and microelectronic memory or piezoelectric devices. In comparison with bulk multiferroic, the fabrication of multiferroic thin film with different structural geometries on substrate has reducible clamping effect. A brief procedure for multiferroic thin film fabrication in terms of their thermal conditions (temperature for film processing and annealing for crystallization) are described. Each synthesis methods have its own characteristic phenomenon in terms of film thickness, defects formation, crack free film, density, chip size, easier steps and availability etc. been described. A brief study towards phase structure and ME coupling for each multiferroic system of BiFeO3, BaTiO3, PbTiO3 and CaTiO3 is shown.",book:{id:"10037",title:"Thermoelectricity - Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10037.jpg"},signatures:"Kuldeep Chand Verma and Manpreet Singh"},{id:"78034",title:"Quantum Physical Interpretation of Thermoelectric Properties of Ruthenate Pyrochlores",slug:"quantum-physical-interpretation-of-thermoelectric-properties-of-ruthenate-pyrochlores",totalDownloads:75,totalDimensionsCites:0,doi:"10.5772/intechopen.99260",abstract:"Lead- and lead-yttrium ruthenate pyrochlores were synthesized and investigated for Seebeck coefficients, electrical- and thermal conductivity. Compounds A2B2O6.5+z with 0 ≤ z < 0.5 were defect pyrochlores and p-type conductors. The thermoelectric data were analyzed using quantum physical models to identify scattering mechanisms underlying electrical (σ) and thermal conductivity (κ) and to understand the temperature dependence of the Seebeck effect (S). In the metal-like lead ruthenates with different Pb:Ru ratios, σ (T) and the electronic thermal conductivity κe (T) were governed by ‘electron impurity scattering’, the lattice thermal conductivity κL (T) by the 3-phonon resistive process (Umklapp scattering). In the lead-yttrium ruthenate solid solutions (Pb(2-x)YxRu2O(6.5±z)), a metal–insulator transition occurred at 0.2 moles of yttrium. On the metallic side (<0.2 moles Y) ‘electron impurity scattering’ prevailed. On the semiconductor/insulator side between x = 0.2 and x = 1.0 several mechanisms were equally likely. At x > 1.5 the Mott Variable Range Hopping mechanism was active. S (T) was discussed for Pb-Y-Ru pyrochlores in terms of the effect of minority carrier excitation at lower- and a broadening of the Fermi distribution at higher temperatures. The figures of merit of all of these pyrochlores were still small (≤7.3 × 10−3).",book:{id:"10037",title:"Thermoelectricity - Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10037.jpg"},signatures:"Sepideh Akhbarifar"},{id:"77635",title:"Optimization of Thermoelectric Properties Based on Rashba Spin Splitting",slug:"optimization-of-thermoelectric-properties-based-on-rashba-spin-splitting",totalDownloads:124,totalDimensionsCites:0,doi:"10.5772/intechopen.98788",abstract:"In recent years, the application of thermoelectricity has become more and more widespread. Thermoelectric materials provide a simple and environmentally friendly solution for the direct conversion of heat to electricity. The development of higher performance thermoelectric materials and their performance optimization have become more important. Generally, to improve the ZT value, electrical conductivity, Seebeck coefficient and thermal conductivity must be globally optimized as a whole object. However, due to the strong coupling among ZT parameters in many cases, it is very challenging to break the bottleneck of ZT optimization currently. Beyond the traditional optimization methods (such as inducing defects, varying temperature), the Rashba effect is expected to effectively increase the S2σ and decrease the κ, thus enhancing thermoelectric performance, which provides a new strategy to develop new-generation thermoelectric materials. Although the Rashba effect has great potential in enhancing thermoelectric performance, the underlying mechanism of Rashba-type thermoelectric materials needs further research. In addition, how to introduce Rashba spin splitting into current thermoelectric materials is also of great significance to the optimization of thermoelectricity.",book:{id:"10037",title:"Thermoelectricity - Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10037.jpg"},signatures:"Zhenzhen Qin"},{id:"75364",title:"Challenges in Improving Performance of Oxide Thermoelectrics Using Defect Engineering",slug:"challenges-in-improving-performance-of-oxide-thermoelectrics-using-defect-engineering",totalDownloads:214,totalDimensionsCites:0,doi:"10.5772/intechopen.96278",abstract:"Oxide thermoelectric materials are considered promising for high-temperature thermoelectric applications in terms of low cost, temperature stability, reversible reaction, and so on. Oxide materials have been intensively studied to suppress the defects and electronic charge carriers for many electronic device applications, but the studies with a high concentration of defects are limited. It desires to improve thermoelectric performance by enhancing its charge transport and lowering its lattice thermal conductivity. For this purpose, here, we modified the stoichiometry of cation and anion vacancies in two different systems to regulate the carrier concentration and explored their thermoelectric properties. Both cation and anion vacancies act as a donor of charge carriers and act as phonon scattering centers, decoupling the electrical conductivity and thermal conductivity.",book:{id:"10037",title:"Thermoelectricity - Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/10037.jpg"},signatures:"Jamil Ur Rahman, Gul Rahman and Soonil Lee"}],onlineFirstChaptersTotal:6},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},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:"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"}}}},{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"}}}}]},series:{item:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. This Biochemistry Series will address the current research on biomolecules and the emerging trends with great promise.",coverUrl:"https://cdn.intechopen.com/series/covers/11.jpg",latestPublicationDate:"May 18th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:27,editor:{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"14",title:"Cell and Molecular Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",isOpenForSubmission:!0,editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",slug:"rosa-maria-martinez-espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",biography:"Dr. Rosa María Martínez-Espinosa has been a Spanish Full Professor since 2020 (Biochemistry and Molecular Biology) and is currently Vice-President of International Relations and Cooperation development and leader of the research group 'Applied Biochemistry” (University of Alicante, Spain). Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. 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He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. 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He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. 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