Reported outcomes in laparoscopic pancreaticoduodenectomy.
\r\n\tThe present book intends to provide to the reader a comprehensive overview of the state of art in empathy studies, embracing the different theoretical points of view and illustrating the advanced research such as the application of new technologies to promote perspective-taking. The critical aspects and the future directions of the study on empathy will also be presented.
",isbn:"978-1-80356-612-2",printIsbn:"978-1-80356-611-5",pdfIsbn:"978-1-80356-613-9",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,hash:"4c1042dfe15aa9cea6019524c4cbff38",bookSignature:"Ph.D. Sara Ventura",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11443.jpg",keywords:"Theoretical Model, Skill, Perspective Taking, Training Programs, Practical Implications, Advanced Research, Future Directions, Virtual Reality, Augmented Reality, New Trends, Assistive Technology",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 1st 2022",dateEndSecondStepPublish:"June 8th 2022",dateEndThirdStepPublish:"August 7th 2022",dateEndFourthStepPublish:"October 26th 2022",dateEndFifthStepPublish:"December 25th 2022",remainingDaysToSecondStep:"19 days",secondStepPassed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:"Passionate researcher in the application of new technologies to psychological treatments, neuro-rehabilitation, human behavior, and the evolution of the human-computer interaction. In 2017 Dr. Ventura won a competitive grant (Santiago Grisolia) at the University of Valencia at LABPSITEC group, where she was awarded her Ph.D. degree, supervised by Prof. Rosa Baños at the University of Valencia, and co-directed by Prof. Giuseppe Riva of the Catholic University of Milan.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"227763",title:"Ph.D.",name:"Sara",middleName:null,surname:"Ventura",slug:"sara-ventura",fullName:"Sara Ventura",profilePictureURL:"https://mts.intechopen.com/storage/users/227763/images/system/227763.jpg",biography:"Sara Ventura gained a B.Sc in Psychology at the University of Padua (Italy) in 2013 and an M.Sc. in Ergonomic Psychology at the Catholic University of Milan (Italy) in 2015. In 2016, she carried out a postgraduate training at Universidad Nacional Autónoma de Mexico (Mexico) at the Ciberpsychology lab, working on a rehabilitation protocol for people with acquired brain injury through Virtual Reality. In 2020, Sara gained the Ph.D. in Clinical Psychology at University of Valencia (Spain) working with the LabPsitec group and focusing her research on the study of embodiment and empathy with the support of Virtual Reality. Actually, she is working both with Alma Mater Studiorum – University of Bologna (Italy), and the University of Valencia (Spain) on the fields of embodiment, stroke rehabilitation, empathy and patient care. Her research interests mainly focus on the adoption of new technologies, particularly Virtual/Augmented Reality and Artificial Intelligence for the psycho-social wellbeing with clinical and non-clinical populations, the study of human-computer interaction, and the user experience. She is the author of several scientific papers and various presentations at national and international conferences.",institutionString:"University of Valencia",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Valencia",institutionURL:null,country:{name:"Spain"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"21",title:"Psychology",slug:"psychology"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"455410",firstName:"Dajana",lastName:"Jusic",middleName:null,title:"Mrs.",imageUrl:"https://mts.intechopen.com/storage/users/455410/images/20500_n.jpeg",email:"dajana.j@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"6494",title:"Behavior Analysis",subtitle:null,isOpenForSubmission:!1,hash:"72a81a7163705b2765f9eb0b21dec70e",slug:"behavior-analysis",bookSignature:"Huei-Tse Hou and Carolyn S. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"52989",title:"Laparoscopic Pancreas Surgery: Image Guidance Solutions",doi:"10.5772/66171",slug:"laparoscopic-pancreas-surgery-image-guidance-solutions",body:'\nCancer is the second leading cause of death worldwide after heart disease, with 14.9 million cases and 8.2 million deaths in 2013 [1, 2] and the first leading cause of death among adults aged 40–79 years [3, 4]. Worldwide, pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer-related deaths [2, 3]. The incidence of all types of pancreatic cancer ranges from 1 to 10 cases per 100,000 people and is generally higher in developed countries and among men [1, 2]. This has remained stable for the past 30 years relative to the incidence of other common solid tumors [5]. Each year about 233,000 new cases of pancreatic cancer are diagnosed worldwide [2, 3]. In the United States, the American Cancer Association expected about 48,960 (24,840 men and 24,120 women) cases of incidence in pancreatic cancer in 2015, with a mortality rate of 83% [6]. In Europe, the estimated number of new cases of pancreatic cancer in 2012 was 79,331 and the estimated number of cases of deaths was 78,669 [7, 8], which is almost the double than in the United States. The 5-year survival rate in the world for pancreatic cancer is still very low, with only 6%. In addition, the overall 2-year survival rate is less than 10%, which has hardly improved over the past two decades [3–5]. In fact, in contrast to the stable or declining trends for most cancer types in the United States, a trend analysis for 2001–2010 indicated that death rates are rising for pancreatic cancer [3, 4].
\nAnatomy of the pancreas.
Pancreatic tumors are mainly classified as exocrine and endocrine tumors, also known as pancreatic neuroendocrine tumors (NETs). Exocrine tumors are approximately 99% of all primary pancreatic tumors [9] and are divided into ductal adenocarcinomas (80–90% of exocrine tumors), cystic neoplasms, and solid pseudopapillary neoplasms [5, 6, 10]. Ductal adenocarcinomas usually begin in the ducts of the pancreas and are located in the head of the pancreas (60–70%) (Figure 1) [10]. Approximately 5–10% of PDA cases are believed to be due to hereditary conditions, such as hereditary pancreatitis, Gardner syndrome, familial colon cancer, and others [11].
\nPancreatic cases are usually diagnosed at an advanced stage but with few treatment options available. This is attributed primarily to a lack of reliable methods for early diagnosis and rapid metastasis of pancreatic cancer [12]. At the time of diagnosis, less than 20% of patients with pancreatic cancer present with localized, potentially curable tumors [13, 14]. Approximately, 30% of patients receive a diagnosis of advanced loco-regional disease. In addition, 30% of patients have local recurrence of tumors after treatment for an early disease [14].
\n\nAlthough there are several available treatments for pancreatic cancer such as ablative techniques, radiation therapies, and chemotherapy, surgery is the only viable treatment. However, only 10–20% of pancreatic tumors are candidates to be surgically resected at diagnosis [10, 15]. The required surgical intervention for pancreatic cancer treatment depends on the location of tumors. Cancers arising in the head of the pancreas require a pancreaticoduodenectomy (Whipple operation), while those in the tail require a distal pancreatectomy with or without splenectomy [16]. Lesions located in the neck and body may require a distal pancreatectomy, pancreaticoduodenectomy or, rarely, a total pancreatectomy. After surgery, patients with no positive resection margins (R0) have the most favorable prognosis [17]. The median survival length reported for resected (R0) pancreatic cancer ranges from 17–27 months and, after a R1 resection, the average survival length is 10.3 months [18]. However, irradical resection of pancreatic cancers still occurs in 35–42% of patients [16, 19]. This survival time is longer in patients with malignant disease localized to the pancreas and less than 3 cm in diameter than in patients with tumors of greater size or with retroperitoneal invasion (6–15 months) [13]. Other factors, such as tumor size, lymph node status, tumor grade and blood vessel invasion, are also correlated with prognosis [20].
\nThe introduction of minimally invasive surgical techniques in the treatment of pancreatic cancer has allowed almost any pancreatic tumor to be operated by laparoscopic or robotic approaches with similar outcomes to the standard approach [21, 22]. Even new approaches such as laparosendoscopic single-site surgery (LESS) are being applied recently in the field of pancreatic surgery [23, 24]. However, there are some limitations that have hindered the wide use of minimally invasive pancreatic surgery, mainly due to the challenges of these kinds of interventions. The retroperitoneal location of the pancreas makes it difficult to reach during surgery. In addition, this glandular organ presents a delicate structure close to major vascular structures. There are also some technical limitations related to minimally invasive surgery (MIS) such as the lack of visual and tactile information. Increasing the capability to visualize tumor margins or to identify small metastatic nodules may significantly improve the surgical procedure to prevent positive resection margins, and therefore, surgical outcomes [25]. Image-guided techniques can provide intraoperative margin assessment and visualization methods, which may be advantageous in guiding the surgeon to achieve curative resections. Some of these emerging modalities are intraoperative near-infrared fluorescence imaging and surgical navigation systems [26, 27]. However, despite the high rate of positive resections in pancreatic surgery, there is limited medical literature regarding the use of navigation systems as a support during pancreatic interventions. In this chapter, the current laparoscopic surgical techniques and image-guided methods for pancreatic surgery and their associate surgical outcomes will be reviewed.
\nPancreatic cancer is a complex disease, whose optimal treatment depends heavily on careful accurate staging [28]. Surgical resection is still the only potentially curative therapy for pancreatic cancer. However, pancreatic resection is technically challenging and a complex surgical procedure. In this section, the current laparoscopic surgical techniques for pancreatic surgery and their associated surgical outcomes will be reviewed. In order to reach more representative information, only studies published after 2010 and with more than 50 patients included, were taken into account. No limitation in the number of patients was set for the studies using LESS.
\nThe first laparoscopic pancreaticoduodenectomy (LPD) was published by Gagner and Pomp in 1994 [29]. They concluded that, although technically feasible, this approach did not confer significant benefit over the conventional open approach in terms of postoperative outcomes or reduced postoperative recovery period. One of the largest barriers of this complex procedure is the reconstruction phase due to the three separate anastomoses to be performed (pancreaticojejunostomy, hepaticojejunostomy, and gastrojejunostomy).
\n\n | Conv. (%) | \nTime (min) | \nEBL (ml) | \nLHS (days) | \nMorb. (%) | \nMort. (%) | \nPF (%) | \nLN (%) | \nR0 (%) | \n|
---|---|---|---|---|---|---|---|---|---|---|
[30] | \n53 | \n17 | \n541 | \n195 | \n8 | \n77.3 | \n5.7 | \n13.2 | \n44.2 | \n94.9 | \n
[31] | \n384 | \n\n | \n | \n | 10 | \n\n | 5.2 | \n\n | 4.7 | \n80 | \n
[32] | \n983 | \n\n | \n | \n | \n | \n | 5. 1 | \n\n | \n | \n |
[33] | \n108 | \n\n | 379.4 | \n492.4 | \n6 | \n\n | \n | \n | \n | \n |
[34] | \n65 | \n4.6 | \n368 | \n240 | \n7 | \n40 | \n1.5 | \n16.9 | \n23.1 | \n89 | \n
[35] | \n105 | \n4.7 | \n487.3 | \n\n | 15 | \n25 | \n0.9 | \n5.7 | \n12.4 | \n100 | \n
[36] | \n96 | \n3.1 | \n\n | \n | \n | \n | 0 | \n28.1 | \n\n | \n |
[37] | \n75 | \n13.3 | \n551 | \n\n | 7 | \n31 | \n\n | 9.3 | \n\n | \n |
[38] | \n137 | \n\n | 480.4 | \n592 | \n14.1 | \n\n | \n | \n | \n | \n |
[39] | \n681 | \n\n | \n | \n | 9 | \n39.4 | \n3.8 | \n\n | \n | \n |
Reported outcomes in laparoscopic pancreaticoduodenectomy.
A summary of the outcomes reported for LPDs are presented in Table 1. The average operation time was 486.7 min (range 368–551 min), 8.5% (range 3–17%) conversions, 342.3 ml (range 195–592 ml) blood loss, 8.9 days (range 6–15 days) hospital stay, 32% (range 25–40%) morbidity, 2.6% (range 0–5%) mortality, 14.7% (range 6–28%) pancreatic fistulas, 21.1% (range 6–28%) harvested lymph nodes, and 89.7% (range 80–100%) R0 resection. The highest rate of conversions reported was due to suspected portal vein involvement [30]. Regarding morbidity rates, the highest rate was caused mainly by surgical site infection, postoperative pancreatic fistula, and intraabdominal access [30]. Myocardial infarctions and positive margins were the main mortality causes [30, 31]. Comparing these results with the conventional open approach [16], LPD leads to an increase in operating time, rate of pancreatic fistulas, and R0 resections; a decrease in estimated blood loss and harvested lymph nodes; and similar results in length of hospital stay, morbidity, and mortality rates.
\n\nMost of the studies reported longer operation times using the laparoscopic approach compared to the open approach [30, 35, 37]. Although some studies reported comparable outcomes between open and LPD [30], in general, reduction of blood loss and hospital stay [33, 34] are shown for LPD. In some studies, LPD was associated with equivalent overall hospital cost compared with open pancreaticoduodenectomy [37, 39]. While operating time and supply costs were higher for LPD, it was balanced by reduced cost due to the shorter postoperative hospital stay. A steep learning curve is another aspect associated with LDP and some researchers stated that this procedure should be performed in centers by surgeons with substantial knowledge, experience, and skills [34, 36].
\nLaparoscopic distal pancreatectomy (LDP) was first reported in 1996 by Gagner and Cuschieri [40, 41]. During this intervention, the tail of the pancreas or the tail and a portion of the body of the pancreas are removed. In some cases, the spleen is also removed. This operation is used more often to treat pancreatic NETs found in the tail and body of the pancreas. The determination of resectability is often based on the extent of involvement of the celiac axis [42].
\n\nA summary of the outcomes for LDPs are shown in Table 2. In brief, the average operation time was 215.2 min, 12% conversion rate, 241.7 ml estimated blood loss, 7.6 days length of hospital stay, 32.5% morbidity rate, 0.3% mortality rate, 21.2% pancreatic fistulas, 10.2% harvested lymph nodes, 89.5% R0 resection, and 46.3% spleen-preserving rate. Comparing these results with the outcomes from conventional open surgery [43, 44], there is a decrease in operation time, estimated blood loss, length of hospital stay, and mortality rate; similar morbidity rates; and an increased rate of pancreatic fistulas and spleen preservation.
\n\nSatisfactory oncological outcomes have been reported for LDP in patients with PDA and left-side pancreatic neoplasms [58, 61]. Although some studies reported similar outcomes as open distal pancreatectomy [21], most of the studies reported a clear reduction of blood loss [50, 53, 62, 63, 65] and hospital stay [45, 48, 50, 53, 31, 59, 61–65]. An increase in quality of life is reported when compared to the conventional approach [46]. Similar costs for the laparoscopic and open approaches are reported [63]. The increased OR cost associated with LDP is often offset by the shorter hospitalization and lower overall cost of postoperative care [57].
\n\nRegarding the spleen-preserving rate, results stated that it is worth to attempt laparoscopic spleen-preserving DP in patients with a presumed benign to borderline tumor of the body-tail of the pancreas [54]. The most positive results were reported for the splenic vessels preservation technique regarding the conservation of the spleen [51, 66].
\n\n | Conv. (%) | \nTime (min) | \nEBL (ml) | \nLHS (days) | \nMorb. (%) | \nMort. (%) | \nPF (%) | \nLN (%) | \nR0 (%) | \nSP (%) | \n|
---|---|---|---|---|---|---|---|---|---|---|---|
[21] | \n64 | \n32.8 | \n213 | \n275 | \n8 | \n16 | \n\n | 11 | \n8 | \n62 | \n79.6 | \n
[45] | \n535 | \n22.8 | \n\n | \n | 7 | \n\n | 0 | \n\n | 15 | \n86 | \n\n |
[46] | \n100 | \n23 | \n239 | \n464 | \n7.7 | \n66 | \n0 | \n53 | \n\n | 73.3 | \n\n |
[47] | \n94 | \n\n | \n | \n | \n | \n | \n | 0 | \n11 | \n\n | \n |
[48] | \n71 | \n9.1 | \n250 | \n150 | \n5 | \n28.2 | \n0 | \n11 | \n\n | 97.2 | \n15.5 | \n
[49] | \n67 | \n14.9 | \n203 | \n100 | \n6 | \n21 | \n1.5 | \n19 | \n6 | \n\n | \n |
[50] | \n107 | \n30 | \n193 | \n150 | \n5 | \n27 | \n0 | \n15 | \n\n | 97 | \n21 | \n
[51]* † | \n55 | \n9 | \n214.7 | \n342.8 | \n8.2 | \n27.3 | \n0 | \n16 | \n\n | \n | 93.4 | \n
[51]* † | \n85 | \n13 | \n199.2 | \n288.9 | \n10.5 | \n38.8 | \n0 | \n26 | \n3 | \n\n | 84.7 | \n
[52] | \n132 | \n6.1 | \n156.5 | \n197.4 | \n6 | \n43.2 | \n0.8 | \n21 | \n8 | \n96.2 | \n9.8 | \n
[53] | \n131 | \n31.3 | \n193 | \n262 | \n5 | \n32 | \n0 | \n8 | \n11 | \n100 | \n22.1 | \n
[54] | \n100 | \n2 | \n207 | \n\n | 8.7 | \n49 | \n0 | \n27 | \n\n | 98 | \n41 | \n
[55] | \n143 | \n5.6 | \n236 | \n334 | \n\n | \n | \n | 17 | \n\n | \n | \n |
[56] | \n902 | \n6.4 | \n316 | \n243 | \n18.9 | \n23.6 | \n\n | 66 | \n11 | \n\n | 32 | \n
[57] | \n70 | \n7.1 | \n145 | \n113 | \n5.8 | \n49 | \n0 | \n36 | \n5 | \n\n | \n |
[58] | \n196 | \n2.5 | \n220 | \n250 | \n8 | \n31.9 | \n0 | \n24 | \n10 | \n83.8 | \n\n |
[59] | \n144 | \n39.5 | \n\n | \n | 6.8 | \n\n | 0 | \n\n | 17 | \n87 | \n\n |
[60] | \n70 | \n7.1 | \n239 | \n\n | 9 | \n25.7 | \n0 | \n19 | \n3 | \n75.7 | \n\n |
[61] | \n359 | \n\n | 195 | \n\n | 8 | \n12 | \n0 | \n28 | \n20 | \n91.6 | \n49.6 | \n
[62] | \n82 | \n7 | \n188 | \n70 | \n4 | \n32.9 | \n0 | \n13 | \n\n | 97 | \n12 | \n
[63] | \n100 | \n4 | \n214 | \n171 | \n6.1 | \n34 | \n3 | \n17 | \n15 | \n100 | \n25 | \n
[64] | \n73 | \n15 | \n352 | \n\n | 5 | \n40 | \n0 | \n22 | \n\n | 97 | \n\n |
[65] | \n45 | \n0 | \n158.7 | \n122.6 | \n7.9 | \n26.7 | \n\n | 16 | \n\n | \n | 53.3 | \n
[66]† | \n70 | \n0 | \n220 | \n352 | \n10.4 | \n32.9 | \n0 | \n17 | \n\n | \n | 100 | \n
[67]* † | \n246 | \n0 | \n193.4 | \n378 | \n8.2 | \n32.5 | \n0 | \n20 | \n\n | \n | 54.8 | \n
[67]* † | \n203 | \n0 | \n204.4 | \n328 | \n7.7 | \n25 | \n0 | \n4 | \n\n | \n | \n |
Reported outcomes in laparoscopic distal pancreatectomy.
*Two groups.
†Spleen-preserving DP.
With growing surgical experience and refinement in the surgical technique, the indications for LDP have substantially broadened [52]. In this sense, the learning curve appeared to have been completed after 17 procedures [68], but strict selection criteria, high-volume hospital, and experienced team in open pancreatic surgery may play an important role in shortening this learning curve [69].
\nRecent interest in improving cosmetic outcomes has led to laparoendoscopic single-site surgery (LESS) being performed in a variety of procedures. In this sense, LESS is now consolidated as a real alternative to conventional laparoscopic surgery, with numerous studies sustaining its feasibility and therapeutic safety. However, single-site pancreatectomy has been explored and described only in recent years, and therefore, literature is limited to DP procedures and mostly to single case reports or small case series, as it is considered to be a challenging procedure. Only one study has been found for a PD through the single-site approach [70]. In this case, a surgical resection for a malignant melanoma metastatic to the pancreas was performed. The resection was carried out preserving the pylorus. No detailed information about the intervention and surgical outcomes were reported.
\n\n | Conv. (%) | \nTime (min) | \nEBL (ml) | \nLHS (days) | \nMorb. (%) | \nMort. (%) | \nPF (%) | \nLN (%) | \nR0 (%) | \nSP (%) | \n|
---|---|---|---|---|---|---|---|---|---|---|---|
[23] | \n20 | \n\n | 176 | \n\n | 2 | \n4 | \n20 | \n20 | \n0 | \n100 | \n90 | \n
[24] | \n14 | \n7.1 | \n166.4 | \n157.1 | \n7.6 | \n0 | \n7.1 | \n0 | \n\n | \n | 50 | \n
[71] | \n1 | \n0 | \n330 | \n100 | \n7 | \n1 | \n\n | 100 | \n0 | \n100 | \n0 | \n
[72] | \n1 | \n0 | \n170 | \n\n | 5 | \n\n | 0 | \n\n | \n | 100 | \n0 | \n
[73]† | \n1 | \n0 | \n233 | \n<100 | \n3 | \n\n | 0 | \n\n | \n | 100 | \n100 | \n
[74] | \n12 | \n20 | \n279.8 | \n185 | \n12.2 | \n3 | \n41.6 | \n25 | \n\n | 100 | \n33.3 | \n
[75] | \n8 | \n0 | \n145 | \n225 | \n6 | \n2 | \n50 | \n25 | \n\n | 100 | \n62.5 | \n
[76]* | \n2 | \n0 | \n232.5 | \n100 | \n7, 5 | \n\n | 0 | \n100 | \n\n | \n | \n |
[77] | \n1 | \n0 | \n\n | \n | 5 | \n0 | \n\n | \n | 0 | \n100 | \n0 | \n
Reported outcomes in single-site distal pancreatectomy.
*Two groups.
†Spleen-preserving DP.
The average operation time reported for LESS distal pancreatectomy (Table 3) was 218 min (range 145–330 min), 3% (range 0–20%) conversion rate, 144 ml (range 100–225 ml) estimated blood loss, 6 days (range 2–12 days) length of hospital stay, 15% (range 0–50%) morbidity, 0% mortality, 100% R0 resection, and 42% (range 0–100) spleen-preserving rate. Comparing the results with the conventional laparoscopic approach, there is a decreased rate of conversions, estimated blood loss, length of hospital stay, and morbidity; a similar mortality rate; increased average of pancreatic fistulas and R0 resections; and lower spleen-preserving rate.
\n\nBarbaros et al. [71] reported the first transumbilical laparoscopic single-site DP in a patient with metastatic lesions on the pancreas. The patient developed a pancreatic fistula. Haugvik et al. [75] compared the results of 8 single-incision DPs with 16 conventional LDPs. They reported no significant differences in operative time, intraoperative bleeding, resection status, and hospital stay between the two groups. Four surgical complications were reported for LESS and five for the conventional approach, including two patients for each group who developed a pancreatic fistula. There was no conversion to conventional laparoscopic or open surgery in any procedure. No differences between operative and postoperative results were also obtained by Yao et al. [24], who compared the surgical outcomes of 14 transumbilical laparoscopic single-site DPs with seven conventional multiport interventions. One conversion to open surgery and one case of leakage were reported for the LESS interventions. Machado et al. [23] reported 4 cases of pancreatic fistula in a study of 20 DPs. Some cases reported no surgical complications during the intervention [72, 76]. In a case study without using any commercial surgical port for LESS [77], the patient developed fever and leukocytosis after surgery. Bracale et al. [72] presented the first LESS DP for an adenocarcinoma. They reported no postoperative complications after 4 months follow-up.
\nSpleen preservation is an important issue in patients undergoing DP. However, only a few studies have reported spleen preservation through LESS. Chang et al. [73] reported a case of ransumbilical LESS spleen-preserving DP for a cystic tumor in the body of the pancreas. No surgical complications were reported. In another study, Han et al. [74] compared the results from 12 LESS DPs to 28 cases using a conventional laparoscopic approach. The mean surgery time and hospital stay in the LESS group were significantly longer. The spleen preservation was possible in 60.7% of the patients who underwent the conventional approach and 33.3% for the LESS. No significant differences in intraoperative blood loss, tumor size, conversion rate, and postoperative complications between the two groups were found.
\nIn general, authors stated that single-site laparoscopic PD is a feasible and safe technique [23, 72, 74], which can be successfully performed in selected cases and qualified centers [71, 73]. However, they also stated that it is a very demanding procedure with a steep learning curve [74].
\nRobotic platforms, as the da Vinci® Surgical System (Intuitive Surgical, Sunnyvale, CA, USA), try to overcome many of the key shortcomings of traditional laparoscopy that include monocular vision, limited degrees of freedom, and the effects of pivot and fulcrum, which make complex tasks difficult to master. However, there are also some drawbacks regarding the use of these systems such as the lack of tactile feedback and their cost, including maintenance. Since its first reported application in 2003 [78], the application of robotic technology in pancreatic interventions has been increasing. The main benefit of robotic-assisted PD in comparison with LPD may be the ease of intracorporeal reconstruction after a long resection [78].
\nIn the scientific literature, most of the studies regarding the robotic-assisted PD and DP are retrospective reviews and case reports (Table 4 and 5). The average operation time reported for robot-assisted PD (Table 4) was 489.1 min (range 410–568 min), 10% (range 0–22%) conversion rate, 324 ml (range 250–400 ml) estimated blood loss, 13.4 days (range 9–22 days) hospital stay, 48.6% (range 21–67%) morbidity rate, 3.8% (range 1–7%) mortality rate, 17.4% (range 7–30) pancreatic fistulas, 29% (range 11–70%) harvested lymph nodes, and 91% (range 87–95%) R0 resection. Comparing the results with conventional laparoscopic approach, operative time, length of hospital stay, and negative resections margins are similar; the rate of conversions, morbidity, mortality, and pancreatic fistulas are increased. Positive results have been obtained for robotic-assisted PD in patients with aberrant or anomalous hepatic arterial anatomy [22]. \nIn a prospective analysis with 150 patients, Polanco et al. [79] concluded that larger body mass index, higher EBL, smaller tumor size and smaller duct diameter are the main predictors of postoperative PF in robot-assisted PD. It appears that the learning curve for robot-assisted PD is attained within 80 cases [80].
\n\n | Conv. (%) | \nTime (min) | \nEBL (ml) | \nLHS (days) | \nMorb. (%) | \nMort. (%) | \nPF (%) | \nLN (%) | \nR0 (%) | \n|
---|---|---|---|---|---|---|---|---|---|---|
[22]* | \n112 | \n0 | \n500 | \n250 | \n9.5 | \n63.3 | \n6.7 | \n7 | \n20 | \n92.6 | \n
[79] | \n150 | \n7.3 | \n515 | \n300 | \n\n | \n | \n | 17 | \n\n | \n |
[80] | \n200 | \n6.5 | \n483 | \n250 | \n9 | \n67.5 | \n3.3 | \n17 | \n11 | \n92 | \n
[84] | \n60 | \n\n | 410 | \n400 | \n20 | \n35 | \n1.7 | \n13 | \n23 | \n94.7 | \n
[85] | \n50 | \n22 | \n421 | \n394 | \n22 | \n\n | \n | 30 | \n70 | \n90 | \n
[86] | \n50 | \n16 | \n568 | \n350 | \n10 | \n56 | \n2 | \n20 | \n36 | \n89 | \n
[87] | \n132 | \n8.3 | \n527 | \n>400 | \n10 | \n21 | \n5.3 | \n17 | \n14 | \n87.7 | \n
Reported outcomes in robotic-assisted pancreaticoduodenectomy.
*Two groups.
\n | Conv. (%) | \nTime (min) | \nEBL (ml) | \nLHS (days) | \nMorb. (%) | \nMort. (%) | \nPF (%) | \nLN (%) | \nR0 (%) | \nSP (%) | \n|
---|---|---|---|---|---|---|---|---|---|---|---|
[45] | \n535 | \n23 | \n\n | \n | 7 | \n\n | \n | \n | 3 | \n86 | \n\n |
[82] | \n100 | \n2 | \n246 | \n150 | \n\n | 72 | \n0 | \n42 | \n13 | \n95.7 | \n\n |
[83] | \n55 | \n0 | \n278.2 | \n\n | 12.6 | \n61.8 | \n0 | \n53 | \n58 | \n100 | \n61.8 | \n
[87] | \n83 | \n2.4 | \n256 | \n>200 | \n6 | \n13 | \n0 | \n43 | \n17 | \n97 | \n\n |
[88]† | \n69 | \n0 | \n150 | \n100 | \n11.6 | \n40.6 | \n0 | \n25 | \n22 | \n100 | \n65.2 | \n
Reported outcomes in robotic-assisted distal pancreatectomy.
†Spleen-preserving DP.
Regarding robot-assisted DP, the average operation time was 232.6 min (range 150–278 min), 5.5% (range 0–23%) conversion rate, 125 ml (range 100–150 ml) estimated blood loss, 9.3 days (range 6–13 days) hospital stay, 46.9% (range 13–72%) morbidity rate, 0% mortality rate, 40.7% (range 24–53%) pancreatic fistula, 22.6% (range 3–58%) harvested lymph nodes, 95.7% (range 86–100%) R0 resection, and 63.5% (range 62–65%) spleen-preserving rate. Comparing these results with the conventional laparoscopic approach, there is a decreased conversion rate and EBL; and increased operation time, length of hospital stay, morbidity, rate of pancreatic fistulas, R0 resections, and spleen-preserving rate. Morbid obesity and technical difficulty seem to be the two most common reasons for conversion from robotic-assisted hepatobiliary and pancreatic surgery [81]. It appears that the learning curve for robot-assisted DP is approximately 10–40 cases [82, 83].
\nIn order to cope with some of the limitations in MIS and guide the surgeon during the surgical procedure, image-guided techniques have been developed. The lack of tactile feedback and 3D sensation in video-assisted surgery accelerated the need for these techniques. In addition, for the human eye, several pathologies, such as the presence of nonsuperficial tumors, are not easily distinguishable from surrounding normal tissue. This makes, in some occasions, decision-making during surgery a very difficult process. During image-guided surgery, diagnostic imaging is used in conjunction with images from the operative field to improve the localization and targeting of pathologies, as well as to monitor and control treatments. The combination of tracking technologies for recording the position of the patient and the surgical instruments with preoperative and intraoperative images provides a comprehensive assistance tool for guiding any MIS intervention [27, 89–91]. Image-guided technology allows for more precise and accurate procedures, allowing surgeons to decide the best approach to address a specific disease before the intervention [92].
\nRadical surgical resection of tumor tissue is currently the best chance for cure. However, this option is only suitable for a minority of patients, and surgical procedures are complex with high rates of local recurrence. The presence of microscopic residual tumor tissue at the resection margins is one of the main prognostic factors, and therefore optimizing the surgical procedure to prevent positive resection margins is of the utmost importance. Accordingly, intraoperative margin assessment and visualization techniques, as well as image-guided techniques may be advantageous in guiding the surgeon to achieve curative resections.
\nAdvances in technology over the last 30 years have seen the application of laparoscopic ultrasound (LUS) expand beyond its initial limited diagnostic role to assisting in tumor staging, guiding intervention, locating lesions intraoperatively, assessing anatomic relationships, and in directed therapy [93–95]. The main application of LUS during pancreatic and liver surgery is providing real-time imaging guidance for resectability assessment and detection of vessel involvement, aiming to decrease the number of irradical resections [95]. The reported overall sensitivity, specificity, and accuracy of combined diagnostic laparoscopy and LUS in predicting resectability has been reported to be 100, 91, and 96%, respectively [96]. LUS should be considered for confirmation of staging of disease when there is a strong suspicion of unresectability and tumor borders are not clearly defined by CT scan [96].
\nLUS plays an integral part in the management of cystic lesions of the pancreas, particularly the characterization of suspected intraductal papillary mucinous neoplasms (IPMNs) [95, 97, 98]. IPMNs appear as well-defined hypoechoic masses with associated posterior enhancement. The malignant potential of IPMNs is directly related to its relationship with the main pancreatic duct and adjacent blood vessels (Figure 1). LUS allows defining the cysts borders (Figure 2) and evaluating the relationship of the lesion with the main duct and any major vessels [95, 98, 99].
\nLUS image of a pancreatic cystic tumor. The lesion appears as a hypoechoic mass (yellow arrow).
In the case of pancreatic adenocarcinomas, they appear as a homogeneous hypoechoic mass with poorly defined margins. Large tumors can display a mixed echogenicity. A sensitivity of 90% for assessing positive lymph nodes and 100% for venous invasion have been reported for laparoscopy combined with LUS examination [100]. Regarding NETs, LUS facilitates intraoperative decision-making and demonstrates anatomic details, such as the tumor location and its relation to the adjacent vascular structures and main pancreatic duct [95, 97]. In ultrasound images, NETs typically appear as well-defined, homogeneous, and hypoechoic masses [93]. Findings from LUS inspection help to decide whether to perform either tumor enucleation or resection during laparoscopic intervention [93].
\nNear-infrared (NIR) light (700–900 nm) is a novel imaging technique that can penetrate through several millimeters even centimeters of tissue, revealing targets below the tissue surface [101]. This imaging modality does not use ionizing radiation or direct tissue contact, making it a remarkably safe technique. NIR fluorescent contrast agents can be visualized with acquisition times in the millisecond range, enabling real-time guidance during surgery. Furthermore, as NIR light is invisible to the human eye, it does not alter the look of the surgical field, thus minimizing the learning curve [102]. The main aim of this imaging modality is to fill the gap between preoperative imaging and intraoperative reality.
\nFluorescence-guided systems provide an additional tool for diagnosis of pancreatic cancer, real-time image guidance during tumor resection, and inspection to confirm complete resection [103]. This intraoperative modality can assist surgeons to visualize tumors, sentinel lymph nodes, and vital structures in real time [102]. This technology could represent the next step to improving treatment of pancreatic cancer in laparoscopic resections. However, most of the published studies for pancreatic surgery are limited to animal models.
\nTwo main components are needed for fluorescence-guided surgery, fluorescent contrast agents and a NIR camera system. Several intraoperative NIR fluorescence camera systems have been developed for both open and laparoscopic surgery, some of which are commercially available and Food and Drug Administration (FDA) approved [104]. Fluorescent contrast agents contain a fluorescent component (fluorophore), which emits NIR fluorescent light after being excited with a NIR light source. Visualization of the tissue is based on the signal of the contrast agent in the region of interest relative to the background signal, known as signal-to-background ratio.
\nIndocyanine green (ICG) and methylene blue (MB) are the only NIR fluorophores that are registered with the FDA and the European Medicines Agency for clinical use. ICG emits fluorescent light at ≈800 nm and it is cleared rapidly by the liver and almost exclusively excreted into the bile, permitting imaging of bile ducts. MB has been applied clinically for many years as a visible contrast agent, and when diluted to levels that are almost undetectable to the human eye, MB becomes a fluorophore emitting at ≈700 nm. MB is cleared equally by both liver and kidney, permitting imaging of both bile ducts and ureters. ICG has been shown to accumulate around hepatic metastasis of pancreatic and colorectal cancers [105]. Methylene blue tends to accumulate in NETs after high-dose intra-arterial injection [103, 106]. The chemical structures of both ICG and MB do not allow these agents to be conjugated to tissue-specific, therefore, they are nonspecific NIR contrast agents [102, 107].
\nApplications of this technique during hepatopancreatobiliary surgery include tumor imaging in liver and pancreas, and real-time imaging of the biliary tree. Pessaux et al. [26] presented a robotic pancreaticoduodenectomy assisted by fluorescence imaging, providing enhanced visualization of the common bile and cystic ducts during the intervention (Figure 1). Subar et al. [108] reported a case of a LPD to treat an ampullary lesion in the duodenum. Before the pancreaticojejunostomy, the viability of the margin of the remnant pancreas was assessed with NIR imaging. The NIR technique improved the detection of ischemic tissue of the pancreatic margin after resection. This may lead to an increase in blood supply to the pancreatic anastomosis, and therefore potentially help to decrease the incidence of pancreatic fistulas.
\nIn a study with different pancreatic tumors on three experimental porcine models, we analyzed the usefulness of NIR imaging during laparoscopic pancreaticoduodenectomy and single-site distal pancreatectomy procedures. In two animals, a tumor model was created in the head of the pancreas. In the third animal, the tumor model was developed in the tail of the pancreas. NIR imaging was used as guidance during LPD and LESS distal pancreatectomy. The patency of the hepaticojejunostomy was assessed by means of ICG excretion and fluoroscopic imaging. During surgery, identification of the biliary anatomy and vascular anatomy of the pancreas was possible in all procedures using NIR imaging (Figure 3). Biliary excretion of ICG was not clearly visualized during the patency test, but fluoroscopic imaging was positive in one case.
\nNIR image of biliary and pancreatic anatomy: Cystic artery (a, yellow arrow), cystic duct (b, yellow arrow), and pancreaticoduodenal artery (c, yellow arrow).
To obtain the full advantage of NIR fluorescence imaging for pancreatic cancer visualization, such as tumor imaging, tumor specific NIR conjugated agents need to be designed and tested. The tumor-targeting capability of the fluorophore-conjugated anticarcinoembryonic antigen antibody has been demonstrated in orthotopic models for intraoperative tumor visualization of both primary and metastatic deposits of pancreatic cancer [25, 109]. Metildi et al. [109] concluded that mice treated with fluorescence-guided laparoscopic surgery permitted adequate labeling and distinction of tumor margins before tumor resection, decreasing local recurrence, and increasing survival compared to mice treated with standard bright-light laparoscopic surgery.
\nSurgical navigation systems (SNS) combine preoperative and intraoperative image information with position and orientation tracking of surgical instruments during the surgical intervention as a surgical decision-making tool helping to improve the safety, accuracy, and efficiency of surgeries [27, 91, 92]. In MIS, due to surgeon having less visual and tactile perception compared to open surgery, image assistance becomes extensively helpful for 3D understanding of the surgical scenario and localization of lesion and essential anatomic structures.
\nThe basic setup of a SNS consists of a preoperative image data (typically MR and CT), a tracking system (mainly electromagnetic or optical), a computer platform with screen, and the respective navigation software [89]. The combination of image-guided surgery with navigation technology consists of several steps, which are critical to ensure safety and accuracy of a procedure [27]: (1) acquisition of preoperative images and visualization for optimal diagnosis and planning, (2) accurate registration of preoperative data to the patient coordinate space and visualization in the OR, (3) intraoperative image acquisition and visualization/fusion with the preoperative images to update for anatomical shifts, and (4) postoperative imaging and visualization for evaluation of the surgical treatment.
\nDespite the use of navigation systems, abdominal surgery is still a challenging task. Commercial SNS are available for resection and ablation procedures of the liver (example: CAScination AG, Switzerland). However, to the best of our knowledge, no commercial systems are available or studies in the scientific literature have been published regarding the use of SNS for assistance during pancreatic cancer surgery.
\nWe were recently able to demonstrate the usefulness of the CustusX navigation system for image guidance during a patient case, a distal pancreatectomy for the resection of a cystic tumor in the body of the pancreas (unpublished case). CustusX is an open-source navigation research platform for image-guided interventions [91]. This platform has been successfully used for many clinical applications such as neurosurgery, spine procedures, bronchoscopy, endovascular therapy, and laparoscopic procedures like adrenalectomy and lately for liver and pancreas surgery [91, 110–112].
\nSnapshot of the CustusX platform during a distal pancreatectomy. The tumor is shown in green and the pancreas in yellow. The US imaging is superimposed on the 3D model from a preoperative MRI scan.
Prior to surgery, MR and CT images were acquired and imported into the navigation system software for reconstruction into 3D. The anatomical structures of interest, including the pancreas, tumor, and vessels were segmented semiautomatically [112]. The navigation system was integrated with a LUS probe running on an ultrasound scanner (Ultrasonix, Canada) with digital research interface to the navigation system. The probe was tracked by an electromagnetic sensor integrated in the tip. A probe calibration was carried out in a laboratory using a robotic arm and a well-defined geometric structure in a water tank [113]. An intraoperative registration procedure was carried out to combine the intraoperative LUS with the corresponding preoperative MR and CT images, displaying them simultaneously (Figure 4). This enabled the location of the lesion based on multimodal display, providing a useful tool for the surgeons to identify the anatomical structures of interest, meet their relation to other adjacent structures, and define safely and accurately the resection margin during the course of the distal pancreatectomy.
\n\nAnother available technology for intraoperative surgical guidance is augmented reality (AR). In surgery, AR is the fusion of artificial computer-generated images (3D virtual model) generally obtained from preoperative medical imaging and real-time patient images with the aim to visualize unapparent anatomical details. This results in the visualization of internal structures through overlying tissues, providing a virtual transparent vision of surgical anatomy. Potential advantages of the use of this imaging technology in surgery include the delineation of dissection planes or resection margins and the avoidance of injury to invisible structures.
\nThe registration process is one of the main challenges of AR, in which the virtual model and intraoperative images should be merged in real time. In this sense, intraoperative accuracy is highly affected by mobile or deformable structures due to the heartbeat, ventilation, or laparoscopic insufflation.
\nA method to overlay anatomical information from preoperative CT studies onto the patient’s body surface during gastrointestinal, hepatobiliary, and pancreatic surgery was presented by Sugimoto et al. [114]. For enabling the simultaneous display of the gastrointestinal tract and pancreatobiliary duct with associated blood vessels, a carbon dioxide-enhanced virtual multiple detector CT cholangiopancreatography was performed. Manual registration based on physiological markers was used. However, this method does not deal with possible alteration of the patient anatomy during the course of the surgery. A robotic pancreaticoduodenectomy assisted by AR was presented by Pessaux et al. [26]. In this study, a 3D virtual model of the patient from a preoperative CT scan was manually merged with the stereoscopic images from the da Vinci® robotic system.
\nPancreatic cancer has a high mortality rate and, at the time of diagnosis, the number of patients with potentially resectable tumors is considerably low. Surgery is still the only viable option for treatment of pancreatic cancer. However, surgical procedures for pancreatic resection are complex and require high surgical expertise. Pancreatic tumors can be treated through laparoscopic surgery with similar outcomes to the conventional approach. In general, studies reported that minimally invasive pancreatic surgery is feasible, safe, and with a steep learning curve. Laparoscopic procedures reported a reduction of blood loss, length of hospital stay, and positive resection margins, as well as an improvement in spleen-preserving rates when compared to open surgery. Laparoendoscopic single-site surgery reduces the blood loss and morbidity, compared with the conventional laparoscopic approach. In robot-assisted pancreatic surgery, reported surgical outcomes are similar to laparoscopic surgery, with an apparent increase in the splenic preservation rate and negative resection margins.
\nLaparoscopic pancreatic surgery has some technical limitations for the surgeon such as the reduced tactile and visual information. Besides, intraoperative tumor identification may be a challenging task in some cases due to the anatomical location of the pancreas, nearby major vascular structures, and frequently inflamed surrounding pancreatic tissue. These limitations may significantly impact the surgical procedure to prevent positive resection margins. Image-guided techniques provide intraoperative margin assessment and visualization methods, which may be advantageous in guiding the surgeon to achieve curative resections, resulting in improved surgical outcomes. Reported cases of fluorescence-guided pancreatic surgery showed that this imaging technique could be beneficial in surgeries where the pancreatic anatomy is difficult to identify. Navigation systems combine preoperative and intraoperative imaging, providing location of the anatomical structures of interest with respect to surgical instruments as well as the extent of the tumor to be addressed, which allows for a safe and precise definition of resection margins. Thus, surgeons will have a comprehensive system to support and guide pancreatic surgeries, with the ultimate goal of improving surgical outcomes and increase the rate of negative resections and the subsequent positive effect on the life expectancy of the patient.
\nThis study was supported by the Norwegian National Advisory Unit for Ultrasound and Image-Guided Therapy (St. Olav’s Hospital, NTNU, SINTEF); SINTEF; St. Olavs University Hospital; Liaison Committee between the Central Norway Regional Health Authority (RHA); the Norwegian University of Science and Technology (NTNU); the Extremadura Region Government, Spain; and the European Social Fund (PO14034).
\nFunctional near-infrared spectroscopy (fNIRS) is a non-invasive method for the detection of brain activity using changes in the local levels of oxyhemoglobin (oxyHb), deoxyhemoglobin (deoxyHb), and total hemoglobin (total Hb) [1]. fNIRS imposes fewer physical restrictions on patients compared with positron emission tomography (PET) or functional magnetic resonance imaging (fMRI), allowing investigators to measure and analyze cerebral circulation and metabolism while the patient walks or moves his/her upper body. Recently, studies showed that brain activity during rehabilitation [2] and car driving [3, 4, 5, 6] may also be measured using fNIRS. In 1991, the first study of fNIRS utilizing localized changes in the levels of oxyHb and deoxyHb was conducted by Kato and his colleagues at the National Center of Neurology and Psychiatry, Tokyo, Japan [1].
This study was the first to demonstrate that the activation of Hb in the human brain during photic stimuli was associated with increased levels of oxyHb, deoxyHb, and total Hb in the visual cortex. Of note, the measurements in the prefrontal cortex did not show clinically meaningful changes in the levels of these three indices. The original fNIRS technique was able to detect local activation of the brain during a task that is stronger than the signals during rest, by placing pairs of probes 2.5 cm apart on the scalp over the targeted cortex [7, 8, 9].
Thus, fNIRS solved the problem of oxygenation monitoring in NIRS [10, 11]. The measurement of targeted temporal changes in task-related activation markedly reduced data noise from the blood flow in the scalp at rest and from artifact-related bodily movement. Nowadays, more than 25 years later, statistical processing and mapping of changes in the levels of hemoglobin measured by fNIRS are used for the evaluation of brain activity.
The advantage of fNIRS over fMRI and other modalities is the ability to simultaneously and independently measure the levels of oxyHb and deoxyHb. Combined, these data may be used as indices reflecting changes in both blood volume and oxygenation.
However, the temporal resolution of fNIRS is fairly low on a 40–100 ms scale, compared with the underlying neural activity which is spanning from 1 to 3 ms of action potential firing and can be recorded extracranially using magnetoencephalography (MEG). MEG can be sensitive on subcortical activity in a case of large extent of activated neuronal assembly and spatial extent of activated cortical assembly [12, 13].
In slow voluntary movements of the self-paced index finger, the activity of the sensorimotor area was detected before 4.5 seconds of the pre-movement using electroencephalography (EEG) [14]. Consistent with the findings of EEG, early deoxygenation of 3–4 seconds prior to the movement of the finger was observed in the sensorimotor area using fNIRS [15]. Presently, research on simultaneous measurements using fNIRS and EEG is becoming an effective means of brain-computer interface [16].
In addition, a disadvantage of fNIRS is the low spatial resolution (5–10 mm) of the activation mapping of the cortical surface compared with those obtained from fMRI and PET. Research combining the use of fNIRS, fMRI, and MEG for source localization is currently ongoing [17]. These combination studies have advantages in temporal and spatial mapping of brain function.
A response involving increased and decreased levels of oxyHb and deoxyHb, respectively, has been considered the model of canonical activation in numerous studies utilizing fNIRS. However, the actual frequency of the occurrence of canonical activation, the most suitable index or indices for the differentiation between the center of activation and the surrounding area, and the associated degree of probability remain to be investigated. Following canonical activation, the rates of change in the levels of oxyHb and deoxyHb are not constant and may differ according to the task. Wylie et al. [18] performed a qualitative differentiation between two types of canonical activation according to the increase/decrease in the levels of total Hb. The investigators of that study identified four additional patterns of increase and decrease in the levels of oxyHb, deoxyHb, and total Hb that do not correspond to canonical activation.
Presently, the detection of the spatiotemporal characteristics of brain activity using fNIRS remains suboptimal. This fundamental limitation in evaluating brain activity may lead to misdiagnosis. fNIRS research is particularly challenging in the prefrontal cortex, responsible for complex higher functions. In areas of the brain with clear localization of cerebral function (i.e., primary motor or visual cortices), it is possible to verify the accuracy of fNIRS data. However, in the human prefrontal cortex, there is currently no clear understanding of the localization of the more complex functions, and thus, the verification of the reliability of fNIRS data in this area remains a challenge.
Studies have attempted to bolster the reliability of fNIRS in the prefrontal cortex by comparing data obtained from fNIRS and fMRI [19, 20]. However, because the mechanisms differ between the two modalities [21, 22, 23, 24], even if conformity is found between fMRI and fNIRS data, the reliability of the results is not necessarily increased. Several problems have been pointed out. Considerable attention is required when analyzing with the index of oxyHb alone. In the prefrontal region, task-dependent data noise in the oxyHb response (increased levels) resulting from skin blood flow has been reported [25, 26]. In 2011, an article criticized the use of NIRS in the clinical diagnosis of psychiatric disorders as being insufficiently supported by scientific evidence [27]. In mental illness studies, the actual localization of increases in the levels of oxyHb is not clear [28], and therefore, measurements of oxyHb levels cannot be linked to a specific brain activity.
Furthermore, analytical challenges in the field of fNIRS have been reported. This review introduces new composite functional indices incorporating ratios of changes in the levels of oxyHb and deoxyHb, along with a novel vector-based fNIRS method [29, 30]. This vector-based approach can be used to visually and quantitatively evaluate combinations of changes in the levels of oxyHb and deoxyHb as new indices. It was useful to classify variations in the levels of hemoglobin in response to neural activity, using combinations of changes in the levels of hemoglobin. It was effective especially when the signal change is small such as initial dips. Initial dips are the hemodynamic reactions of oxyHb and deoxyHb induced by increased oxygen consumption in the early tasks of approximately 2–3 seconds [31, 32]. The vector-based approach could improve the sensitivity of fNIRS in the detection of brain activity both temporally and spatially through recognition of the initial dips from the skull to hemodynamic responses [33, 34, 35, 36].
In addition, this review discusses challenges with data analysis based on a single index, advantages of the simultaneous analysis of multiple indicators, and recently established composite indicators.
Prior to the development of fNIRS, NIRS was used mainly for monitoring cerebral oxygenation. Changes in tissue oxygen saturation are accompanied by simultaneous changes in cerebral blood volume. Using NIRS, Jöbsis [37] reported hypocapnia and a reduction in cerebral blood volume during human hyperventilation. In addition, NIRS was used to prevent hypoxia through monitoring newborn and premature infants [10, 11]. Of note, NIRS had also been used to investigate the brains of animals [38, 39, 40].
In 1990, Takashima et al. [41] used NIRS to examine patients with probes placed 5 cm apart from each other. This study was based on the original concept of the research conducted by Jöbsis [29]. The results of this study showed reductions in the levels of oxyHb, deoxyHb, and total Hb in the prefrontal area during hyperventilation. Until 1990, research on NIRS did not target the specific localized brain function of the cerebral cortex. The technique was merely used to observe changes in the levels of hemoglobin (task-related and at rest), without specific spatial identification.
Hypocapnia is known to cause global changes in the scalp and the entire brain. Hence, the changes reported during hyperventilation did not constitute proof of functional local brain activity. These early studies of hyperventilation suggested that blood volume was reduced in the region supplied by the external carotid artery, which distributes blood mainly to the scalp and muscles outside the skull. In brain death, in spite of the absence of blood flow through the internal carotid artery, the blood flow distribution through the external carotid artery remains unimpaired—an observation known as “the finding of the hollow skull” [42]. Early data obtained using NIRS data were affected by this blood flow from areas of the scalp supplied by the external carotid artery and the veins.
In addition, probes placed in the prefrontal area of seven healthy patients in a task of pressure for 1 minute on the jugular vein reported increases in the levels of oxyHb, deoxyHb, and total Hb [41]. These results were consistent with those obtained from an animal study (Figure 1 [40]), indicating task-related hemodynamic changes prior to 1990. Importantly, the presence of a task does not differentiate fNIRS from NIRS.
Changes in the levels of HbO2 (oxyhemoglobin, oxyHb), HbR (deoxyhemoglobin, deoxyHb), and HbO2 + HbR (total hemoglobin, total Hb) with neck compression [
Until 1990, NIRS had not been considered a tool for the identification of specific cortical activity. In the usage of NIRS at the time, there was no technique that data could be obtained selectively from a site on the cortex located directly under a site sandwiched between irradiation and detection probes, let alone evidence of brain activity. The near-infrared light paths and the range and depth of irradiation were unknown. Moreover, the influence of factors such as the external carotid artery was undeniable. Early NIRS did not associate changes in the levels of Hb with localized brain activity and was unable to clearly distinguish between signals derived from the external carotid artery or the veins and those derived from the cortex.
fNIRS was developed in 1991 [1, 7, 8, 9, 31] as a functional imaging method using NIRS to detect local brain activity accurately. This was achieved by identifying changes in the levels of Hb in different areas of the brain at rest and during a task. It was necessary to initially demonstrate that NIRS was able to detect localized brain activity to establish fNIRS. The selection of an experimental task and the settings of the probe were the key factors in this process. In the search for a task, lesion studies and PET studies were reviewed to identify a small part of the brain that could be clearly stimulated and measured from the frontal lobe. A multifocal increase in regional cerebral blood flow (CBF) had been reported in a mental arithmetic task in the frontal lobe [43]. Furthermore, mental arithmetic tasks to induce an autonomic nerve stimulus had been used to show the possibility of blood volume changes in the region supplied by the external carotid artery [44, 45]. Dyscalculia was not sufficiently localized, because it occurs in multiple sites of the frontal and temporal lobes from injury, etc. [46].
The cerebral metabolic rate of oxygen (CMRO2) was shown to increase by approximately 10% in a study using thinking tasks [47]. However, when compared with that observed at rest, this change in regional cerebral blood volume (CBV) was not significant. Exercise tasks produced side effects from movement of the probes and systemic circulation. In addition, a PET study had shown that blood flow increased in both the primary motor area of the frontal lobe and the nearby supplemental motor areas [48]. Overall, the confirmation of localization in the frontal lobe was challenging. The primary auditory cortex is located inside the Sylvian fissure, and there was no certainty that near-infrared light would be able to reach the site and reflect back to produce meaningful data.
In summary, an experiment designed to confirm that localization was possible using fNIRS required a task meeting the following conditions:
It should not stimulate the autonomous nervous system.
It should not induce global activation of the brain.
It should avoid the region supplied by the external carotid artery (possibility of changes in the volume of blood).
It should not involve pressure on the carotid artery.
It should not require bodily motion.
It should not target brain activity from the frontal or temporal lobes (possibility of movement of the scalp or muscles).
It should induce brain activity within a well-defined site.
According to these conditions, a suitable task would be one that stimulates the primary visual cortex, located in the occipital lobe and supplied with blood mostly from the posterior cerebral artery. An earlier study had reported an increase in CBF in the visual cortex with a task of 7.8 Hz photic stimulation [49]. A major question at that point was the following: “What kind of response in terms of local Hb levels would be obtained in a photic stimulation experiment using NIRS?” Other, more practical problems included the use of external light with the NIRS equipment and the irradiation of the stimulus light to the patient wearing the probes. However, these problems were resolved during the experiment. As shown by PC darkness in Figure 2, the influence of extraneous light could be eliminated in actual experiments.
Changes in the levels of oxyhemoglobin (oxyHb), deoxyhemoglobin (deoxyHb), total hemoglobin (total Hb), Cyt (Cytochromeaa3), and PC darkness (photon counting darkness) measured over the occipital surface (above) and the frontal surface (below) prior to, during, and after photic stimulation in a healthy adult. Background noise from extraneous light was monitored as PC darkness. The data show spatial (site-dependent) and temporal (task on/off) differences in response [
In 1991, the time course of responses arising from changes in the local levels of oxyHb, deoxyHb, and total Hb remained unknown. Therefore, it was necessary to perform measurements on different sites that would demonstrate brain activity and a null response. It was thought that the detection of varied responses from different sites in response to a given stimulus could demonstrate the localization of function.
In the actual experiment, photic stimulation (8 Hz) was delivered using a photosonic stimulator (Nihon Kohden Co., Japan) from the front and at the height of the patient’s line of sight for 5 minutes. As Figure 2 shows, the activation observed in the visual cortex during the photic stimulus was associated with increased levels of oxyHb, deoxyHb (slightly), and total Hb. No changes were observed in the prefrontal cortex following photic stimulation. These findings demonstrated that fNIRS is able to detect spatial and temporal information (i.e., different hemodynamic responses), depending on the site and the presence or absence of stimulation.
Today, fNIRS is widely used for tasks or in environments difficult for other modalities. Although the above list of requirements for task selection may seem outdated, the first four conditions are still required to distinguish between local activity and global change. The difference between local activity and global changes is still determined by the presence or absence of a response, limitation to a specific site, and dependence on the duration of the task.
A fundamental part for fNIRS is probe placement. As Figure 3A shows, Jöbsis [37] used infrared transillumination and optical computed tomography (CT) to create images of blood flow distribution at rest corresponding to brain structures. He estimated the optical path length of the human head to be 13.3 cm [37]. In addition, he stated that an interprobe distance of ≥4.25 cm would allow the detection of data from the brain tissue rather than the scalp (Figure 3B [50]). Although the diffused and reflected light used today had already replaced infrared transillumination, subsequent research on cerebral oxygenation monitoring [41] continued to use this setting (distance between probes ≥4.25 cm).
(A) Conceptual schema of optical computed tomography performed by Jöbsis illustrated on a magnetic resonance imaging (MRI) image (revision from [
During the design of the first investigation using fNIRS, MRI showed that the distance between the scalp and the primary visual cortex was <1 cm in neonates and <2 cm in adults and demonstrated the gentle curvature of the skull [51]. The shape of the skull permitted further reduction in the distance between the probes (Figure 3C) and improved the detection of activity in the cerebral cortex.
In the study, placement of the probes 5 cm apart revealed only a slight increase in the levels of oxyHb. When the distance between the probes was shortened to 4 cm, the increase in the levels of oxyHb became more pronounced. At an interprobe distance of 2.5 cm, a transient dip in the levels of oxyHb was observed. This effect occurred simultaneously with the initiation of the stimulus, followed promptly by an increase in the levels of oxyHb, faster peak latency, and a post-stimulus undershoot in oxyHb. At an interprobe distance of 1.0–1.5 cm, there was either no response at all or the total amounts of Hb remained unchanged while small mirror-image changes were observed, namely an increase and decrease in the levels of oxyHb and deoxyHb, respectively. These mirror-image changes may have been derived from either the scalp (where metabolism does not increase) or from vascular changes in the veins on the surface of the brain. From these findings, it was established that an interprobe distance of 2.5 cm provided the most robust results (Figure 3D).
Based on this empirical hypothesis, the area on the scalp corresponding to the visual cortex that can be covered with two probes was considered to be 1.0 × 2.5 cm, as identified through sagittal MRI. Each pair of emitter and receptor probes was placed 2.5 cm apart vertically to prevent data noise from activity in the secondary visual cortex and the large vein running vertically through the sagittal sinus.
The movement of the probes outward by 1.0 cm impaired the detection of response in the pilot study. Thus, pairs of probes (channels) were placed within 1.0 cm of the target in the horizontal direction to ensure accuracy. This adjustment permitted the investigators to develop the concept of functional resolution (in this case 1.0 × 2.5 cm) for the identification of the precise area of response. The original NIRS apparatus used (NIRO 1000, Hamamatsu Photonics K.K., Japan), shown in Figure 4, had only two channels and 5-mm diameter optical fibers for the emission and reception of light with 8 × 8 mm contact surfaces.
The NIRO 1000 (Hamamatsu Photonics K.K., Japan) used in the first functional near-infrared spectroscopy experiment [
The concept that the spatial resolution of fNIRS should be determined by the anatomy of the cerebral cortex and the range in which a response occurs was developed from this early research. To establish the desired resolution, the distance between the probes and the distance between the channels should be controlled independently. The more recently available multichannel fNIRS devices have become essential for the localization of brain activity. Unless the interchannel distance is changed depending on whether the measurement target is deep or wide from the scalp, the likelihood of detecting a localized response is reduced. In newborns, the distance between the brain and the surface of the cortex is <1 cm [51, 52]. Thus, in infants, the distance between probes should be shortened to 1–2 cm [53], rather than being set at 2.5 cm apart [7, 8, 9, 54]. The 3-cm apart matrix array of probes commonly used in recent years [55, 56] cannot necessarily provide results corresponding to the actual distribution of brain function in usage not considering age and head size. Spatial identification may not be performed effectively when a probe “hat” with probes arranged without reference to the anatomy of the brain/scalp is used. Registration markers and MRI should be used to determine the localization of probe placement for each individual.
In late 1992, Hoshi and Tamura [57] reported findings from research using task-related NIRS. The investigators reported a calculation task which stimulated the autonomic nervous system with an interprobe distance of 4 cm. This protocol did not meet the requirements for either task selection or probe settings described earlier in this review, and thus, the method is not considered fNIRS. Villringer et al. [58] selected probe positions on the scalp with interprobe distances ranging from 4 to 7 cm. In 1993, Chance et al. [59] also performed the task-related NIRS experiments from the frontal skull. However, they were unable to demonstrate localization. Advances in techniques for the improvement of spatial resolution continued. The spatial resolution of the 3 cm2 probe arrangement failed to provide detailed information regarding responses in the cortex [60]. Highly selective probe arrangements for establishing high-density measurement points have been reported (e.g., one with 10-mm channel interval and 25-mm probe interval [31, 32], and one with a center probe and surrounding probes [61]). Structural MRI has been used to evaluate the distance between the brain and the scalp [62]. Moreover, a method using diffuse optical tomography for removing signals on the scalp has been reported [63, 64, 65].
Of note, fNIRS has also been used in animal studies. The results have shown that measurement of fNIRS indices from the scalp with an interprobe distance of 4 and 8 mm was possible in the brain of rats [66] and cats, respectively. As Figure 5 shows, using fNIRS (ETG-100, Hitachi Medical Co., Tokyo, Japan), an initial dip was able to measure hemoglobin indices in the visual cortex during photic stimulation from outside the skull of a cat. In particular, the fNIRS response pattern to photic stimulation was identical between the cat and the human brains [67, 68]. These animal studies suggested that it was possible to use fNIRS for the detection of activity in a 1–2 mm region of the targeting cortex from the scalp.
Time series data of hemodynamic response showing an initial dip in the levels of total hemoglobin decreased through stimulation using light in the cat brain. A thick black line indicates stimulation using light.
Numerous current fNIRS devices measure the levels of oxyHb, deoxyHb, and total Hb independently. A new challenge is that spatiotemporal characteristics may vary in functional brain imaging depending on the index used, and this problem has not been widely recognized or studied. In 1991, Kato et al. reported increases in the levels of oxyHb, deoxyHb (slight), and total Hb in the primary visual cortex during photic stimulation. Subsequent studies using fMRI and fNIRS reported increases and decreases in the levels of oxyHb and deoxyHb, respectively, in motor and visual tasks [69, 70, 71]. These results were accepted as typical fNIRS responses and have been corroborated by numerous fNIRS studies [1].
Nowadays, atypical responses are mostly ignored and left unexplained. There is a widespread tendency, hypothesized patterns of hemoglobin reaction in advance and those that are not hypothesized reaction types tend to be statistically excluded from the analysis data without being insufficiently examined [72]. In response to this trend, recent studies also have processed statistically and mapped independently the observed increase and decrease in the levels of oxyHb [73, 74] and deoxyHb [75, 76], respectively. Even in studies using rats, their analysis may be performed using only oxyHb [77].
However, evaluation of brain activity using a single hemoglobin index is contrary to the physiological mechanisms involved, ignoring the fact that hemodynamic responses include both blood volume and oxygenation. The distinction between blood volume and oxygenation, applying to fNIRS and fMRI [23, 24], has been a subject of controversy. This remains an unresolved problem common to all brain functional imaging research based on hemodynamic responses. The beginning of this argument can be traced back to Roy and Sherrington, who in 1890 proposed neurovascular coupling. Changes in oxygenation and blood volume in the capillaries reflect neuronal activity. However, as Roy and Sherrington noted, these data were not derived from the capillaries [78].
The first to report the quantification of CBF using Fick’s law (i.e., subtracting the value of the veins from that of arteries, in units of per 100 g per minute) were Kety et al. [79]. Increases in CBF, calculated without taking the capillaries into account, show a positive correlation with increasing CMRO2 [80]. Based on slight increases in CMRO2 observed following an increase in CBF [81], a coupling model of a positive correlation between CBF and CMRO2 [82, 83] was used widely to evaluate vascular response. Changes in CBF were used as a substitute for changes in oxygen metabolism. It is likely that this trend also affected fNIRS and led to the independent analysis of the levels of oxyHb, as performed today. Recent waveforms of increases in the levels of oxyHb closely resemble the waveforms of increases in blood flow reported by Roy and Sherrington in 1890. After more than 120 years, the interpretation of neurovascular coupling has not advanced considerably. Roy and Sherrington had foresight in their interpretation related to blood flow, but they did not observe cerebral oxygen metabolism.
Although the capillary transit time in humans is reported to be <10 seconds [84], PET sampling times are markedly longer. For this reason, PET data include changes in CBF in the capillaries related to oxygen exchange, coupled with the additional component of the delayed increase in CBF in the veins not accompanied by oxygen exchange. Using PET, a dissociation between CMRO2 and CBF has been reported [85, 86]. Using fMRI, signals have been shown to remain unaltered during the capillary transit time [87]. In other words, there is a need to move beyond the simplistic interpretation of neurovascular coupling, which predicts an increase in the levels of oxyHb and blood flow in response to neural activity. Figure 6 shows the relationship between neural activity and hemodynamic response schematically.
Schematic diagram of the possible hemodynamic responses occurring simultaneously with neural activity (revision from [
fNIRS is able to measure the levels of oxyHb and deoxyHb at the same time. Therefore, it is a useful tool to solve this serious problem of simultaneously measuring cerebral blood flow and cerebral oxygen metabolism which are faced by brain researchers for over 120 years. Future fNIRS research should distinguish between changes in blood volume and oxygenation occurring simultaneously with brain activity in the analysis of hemodynamic responses. In addition, it is necessary to re-evaluate activity-based hemodynamic responses using modalities such as EEG and MEG.
Research involving event-related optical signals [87] and invasive optical measurements [88, 89] has been unable to distinguish between oxygenation and blood volume. OxyHb and deoxyHb are involved in both oxygenation and blood volume. Thus, it may not be possible to evaluate brain activity based exclusively on the measurement of the levels of oxyHb.
Currently, an experimental protocol termed block task design, employing tasks that continue for ≥10 seconds (longer than the capillary transit time), is being used in many fNIRS studies. The reason for this is that the peak latency of oxyHb is generally 10 seconds (occasionally longer) from the initiation of a task. The use of this method in fNIRS studies has followed from its use in fMRI and PET research, where the low temporal resolution of the modality justifies the use of a block design. When a task requires a longer period of time corresponding to a block design or the task requires a certain amount of time to elapse for observation, the selection of a block design protocol in research using fNIRS, providing higher temporal resolution, is appropriate. With fNIRS, there is no need to repeat cognitive tasks involving factors such as perception, recognition, or judgment for prolonged time to obtain a sufficiently strong peak response in oxyHb levels. A block design including many task components does not clarify the correspondence between each task component and spatiotemporal local brain activity. Studies have also analyzed post-task time periods [90, 91]. However, the data from these studies lacked simultaneity with local brain activity and were unable to temporally and spatially identify local brain activity. Although EEG shows high simultaneity between data and brain activity, it is characterized by poor spatial resolution. In this respect, if the spatial resolution of fNIRS can be set from the standpoint of functional resolution as described earlier, its high temporal resolution may be valuable for event-related measurements.
The initial dip, which is early deoxygenation in event-related experiments, is a highly accurate spatial indicator of neural activity [92]. In studies using optical intrinsic signals (OIS), increase in the levels of deoxyHb occurring prior to slow increases in the levels of oxyHb or total Hb has also been considered to be an index of increased oxygen metabolism [88, 93, 94, 95, 96, 97]. The absence of a correspondence (spatial or temporal) between increases in early deoxygenation and blood volume was also shown in a human study using invasive optical imaging [98]. Kato et al. [67, 68, 99, 100] conducted the first fNIRS study measuring initial dips appearing in fNIRS signals from the motor, visual, and language areas. Subsequently, the initial dip was observed in several fNIRS studies [18, 32, 33, 34, 35, 36, 101].
It has been suggested that this early increase in the levels of deoxyHb may arise from a transient increase in the consumption of oxygen in tissues [102, 103]. It has been obvious that this deoxyHb increase is useful as a precise indicator of brain activity, but against the background that this increase in deoxyHb has been difficult to detect. For example, there is the case of less likely early deoxyHb increase depend on factors such as the type of task or the use of anesthesia [92]. A minimal and very localized increase may be attributed to imprecise fNIRS probe settings (i.e., missing the center of activity) or masking due to a strong increase in blood flow in the veins compromising detection.
With fMRI, what was reported previously as an early increase in the levels of deoxyHb was observed as an “initial dip” [21, 104, 105]. However, fMRI does not differentiate between oxyHb and deoxyHb. In addition, the relationship between increases or decreases in the levels of oxyHb and the increase in the levels of deoxyHb has not been investigated.
The more recently developed vector-based NIRS method [29, 30] is able to measure initial dips characterized by the canonical dip pattern showing increased deoxyhemoglobin, as well as several different hemoglobin patterns corresponding to differences in the degree of oxygen metabolism [32]. This method has permitted the reproducible measurement of hypoxic–ischemic initial dips (i.e., decreased levels of oxyHb) [34, 35, 36]. The initial dip at which the level of deoxyHb increases and the reaction where oxyHb increases after 2–3 seconds do not necessarily occur at the same site. Moreover, research on the intersection of these responses is limited, leading investigators to select one of the two responses (i.e., the typical oxyHb response or the initial dip) for the evaluation of brain activity. This serious problem may arise from the lack of quantification of brain activity. Indeed, the results of the evaluation of laterality in the language area [106, 107] may differ depending on the index used [108]. In addition, investigation of the relationship between event-related oxyHb and deoxyHb responses, especially those within seconds from neural activity, in previous fNIRS studies has been limited.
An advantage of fNIRS over other modalities is the simultaneous measurement of the levels of oxyHb and deoxyHb. However, this advantage leads to the following question: What do the various possible combinations of oxyHb, deoxyHb, and total Hb mean? Early fNIRS lacked a quantitative integrated theory for the interpretation of combinations of hemoglobin indices from multiple channels. Kato [29, 30] developed a quantitative method of analysis of the ratios between changes in the levels of oxyHb (ΔO) and deoxyHb (ΔD) to differentiate between oxygenation and blood volume.
This technique uses a two-dimensional vector plane on which vector tracks generated by task-related changes in cerebral blood volume (ΔCBV) and change in cerebral oxygen exchange (ΔCOE) are quantitatively classified into eight “phases.” This provides a visible graphical display of information concerning hemodynamic responses (Figure 7). This vector-based approach is able to calculate the angle
Functional near-infrared spectroscopy vector plane. Revised from [
Figure 7 shows an orthogonal vector coordinate plane defined by the ΔO and ΔD axes. Rotating this vector plane 45° counterclockwise results in an orthogonal vector coordinate plane defined by the ΔCBV and ΔCOE axes. For ΔCOE, a positive value indicates hypoxic change from ΔCOE = 0, whereas a negative value indicates hyperoxic change. The relationships among these four axes are described by the following square matrix:
Expansion of these shows ΔCBV and ΔCOE representing blood volume and oxygenation, respectively:
The scalar
The angle
A vector on the polar coordinate plane contains the four Hb indices (i.e., ΔO, ΔD, ΔCBV, and ΔCOE). The relationships between the four Hb vectors (Figure 7) are defined by the equations shown earlier in this section: Eqs. (1) and (2) define hemoglobin changes; Eq. (5) defines the scalar
The angle
Phases 1 through 5 on the vector plane were dip phases, showing increases in ΔD or ΔCOE; the presence of an event-related vector in these phases defined an initial dip.
Phase 1 (0 < ΔD < ΔO, ΔCOE<0 < ΔCBV) and Phase 2 (0 < ΔO < ΔD, 0 < ΔCOE<ΔCBV) are canonical dips [79], in which both ΔD and ΔO increase.
Phase 3 (ΔO < 0 < ΔD, 0 < ΔCBV<ΔCOE) is a hypoxic-hyperemic dip, in which ΔO decreases and ΔCBV increases.
Phase 4 (ΔO < 0 < ΔD, ΔCBV<0 < ΔCOE) and Phase 5 (ΔO < ΔD < 0, ΔCBV<0 < ΔCOE) are hypoxic–ischemic dips, in which ΔCOE increases and ΔCBV decreases.
Phases −1 through −3 are non-dip phases, in which ΔD and ΔCOE decrease.
Regarding oxygen metabolism, responses in the dip phases may indicate stronger brain activity than those in the non-dip phases. It is necessary to verify the strongest dip phases during the evaluation of the regulation between the oxygenation axis (ΔCOE) and the blood volume axis (ΔCBV) in the vector plane. The typical response corresponds to Phases −1 and − 2, interpreted as brain activity with a low degree of oxygen exchange. The responses in other phases should be evaluated in the same manner and the frequency of their occurrence should be investigated based on phase classifications. The percentage of dips in Wernicke’s area in Phases 1 and 2 was low (total: 15–21%). However, in Phases 4 and 5, this percentage was higher (total: 62–68%) [32]. Differences in the frequency of phase depending on the brain site and the task may have different physiological implications. The ratio between the decrease and increase in the levels of deoxyHb and oxyHb, respectively, in a typical response is not constant. The quantitative values of the phase angle
In Figure 8, time course data for previously reported initial dips are reproduced on a vector plane using the vector-based technique. Figure 8A and 8B show two different types of dip in different phases, depending on the observed change in the ΔCBV. In both fMRI and OIS, the canonical initial dip has been considered to be a response induced by increased levels of deoxyHb. Figure 8B shows an fNIRS initial dip (an increased ΔD accompanying a decreased ΔO), indicating Phase 4 [18, 32, 67, 68]. Recently, fNIRS was used to observe this new type of initial dip in primates [109].
Two kinds of initial dips [
As shown in Figure 8A, if this canonical initial dip detected by Malonek and Grinvald using OIS [94] corresponds to that of fMRI [95, 104], this would mean that the a blood oxygenation level-dependent (BOLD) signal from fMRI was able to differentiate between Phase 1, as a signal decrease, and Phase −1, as a signal increase. However, Phase 1 is an increased ΔCBV dip, in which ΔCOE decreases while the levels of deoxyHb increase. Thus, there is a discrepancy between the results from the two modalities. A theory bridging fNIRS and fMRI has been proposed, suggesting that a BOLD signal influenced by changes in ΔCBV closely resembles an increase in the levels of oxyHb [24]. In this model, the fMRI signal in the increased ΔCBV phase depends on the observed change in ΔO (not ΔD). Theoretically, this change may be considered to be a BOLD signal increase rather than a dip. Indeed, the use of the vector plane may explain the fact that the OIS initial dip does not correspond to that of fMRI.
In present, initial dips could be reliably detected with OIS [92, 93, 94, 95, 96, 97] and fNIRS [31, 32, 33, 34, 35, 36, 109]. On the other hand, the occurrence of the initial dip in fMRI has been doubted and its mechanism is still controversial [21, 22, 23, 24, 105]. Logothetis et al. [86] reported a period of latency, when the increase in the BOLD signal was flat for a few seconds at the beginning of the task. This shows the difficulty in detecting changes in phases during passage through the capillaries from those in the BOLD signal. Of note, the sensitivity of fMRI declines at detecting activities with high oxygen consumption. During early research on the combination of fMRI and fNIRS [9, 110], the concept of phases had not been introduced and the differences between these methods were not understood clearly.
Collectively, research has shown that these two modalities are physiologically inconsistent in their sensitivity to the initial dip, with significant differences between them. Moreover, animal studies have demonstrated the variation of ratios between changes in the levels of deoxyHb and oxyHb occurring simultaneously with neural activity (i.e., diversity of phase) [103, 109]. Using the concept of phases, it is also possible to re-evaluate the results of a previous fNIRS study [8] (Figure 2) and confirm that the results indicate Phase 1 in areas where oxygen consumption is high or in the time zone. The vector-based evaluation was able to show a short initial dip and sustained oxygen metabolism because the period of the task was long in this study. On the other hand, investigations that followed this previous study [8] may have evaluated the intensity of brain activity only (similar to
Local brain activity was quantified for the first time in 1993 using continuous-wave fNIRS, by substituting optical differential path length factors [8]. At that time, mmol∙mm (or mmol∙cm) was commonly used as the unit expressing the degree of change in the levels of Hb, taking the differential path length factor as 1 [111, 112]. The phase angle k expresses oxygen metabolism quantitatively in degrees. This offers the advantage of being independent of the actual levels of Hb. Figure 9 shows image displays from a verbal task [29, 30]. Local increases in the angle
Spatiotemporal imaging of cerebral oxygen exchange for a verbal task [
It has been shown that vector-based NIRS is able to quantitatively evaluate differences in the oxygen load in the prefrontal cortex arising from different breathing routes (Figure 10 [113]). In that study, although there were no significant differences in
Time courses of the angle
In usage of this vector-based approach, it may not be possible to obtain the correct phase value by conventional data processing. For example, if the deoxyHb and oxyHb data are processed independently (e.g., when normalization or statistical parametric mapping has been performed on only the oxyHb data) [114], this will change the ratios, and there is a risk that the values of k will be distorted.
In addition, a method of baseline correction, in which linear regression connecting the pre- and post-task period is used to emphasize the typical response, is available [115]. This may affect the angle
The precise detection of local brain activity was the original purpose of fNIRS. Nowadays, because of the vector-based approach, investigators can measure initial dips from the scalp. Progress has been achieved in the quantitative detection of local brain activity and the development of spatiotemporal imaging. However, some fNIRS studies are actually task-related studies using NIRS, never intended for the spatial localization of brain function. This together with other factors has introduced doubts regarding the validity of fNIRS. The historical background described earlier in this review may be useful as we attempt to erase these doubts and improve the spatial and temporal accuracy of fNIRS. Studies are warranted to examine the physiological significance of the different combinations of changes in the levels of the different Hb and changes in the characteristics of mapping depending on the selection of indices.
Local brain activity induces local oxygen consumption and demand for oxygen supply. Further research is required to investigate the relationship between the consumption of oxygen and the spatial distribution of oxygen supply accompanying local brain activity. The indices angle
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Ismail"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7504",title:"Renewable Geothermal Energy Explorations",subtitle:null,isOpenForSubmission:!1,hash:"d47d551b0fcf11a4328c8a38f2499844",slug:"renewable-geothermal-energy-explorations",bookSignature:"Basel I. Ismail",coverURL:"https://cdn.intechopen.com/books/images_new/7504.jpg",editedByType:"Edited by",editors:[{id:"62122",title:"Dr.",name:"Basel I.",middleName:"I.",surname:"Ismail",slug:"basel-i.-ismail",fullName:"Basel I. Ismail"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5084",title:"Advances in Geothermal Energy",subtitle:null,isOpenForSubmission:!1,hash:"d4647f1f9dae170acf327283d55abbf1",slug:"advances-in-geothermal-energy",bookSignature:"Basel I. Ismail",coverURL:"https://cdn.intechopen.com/books/images_new/5084.jpg",editedByType:"Edited by",editors:[{id:"62122",title:"Dr.",name:"Basel I.",middleName:"I.",surname:"Ismail",slug:"basel-i.-ismail",fullName:"Basel I. Ismail"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:3,seriesByTopicCollection:[],seriesByTopicTotal:0,mostCitedChapters:[{id:"49252",doi:"10.5772/61372",title:"Using Ground-Source Heat Pump Systems for Heating/Cooling of Buildings",slug:"using-ground-source-heat-pump-systems-for-heating-cooling-of-buildings",totalDownloads:3847,totalCrossrefCites:3,totalDimensionsCites:14,abstract:"This chapter mainly presents a detailed theoretical study and experimental investigations of ground-source heat pump (GSHP) technology, concentrating on the ground-coupled heat pump (GCHP) systems. A general introduction on the GSHPs and its development, and a description of the surface water (SWHP), ground-water (GWHP), and ground-coupled heat pumps are briefly performed. The most typical simulation and ground thermal response test models for the vertical ground heat exchangers (GHEs) currently available are summarized. Also, a new GWHP using a heat exchanger with special construction, tested in laboratory, is well presented. The second objective of the chapter is to compare the main performance parameters (energy efficiency and CO2 emissions) of radiator and radiant floor heating systems connected to a GCHP. These performances were obtained with site measurements in an office room. Furthermore, the thermal comfort for these systems is compared using the ASHRAE Thermal Comfort program. Additionally, two numerical simulation models of useful thermal energy and the system coefficient of performance (COPsys) in heating mode are developed using the TRNSYS (Transient Systems Simulation) software. Finally, the simulations obtained in TRNSYS program are analysed and compared to experimental measurements.",book:{id:"5084",slug:"advances-in-geothermal-energy",title:"Advances in Geothermal Energy",fullTitle:"Advances in Geothermal Energy"},signatures:"Ioan Sarbu and Calin Sebarchievici",authors:[{id:"173440",title:"Prof.",name:"Ioan",middleName:null,surname:"Sarbu",slug:"ioan-sarbu",fullName:"Ioan Sarbu"},{id:"176508",title:"Dr.",name:"Calin",middleName:null,surname:"Sebarchievici",slug:"calin-sebarchievici",fullName:"Calin Sebarchievici"}]},{id:"49547",doi:"10.5772/61651",title:"Airborne Magnetic Surveys to Investigate High Temperature Geothermal Reservoirs",slug:"airborne-magnetic-surveys-to-investigate-high-temperature-geothermal-reservoirs",totalDownloads:2642,totalCrossrefCites:4,totalDimensionsCites:6,abstract:"Airborne magnetic survey is an effective geophysical exploration method in terms of coverage, resolution and cost, particularly for area with restricted or difficult ground access. Research studies in New Zealand have shown airborne magnetic surveys can indicate the regions of high reservoir permeability and thermal up-flow of active geothermal systems. However, the method has not been extensively used in the geothermal investigations, probably because the interpretation of airborne magnetic data has so far been seen as difficult and requires a complex quantitative 3D modelling of subsurface magnetisation.",book:{id:"5084",slug:"advances-in-geothermal-energy",title:"Advances in Geothermal Energy",fullTitle:"Advances in Geothermal Energy"},signatures:"Supri Soengkono",authors:[{id:"176580",title:"Dr.",name:"Supri",middleName:null,surname:"Soengkono",slug:"supri-soengkono",fullName:"Supri Soengkono"}]},{id:"64812",doi:"10.5772/intechopen.81157",title:"Geothermal Explorations on the Slate Formation of Taiwan",slug:"geothermal-explorations-on-the-slate-formation-of-taiwan",totalDownloads:1306,totalCrossrefCites:3,totalDimensionsCites:4,abstract:"Currently, over 90% operated geothermal power plants are distributed in the volcanic- or magmatic intrusion-related geological systems. Only a few cases are done in metamorphic terranes, especially on the slate formation. Taiwan is located at the ring of fire and is famous for the young orogenic belt, which has wide distributions of rapid uplifting terranes with few active volcanoes. The metamorphic rocks, for example, schist and slate formations with high geothermal gradients, are occurring in the major mountain range. This chapter introduces the techniques or methods we used for geothermal exploration in the slate formation of the Chingshui geothermal field of Taiwan, where a 3-MW pilot geothermal power plant had been installed in 1983 and operated for 12 years.",book:{id:"7504",slug:"renewable-geothermal-energy-explorations",title:"Renewable Geothermal Energy Explorations",fullTitle:"Renewable Geothermal Energy Explorations"},signatures:"Sheng-Rong Song and Yi-Chia Lu",authors:[{id:"253615",title:"Prof.",name:"Sheng-Rong",middleName:null,surname:"Song",slug:"sheng-rong-song",fullName:"Sheng-Rong Song"},{id:"253623",title:"Dr.",name:"Yi-Chia",middleName:null,surname:"Lu",slug:"yi-chia-lu",fullName:"Yi-Chia Lu"}]},{id:"63548",doi:"10.5772/intechopen.81062",title:"Geothermal Potential of the Global Oil Industry",slug:"geothermal-potential-of-the-global-oil-industry",totalDownloads:1202,totalCrossrefCites:2,totalDimensionsCites:3,abstract:"There are around 40 new geothermal power projects commissioned in each of the last few years. Growth of the market is around 5% annually and current installed capacity is about 13,300 MW with about the same in development in 24 countries. These figures are impressive, but they do not bear comparison with any of the fossil fuels. However, few will realise that the global oil industry has a cryptic geothermal power potential that is equal to the entire current output of the geothermal industry. The oil industry is ageing. Many areas still produce copious quantities of oil, but the oil comes with an unwanted by-product, water. The volume of water produced is typically is 10–20 times that of the oil; and the water is hot—in some places very hot (>100°C). In a recent study we showed that the power depleted oil production platforms of the North Sea’s North Viking Graben produce sufficient hot water to deliver around 60% of the power requirement for each field. A review of global oil and hence water production has enabled us to calculate that power production alone from waste water from producing oilfields could be at least 15,000 MW.",book:{id:"7504",slug:"renewable-geothermal-energy-explorations",title:"Renewable Geothermal Energy Explorations",fullTitle:"Renewable Geothermal Energy Explorations"},signatures:"Jon Gluyas, Alison Auld, Charlotte Adams, Catherine Hirst, Simon Hogg\nand Jonathan Craig",authors:[{id:"258666",title:"Dr.",name:"Jon",middleName:null,surname:"Gluyas",slug:"jon-gluyas",fullName:"Jon Gluyas"},{id:"262369",title:"Dr.",name:"Alison",middleName:null,surname:"Auld",slug:"alison-auld",fullName:"Alison Auld"},{id:"262370",title:"Dr.",name:"Charlotte",middleName:null,surname:"Adams",slug:"charlotte-adams",fullName:"Charlotte Adams"},{id:"262371",title:"Dr.",name:"Catherine",middleName:null,surname:"Hirst",slug:"catherine-hirst",fullName:"Catherine Hirst"},{id:"262372",title:"Prof.",name:"Simon",middleName:null,surname:"Hogg",slug:"simon-hogg",fullName:"Simon Hogg"},{id:"262373",title:"Prof.",name:"Jonthan",middleName:null,surname:"Craig",slug:"jonthan-craig",fullName:"Jonthan Craig"}]},{id:"64027",doi:"10.5772/intechopen.81017",title:"Stages of a Integrated Geothermal Project",slug:"stages-of-a-integrated-geothermal-project",totalDownloads:4195,totalCrossrefCites:2,totalDimensionsCites:3,abstract:"A geothermal project constitutes two big stages: the exploration and the exploitation. Each one has a single task whose results allow defining the feasibility of a geothermal project, until achieving the construction and operation stage of the power generation plant. The first stage contains the area recognition, its limitation to the target, and elimination of external factors until defining a geothermal zone with characteristics to be commercially exploited. The main studies and analysis that can be applied during the exploration stage are listed, and the major indicator to continue with the project or suspend is the prefeasibility report. The major risks in the exploration stage are due to studies that are carried out on the surface; at this stage, the costs can be considered low. The main results of the exploration are the selection of sites to drill three or four initial wells. Each well provides a direct overview of the reservoir: depth, production thicknesses, thermodynamic parameters, and production characteristics. The drilling of three to four exploratory wells is recommended, as far as there is certainty of the feasibility of the project, and the development of the field begins with drilling of sufficient wells to feed the plant. In this stage, the cost increases, but the risks decrease.",book:{id:"7504",slug:"renewable-geothermal-energy-explorations",title:"Renewable Geothermal Energy Explorations",fullTitle:"Renewable Geothermal Energy Explorations"},signatures:"Alfonso Aragón-Aguilar, Georgina Izquierdo-Montalvo,\nDaniel Octavio Aragón-Gaspar and Denise N. Barreto-Rivera",authors:[{id:"258358",title:"Dr.",name:"Alfonso",middleName:null,surname:"Aragón-Aguilar",slug:"alfonso-aragon-aguilar",fullName:"Alfonso Aragón-Aguilar"}]}],mostDownloadedChaptersLast30Days:[{id:"64027",title:"Stages of a Integrated Geothermal Project",slug:"stages-of-a-integrated-geothermal-project",totalDownloads:4216,totalCrossrefCites:2,totalDimensionsCites:3,abstract:"A geothermal project constitutes two big stages: the exploration and the exploitation. Each one has a single task whose results allow defining the feasibility of a geothermal project, until achieving the construction and operation stage of the power generation plant. The first stage contains the area recognition, its limitation to the target, and elimination of external factors until defining a geothermal zone with characteristics to be commercially exploited. The main studies and analysis that can be applied during the exploration stage are listed, and the major indicator to continue with the project or suspend is the prefeasibility report. The major risks in the exploration stage are due to studies that are carried out on the surface; at this stage, the costs can be considered low. The main results of the exploration are the selection of sites to drill three or four initial wells. Each well provides a direct overview of the reservoir: depth, production thicknesses, thermodynamic parameters, and production characteristics. The drilling of three to four exploratory wells is recommended, as far as there is certainty of the feasibility of the project, and the development of the field begins with drilling of sufficient wells to feed the plant. In this stage, the cost increases, but the risks decrease.",book:{id:"7504",slug:"renewable-geothermal-energy-explorations",title:"Renewable Geothermal Energy Explorations",fullTitle:"Renewable Geothermal Energy Explorations"},signatures:"Alfonso Aragón-Aguilar, Georgina Izquierdo-Montalvo,\nDaniel Octavio Aragón-Gaspar and Denise N. Barreto-Rivera",authors:[{id:"258358",title:"Dr.",name:"Alfonso",middleName:null,surname:"Aragón-Aguilar",slug:"alfonso-aragon-aguilar",fullName:"Alfonso Aragón-Aguilar"}]},{id:"64812",title:"Geothermal Explorations on the Slate Formation of Taiwan",slug:"geothermal-explorations-on-the-slate-formation-of-taiwan",totalDownloads:1307,totalCrossrefCites:3,totalDimensionsCites:4,abstract:"Currently, over 90% operated geothermal power plants are distributed in the volcanic- or magmatic intrusion-related geological systems. Only a few cases are done in metamorphic terranes, especially on the slate formation. Taiwan is located at the ring of fire and is famous for the young orogenic belt, which has wide distributions of rapid uplifting terranes with few active volcanoes. The metamorphic rocks, for example, schist and slate formations with high geothermal gradients, are occurring in the major mountain range. This chapter introduces the techniques or methods we used for geothermal exploration in the slate formation of the Chingshui geothermal field of Taiwan, where a 3-MW pilot geothermal power plant had been installed in 1983 and operated for 12 years.",book:{id:"7504",slug:"renewable-geothermal-energy-explorations",title:"Renewable Geothermal Energy Explorations",fullTitle:"Renewable Geothermal Energy Explorations"},signatures:"Sheng-Rong Song and Yi-Chia Lu",authors:[{id:"253615",title:"Prof.",name:"Sheng-Rong",middleName:null,surname:"Song",slug:"sheng-rong-song",fullName:"Sheng-Rong Song"},{id:"253623",title:"Dr.",name:"Yi-Chia",middleName:null,surname:"Lu",slug:"yi-chia-lu",fullName:"Yi-Chia Lu"}]},{id:"49252",title:"Using Ground-Source Heat Pump Systems for Heating/Cooling of Buildings",slug:"using-ground-source-heat-pump-systems-for-heating-cooling-of-buildings",totalDownloads:3851,totalCrossrefCites:4,totalDimensionsCites:15,abstract:"This chapter mainly presents a detailed theoretical study and experimental investigations of ground-source heat pump (GSHP) technology, concentrating on the ground-coupled heat pump (GCHP) systems. A general introduction on the GSHPs and its development, and a description of the surface water (SWHP), ground-water (GWHP), and ground-coupled heat pumps are briefly performed. The most typical simulation and ground thermal response test models for the vertical ground heat exchangers (GHEs) currently available are summarized. Also, a new GWHP using a heat exchanger with special construction, tested in laboratory, is well presented. The second objective of the chapter is to compare the main performance parameters (energy efficiency and CO2 emissions) of radiator and radiant floor heating systems connected to a GCHP. These performances were obtained with site measurements in an office room. Furthermore, the thermal comfort for these systems is compared using the ASHRAE Thermal Comfort program. Additionally, two numerical simulation models of useful thermal energy and the system coefficient of performance (COPsys) in heating mode are developed using the TRNSYS (Transient Systems Simulation) software. Finally, the simulations obtained in TRNSYS program are analysed and compared to experimental measurements.",book:{id:"5084",slug:"advances-in-geothermal-energy",title:"Advances in Geothermal Energy",fullTitle:"Advances in Geothermal Energy"},signatures:"Ioan Sarbu and Calin Sebarchievici",authors:[{id:"173440",title:"Prof.",name:"Ioan",middleName:null,surname:"Sarbu",slug:"ioan-sarbu",fullName:"Ioan Sarbu"},{id:"176508",title:"Dr.",name:"Calin",middleName:null,surname:"Sebarchievici",slug:"calin-sebarchievici",fullName:"Calin Sebarchievici"}]},{id:"49620",title:"Radiogenic Heat Generation in Western Australia — Implications for Geothermal Energy",slug:"radiogenic-heat-generation-in-western-australia-implications-for-geothermal-energy",totalDownloads:2040,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"The chapter reviews heat generation in crystalline rocks and influences on overlying sedimentary basins in Western Australia (WA). Regions of elevated thorium and uranium will cause elevated heat generation, which in turn can cause elevated heat flow. Western Australia hosts several large sedimentary basins with the potential for hot sedimentary aquifers (HSAs). These include the Perth, Carnarvon, and Canning basins. Parts of these basins are underlain by crystalline rocks that contain high levels of heat-generating elements, such as uranium, thorium, and potassium. Also, the Pilbara Craton, which contains both sedimentary and crystalline rocks, that entertains a number of active mines, which may benefit from geothermal energy, is investigated. Further, the southern part of the Perth Basin (Vasse Shelf), which is underlain by crystalline rocks with elevated concentrations of thorium and uranium, is shown to possess higher than usual temperatures. From observations, and geothermal modeling, it is concluded that the Perth Basin has a high potential for medium- to low-temperature geothermal energy developments. In other parts of Western Australia, the Carnarvon Basin has elevated temperatures in artesian groundwater. Heat flow in the Canning Basin is briefly reviewed; this basin has some geothermal potential, but it is far from the major population centers.",book:{id:"5084",slug:"advances-in-geothermal-energy",title:"Advances in Geothermal Energy",fullTitle:"Advances in Geothermal Energy"},signatures:"Mike F. Middleton",authors:[{id:"176416",title:"Dr.",name:"Mike",middleName:null,surname:"Middleton",slug:"mike-middleton",fullName:"Mike Middleton"}]},{id:"66034",title:"Introductory Chapter: Power Generation Using Geothermal Low-Enthalpy Resources and ORC Technology",slug:"introductory-chapter-power-generation-using-geothermal-low-enthalpy-resources-and-orc-technology",totalDownloads:1374,totalCrossrefCites:0,totalDimensionsCites:2,abstract:null,book:{id:"7504",slug:"renewable-geothermal-energy-explorations",title:"Renewable Geothermal Energy Explorations",fullTitle:"Renewable Geothermal Energy Explorations"},signatures:"Basel I. Ismail",authors:[{id:"62122",title:"Dr.",name:"Basel I.",middleName:"I.",surname:"Ismail",slug:"basel-i.-ismail",fullName:"Basel I. Ismail"}]}],onlineFirstChaptersFilter:{topicId:"649",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[],lsSeriesList:[],hsSeriesList:[],sshSeriesList:[],testimonialsList:[]},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. Dr. Beydemir is also Rector of Bilecik Şeyh Edebali University, Turkey.",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",slug:"deniz-ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",biography:"Dr. Deniz Ekinci obtained a BSc in Chemistry in 2004, MSc in Biochemistry in 2006, and PhD in Biochemistry in 2009 from Atatürk University, Turkey. He studied at Stetson University, USA, in 2007-2008 and at the Max Planck Institute of Molecular Cell Biology and Genetics, Germany, in 2009-2010. Dr. Ekinci currently works as a Full Professor of Biochemistry in the Faculty of Agriculture and is the Head of the Enzyme and Microbial Biotechnology Division, Ondokuz Mayıs University, Turkey. 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. Dr. Ekinci serves as the Editor in Chief of four international books and is involved in the Editorial Board of several international journals.",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null},{id:"17",title:"Metabolism",coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",isOpenForSubmission:!0,editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",slug:"yannis-karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",biography:"Yannis Karamanos, born in Greece in 1953, completed his pre-graduate studies at the Université Pierre et Marie Curie, Paris, then his Masters and Doctoral degree at the Université de Lille (1983). He was associate professor at the University of Limoges (1987) before becoming full professor of biochemistry at the Université d’Artois (1996). 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. His teaching areas are energy metabolism and regulation, integration and organ specialization and metabolic adaptation.",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null},{id:"18",title:"Proteomics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",isOpenForSubmission:!0,editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",slug:"paolo-iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",biography:"Paolo Iadarola graduated with a degree in Chemistry from the University of Pavia (Italy) in July 1972. He then worked as an Assistant Professor at the Faculty of Science of the same University until 1984. In 1985, Prof. Iadarola became Associate Professor at the Department of Biology and Biotechnologies of the University of Pavia and retired in October 2017. Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. He is a Consultant Reviewer for several journals, including the Journal of Chromatography A, Journal of Chromatography B, Plos ONE, Proteomes, International Journal of Molecular Science, Biotech, Electrophoresis, and others. He is also Associate Editor of Biotech.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",slug:"simona-viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",biography:"Simona Viglio is an Associate Professor of Biochemistry at the Department of Molecular Medicine at the University of Pavia. She has been working since 1995 on the determination of proteolytic enzymes involved in the degradation process of connective tissue matrix and on the identification of biological markers of lung diseases. She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. She is an author of about 90 publications (According to Scopus: H-Index: 23; According to WOS: H-Index: 20) on peer-reviewed journals, a member of the “Società Italiana di Biochimica e Biologia Molecolare,“ and a Consultant Reviewer for International Journal of Molecular Science, Journal of Chromatography A, COPD, Plos ONE and Nutritional Neuroscience.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null}]},overviewPageOFChapters:{paginationCount:49,paginationItems:[{id:"80495",title:"Iron in Cell Metabolism and Disease",doi:"10.5772/intechopen.101908",signatures:"Eeka Prabhakar",slug:"iron-in-cell-metabolism-and-disease",totalDownloads:2,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Iron Metabolism - Iron a Double‐Edged Sword",coverURL:"https://cdn.intechopen.com/books/images_new/10842.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"81799",title:"Cross Talk of Purinergic and Immune Signaling: Implication in Inflammatory and Pathogenic Diseases",doi:"10.5772/intechopen.104978",signatures:"Richa Rai",slug:"cross-talk-of-purinergic-and-immune-signaling-implication-in-inflammatory-and-pathogenic-diseases",totalDownloads:7,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Purinergic System",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"81764",title:"Involvement of the Purinergic System in Cell Death in Models of Retinopathies",doi:"10.5772/intechopen.103935",signatures:"Douglas Penaforte Cruz, Marinna Garcia Repossi and Lucianne Fragel Madeira",slug:"involvement-of-the-purinergic-system-in-cell-death-in-models-of-retinopathies",totalDownloads:4,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Purinergic System",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"81756",title:"Alteration of Cytokines Level and Oxidative Stress Parameters in COVID-19",doi:"10.5772/intechopen.104950",signatures:"Marija Petrusevska, Emilija Atanasovska, Dragica Zendelovska, Aleksandar Eftimov and Katerina Spasovska",slug:"alteration-of-cytokines-level-and-oxidative-stress-parameters-in-covid-19",totalDownloads:9,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Chemokines Updates",coverURL:"https://cdn.intechopen.com/books/images_new/11672.jpg",subseries:{id:"18",title:"Proteomics"}}}]},overviewPagePublishedBooks:{paginationCount:27,paginationItems:[{type:"book",id:"7006",title:"Biochemistry and Health Benefits of Fatty Acids",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7006.jpg",slug:"biochemistry-and-health-benefits-of-fatty-acids",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Viduranga Waisundara",hash:"c93a00abd68b5eba67e5e719f67fd20b",volumeInSeries:1,fullTitle:"Biochemistry and Health Benefits of Fatty Acids",editors:[{id:"194281",title:"Dr.",name:"Viduranga Y.",middleName:null,surname:"Waisundara",slug:"viduranga-y.-waisundara",fullName:"Viduranga Y. 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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"}}}]},{type:"book",id:"7978",title:"Vitamin A",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7978.jpg",slug:"vitamin-a",publishedDate:"May 15th 2019",editedByType:"Edited by",bookSignature:"Leila Queiroz Zepka, Veridiana Vera de Rosso and Eduardo Jacob-Lopes",hash:"dad04a658ab9e3d851d23705980a688b",volumeInSeries:3,fullTitle:"Vitamin A",editors:[{id:"261969",title:"Dr.",name:"Leila",middleName:null,surname:"Queiroz Zepka",slug:"leila-queiroz-zepka",fullName:"Leila Queiroz Zepka",profilePictureURL:"https://mts.intechopen.com/storage/users/261969/images/system/261969.png",biography:"Prof. Dr. Leila Queiroz Zepka is currently an associate professor in the Department of Food Technology and Science, Federal University of Santa Maria, Brazil. She has more than fifteen years of teaching and research experience. She has published more than 550 scientific publications/communications, including 15 books, 50 book chapters, 100 original research papers, 380 research communications in national and international conferences, and 12 patents. She is a member of the editorial board of five journals and acts as a reviewer for several national and international journals. Her research interests include microalgal biotechnology with an emphasis on microalgae-based products.",institutionString:"Universidade Federal de Santa Maria",institution:{name:"Universidade Federal de Santa Maria",institutionURL:null,country:{name:"Brazil"}}}]},{type:"book",id:"7953",title:"Bioluminescence",subtitle:"Analytical Applications and Basic Biology",coverURL:"https://cdn.intechopen.com/books/images_new/7953.jpg",slug:"bioluminescence-analytical-applications-and-basic-biology",publishedDate:"September 25th 2019",editedByType:"Edited by",bookSignature:"Hirobumi Suzuki",hash:"3a8efa00b71abea11bf01973dc589979",volumeInSeries:4,fullTitle:"Bioluminescence - Analytical Applications and Basic Biology",editors:[{id:"185746",title:"Dr.",name:"Hirobumi",middleName:null,surname:"Suzuki",slug:"hirobumi-suzuki",fullName:"Hirobumi Suzuki",profilePictureURL:"https://mts.intechopen.com/storage/users/185746/images/system/185746.png",biography:"Dr. Hirobumi Suzuki received his Ph.D. in 1997 from Tokyo Metropolitan University, Japan, where he studied firefly phylogeny and the evolution of mating systems. He is especially interested in the genetic differentiation pattern and speciation process that correlate to the flashing pattern and mating behavior of some fireflies in Japan. He then worked for Olympus Corporation, a Japanese manufacturer of optics and imaging products, where he was involved in the development of luminescence technology and produced a bioluminescence microscope that is currently being used for gene expression analysis in chronobiology, neurobiology, and developmental biology. Dr. Suzuki currently serves as a visiting researcher at Kogakuin University, Japan, and also a vice president of the Japan Firefly Society.",institutionString:"Kogakuin University",institution:null}]}]},openForSubmissionBooks:{paginationCount:7,paginationItems:[{id:"11667",title:"Marine Pollution - Recent Developments",coverURL:"https://cdn.intechopen.com/books/images_new/11667.jpg",hash:"e524cd97843b075a724e151256773631",secondStepPassed:!0,currentStepOfPublishingProcess:3,submissionDeadline:"April 20th 2022",isOpenForSubmission:!0,editors:[{id:"318562",title:"Dr.",name:"Monique",surname:"Mancuso",slug:"monique-mancuso",fullName:"Monique Mancuso"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{id:"11664",title:"Recent Advances in Sensing Technologies for Environmental Control and Monitoring",coverURL:"https://cdn.intechopen.com/books/images_new/11664.jpg",hash:"cf1ee76443e393bc7597723c3ee3e26f",secondStepPassed:!0,currentStepOfPublishingProcess:3,submissionDeadline:"May 4th 2022",isOpenForSubmission:!0,editors:[{id:"24687",title:"Dr.",name:"Toonika",surname:"Rinken",slug:"toonika-rinken",fullName:"Toonika Rinken"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{id:"11662",title:"Limnology - The Importance of Monitoring and Correlations of Lentic and Lotic Waters",coverURL:"https://cdn.intechopen.com/books/images_new/11662.jpg",hash:"f1043cf6b1daae7a7b527e1d162ca4a8",secondStepPassed:!0,currentStepOfPublishingProcess:3,submissionDeadline:"May 10th 2022",isOpenForSubmission:!0,editors:[{id:"315689",title:"Dr.",name:"Carmine",surname:"Massarelli",slug:"carmine-massarelli",fullName:"Carmine Massarelli"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null},{id:"10845",title:"Marine Ecosystems - Biodiversity, Ecosystem Services and Human Impacts",coverURL:"https://cdn.intechopen.com/books/images_new/10845.jpg",hash:"727e7eb3d4ba529ec5eb4f150e078523",secondStepPassed:!0,currentStepOfPublishingProcess:3,submissionDeadline:"May 12th 2022",isOpenForSubmission:!0,editors:[{id:"320124",title:"Dr.",name:"Ana M.M.",surname:"Gonçalves",slug:"ana-m.m.-goncalves",fullName:"Ana M.M. 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He is also a faculty member in the Molecular Oncology Program. He obtained his MSc and Ph.D. at Oregon State University and Texas Tech University, respectively. He pursued his postdoctoral studies at Rutgers University Medical School and the National Institutes of Health (NIH/NIDDK), USA. His research focuses on biochemistry, biophysics, genetics, molecular biology, and molecular medicine with specialization in the fields of drug design, protein structure-function, protein folding, prions, microRNA, pseudogenes, molecular cancer, epigenetics, metabolites, proteomics, genomics, protein expression, and characterization by spectroscopic and calorimetric methods.",institutionString:"University of Health Sciences",institution:null},{id:"180528",title:"Dr.",name:"Hiroyuki",middleName:null,surname:"Kagechika",slug:"hiroyuki-kagechika",fullName:"Hiroyuki Kagechika",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180528/images/system/180528.jpg",biography:"Hiroyuki Kagechika received his bachelor’s degree and Ph.D. in Pharmaceutical Sciences from the University of Tokyo, Japan, where he served as an associate professor until 2004. He is currently a professor at the Institute of Biomaterials and Bioengineering (IBB), Tokyo Medical and Dental University (TMDU). From 2010 to 2012, he was the dean of the Graduate School of Biomedical Science. Since 2012, he has served as the vice dean of the Graduate School of Medical and Dental Sciences. He has been the director of the IBB since 2020. Dr. Kagechika’s major research interests are the medicinal chemistry of retinoids, vitamins D/K, and nuclear receptors. He has developed various compounds including a drug for acute promyelocytic leukemia.",institutionString:"Tokyo Medical and Dental University",institution:{name:"Tokyo Medical and Dental University",country:{name:"Japan"}}},{id:"40482",title:null,name:"Rizwan",middleName:null,surname:"Ahmad",slug:"rizwan-ahmad",fullName:"Rizwan Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/40482/images/system/40482.jpeg",biography:"Dr. Rizwan Ahmad is a University Professor and Coordinator, Quality and Development, College of Medicine, Imam Abdulrahman bin Faisal University, Saudi Arabia. Previously, he was Associate Professor of Human Function, Oman Medical College, Oman, and SBS University, Dehradun. Dr. Ahmad completed his education at Aligarh Muslim University, Aligarh. He has published several articles in peer-reviewed journals, chapters, and edited books. His area of specialization is free radical biochemistry and autoimmune diseases.",institutionString:"Imam Abdulrahman Bin Faisal University",institution:{name:"Imam Abdulrahman Bin Faisal University",country:{name:"Saudi Arabia"}}},{id:"41865",title:"Prof.",name:"Farid A.",middleName:null,surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41865/images/system/41865.jpg",biography:"Farid A. Badria, Ph.D., is the recipient of several awards, including The World Academy of Sciences (TWAS) Prize for Public Understanding of Science; the World Intellectual Property Organization (WIPO) Gold Medal for best invention; Outstanding Arab Scholar, Kuwait; and the Khwarizmi International Award, Iran. He has 250 publications, 12 books, 20 patents, and several marketed pharmaceutical products to his credit. He continues to lead research projects on developing new therapies for liver, skin disorders, and cancer. Dr. Badria was listed among the world’s top 2% of scientists in medicinal and biomolecular chemistry in 2019 and 2020. He is a member of the Arab Development Fund, Kuwait; International Cell Research Organization–United Nations Educational, Scientific and Cultural Organization (ICRO–UNESCO), Chile; and UNESCO Biotechnology France",institutionString:"Mansoura University",institution:{name:"Mansoura University",country:{name:"Egypt"}}},{id:"329385",title:"Dr.",name:"Rajesh K.",middleName:"Kumar",surname:"Singh",slug:"rajesh-k.-singh",fullName:"Rajesh K. Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",biography:"Dr. Singh received a BPharm (2003) and MPharm (2005) from Panjab University, Chandigarh, India, and a Ph.D. (2013) from Punjab Technical University (PTU), Jalandhar, India. He has more than sixteen years of teaching experience and has supervised numerous postgraduate and Ph.D. students. He has to his credit more than seventy papers in SCI- and SCOPUS-indexed journals, fifty-five conference proceedings, four books, six Best Paper Awards, and five projects from different government agencies. He is currently an editorial board member of eight international journals and a reviewer for more than fifty scientific journals. He received Top Reviewer and Excellent Peer Reviewer Awards from Publons in 2016 and 2017, respectively. He is also on the panel of The International Reviewer for reviewing research proposals for grants from the Royal Society. He also serves as a Publons Academy mentor and Bentham brand ambassador.",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",country:{name:"India"}}},{id:"142388",title:"Dr.",name:"Thiago",middleName:"Gomes",surname:"Gomes Heck",slug:"thiago-gomes-heck",fullName:"Thiago Gomes Heck",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/142388/images/7259_n.jpg",biography:null,institutionString:null,institution:{name:"Universidade Regional do Noroeste do Estado do Rio Grande do Sul",country:{name:"Brazil"}}},{id:"336273",title:"Assistant Prof.",name:"Janja",middleName:null,surname:"Zupan",slug:"janja-zupan",fullName:"Janja Zupan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/336273/images/14853_n.jpeg",biography:"Janja Zupan graduated in 2005 at the Department of Clinical Biochemistry (superviser prof. dr. Janja Marc) in the field of genetics of osteoporosis. Since November 2009 she is working as a Teaching Assistant at the Faculty of Pharmacy, Department of Clinical Biochemistry. In 2011 she completed part of her research and PhD work at Institute of Genetics and Molecular Medicine, University of Edinburgh. She finished her PhD entitled The influence of the proinflammatory cytokines on the RANK/RANKL/OPG in bone tissue of osteoporotic and osteoarthritic patients in 2012. From 2014-2016 she worked at the Institute of Biomedical Sciences, University of Aberdeen as a postdoctoral research fellow on UK Arthritis research project where she gained knowledge in mesenchymal stem cells and regenerative medicine. She returned back to University of Ljubljana, Faculty of Pharmacy in 2016. She is currently leading project entitled Mesenchymal stem cells-the keepers of tissue endogenous regenerative capacity facing up to aging of the musculoskeletal system funded by Slovenian Research Agency.",institutionString:null,institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"357453",title:"Dr.",name:"Radheshyam",middleName:null,surname:"Maurya",slug:"radheshyam-maurya",fullName:"Radheshyam Maurya",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/357453/images/16535_n.jpg",biography:null,institutionString:null,institution:{name:"University of Hyderabad",country:{name:"India"}}},{id:"311457",title:"Dr.",name:"Júlia",middleName:null,surname:"Scherer Santos",slug:"julia-scherer-santos",fullName:"Júlia Scherer Santos",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311457/images/system/311457.jpg",biography:"Dr. Júlia Scherer Santos works in the areas of cosmetology, nanotechnology, pharmaceutical technology, beauty, and aesthetics. Dr. Santos also has experience as a professor of graduate courses. Graduated in Pharmacy, specialization in Cosmetology and Cosmeceuticals applied to aesthetics, specialization in Aesthetic and Cosmetic Health, and a doctorate in Pharmaceutical Nanotechnology. Teaching experience in Pharmacy and Aesthetics and Cosmetics courses. She works mainly on the following subjects: nanotechnology, cosmetology, pharmaceutical technology, aesthetics.",institutionString:"Universidade Federal de Juiz de Fora",institution:{name:"Universidade Federal de Juiz de Fora",country:{name:"Brazil"}}},{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",slug:"abdulsamed-kukurt",fullName:"Abdulsamed Kükürt",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRNVJQA4/Profile_Picture_2022-03-07T13:23:04.png",biography:"Dr. Kükürt graduated from Uludağ University in Turkey. He started his academic career as a Research Assistant in the Department of Biochemistry at Kafkas University. In 2019, he completed his Ph.D. program in the Department of Biochemistry at the Institute of Health Sciences. He is currently working at the Department of Biochemistry, Kafkas University. He has 27 published research articles in academic journals, 11 book chapters, and 37 papers. He took part in 10 academic projects. He served as a reviewer for many articles. He still serves as a member of the review board in many academic journals. His research interests include biochemistry, oxidative stress, reactive species, antioxidants, lipid peroxidation, inflammation, reproductive hormones, phenolic compounds, female infertility.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Associate Prof.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",biography:"Volkan Gelen is a Physiology specialist who received his veterinary degree from Kafkas University in 2011. Between 2011-2015, he worked as an assistant at Atatürk University, Faculty of Veterinary Medicine, Department of Physiology. In 2016, he joined Kafkas University, Faculty of Veterinary Medicine, Department of Physiology as an assistant professor. Dr. Gelen has been engaged in various academic activities at Kafkas University since 2016. There he completed 5 projects and has 3 ongoing projects. He has 60 articles published in scientific journals and 20 poster presentations in scientific congresses. His research interests include physiology, endocrine system, cancer, diabetes, cardiovascular system diseases, and isolated organ bath system studies.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"418963",title:"Dr.",name:"Augustine Ododo",middleName:"Augustine",surname:"Osagie",slug:"augustine-ododo-osagie",fullName:"Augustine Ododo Osagie",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/418963/images/16900_n.jpg",biography:"Born into the family of Osagie, a prince of the Benin Kingdom. I am currently an academic in the Department of Medical Biochemistry, University of Benin. Part of the duties are to teach undergraduate students and conduct academic research.",institutionString:null,institution:{name:"University of Benin",country:{name:"Nigeria"}}},{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",biography:"Prof. Shagufta Perveen is a Distinguish Professor in the Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Dr. Perveen has acted as the principal investigator of major research projects funded by the research unit of King Saud University. She has more than ninety original research papers in peer-reviewed journals of international repute to her credit. She is a fellow member of the Royal Society of Chemistry UK and the American Chemical Society of the United States.",institutionString:"King Saud University",institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"49848",title:"Dr.",name:"Wen-Long",middleName:null,surname:"Hu",slug:"wen-long-hu",fullName:"Wen-Long Hu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49848/images/system/49848.jpg",biography:"Wen-Long Hu is Chief of the Division of Acupuncture, Department of Chinese Medicine at Kaohsiung Chang Gung Memorial Hospital, as well as an adjunct associate professor at Fooyin University and Kaohsiung Medical University. Wen-Long is President of Taiwan Traditional Chinese Medicine Medical Association. He has 28 years of experience in clinical practice in laser acupuncture therapy and 34 years in acupuncture. He is an invited speaker for lectures and workshops in laser acupuncture at many symposiums held by medical associations. He owns the patent for herbal preparation and producing, and for the supercritical fluid-treated needle. Dr. Hu has published three books, 12 book chapters, and more than 30 papers in reputed journals, besides serving as an editorial board member of repute.",institutionString:"Kaohsiung Chang Gung Memorial Hospital",institution:{name:"Kaohsiung Chang Gung Memorial Hospital",country:{name:"Taiwan"}}},{id:"298472",title:"Prof.",name:"Andrey V.",middleName:null,surname:"Grechko",slug:"andrey-v.-grechko",fullName:"Andrey V. Grechko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/298472/images/system/298472.png",biography:"Andrey Vyacheslavovich Grechko, Ph.D., Professor, is a Corresponding Member of the Russian Academy of Sciences. He graduated from the Semashko Moscow Medical Institute (Semashko National Research Institute of Public Health) with a degree in Medicine (1998), the Clinical Department of Dermatovenerology (2000), and received a second higher education in Psychology (2009). Professor A.V. Grechko held the position of Сhief Physician of the Central Clinical Hospital in Moscow. He worked as a professor at the faculty and was engaged in scientific research at the Medical University. Starting in 2013, he has been the initiator of the creation of the Federal Scientific and Clinical Center for Intensive Care and Rehabilitology, Moscow, Russian Federation, where he also serves as Director since 2015. He has many years of experience in research and teaching in various fields of medicine, is an author/co-author of more than 200 scientific publications, 13 patents, 15 medical books/chapters, including Chapter in Book «Metabolomics», IntechOpen, 2020 «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology».",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",biography:'Natalia Vladimirovna Beloborodova was educated at the Pirogov Russian National Research Medical University, with a degree in pediatrics in 1980, a Ph.D. in 1987, and a specialization in Clinical Microbiology from First Moscow State Medical University in 2004. She has been a Professor since 1996. Currently, she is the Head of the Laboratory of Metabolism, a division of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russian Federation. N.V. Beloborodova has many years of clinical experience in the field of intensive care and surgery. She studies infectious complications and sepsis. She initiated a series of interdisciplinary clinical and experimental studies based on the concept of integrating human metabolism and its microbiota. Her scientific achievements are widely known: she is the recipient of the Marie E. Coates Award \\"Best lecturer-scientist\\" Gustafsson Fund, Karolinska Institutes, Stockholm, Sweden, and the International Sepsis Forum Award, Pasteur Institute, Paris, France (2014), etc. Professor N.V. Beloborodova wrote 210 papers, five books, 10 chapters and has edited four books.',institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"354260",title:"Ph.D.",name:"Tércio Elyan",middleName:"Azevedo",surname:"Azevedo Martins",slug:"tercio-elyan-azevedo-martins",fullName:"Tércio Elyan Azevedo Martins",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/354260/images/16241_n.jpg",biography:"Graduated in Pharmacy from the Federal University of Ceará with the modality in Industrial Pharmacy, Specialist in Production and Control of Medicines from the University of São Paulo (USP), Master in Pharmaceuticals and Medicines from the University of São Paulo (USP) and Doctor of Science in the program of Pharmaceuticals and Medicines by the University of São Paulo. Professor at Universidade Paulista (UNIP) in the areas of chemistry, cosmetology and trichology. Assistant Coordinator of the Higher Course in Aesthetic and Cosmetic Technology at Universidade Paulista Campus Chácara Santo Antônio. Experience in the Pharmacy area, with emphasis on Pharmacotechnics, Pharmaceutical Technology, Research and Development of Cosmetics, acting mainly on topics such as cosmetology, antioxidant activity, aesthetics, photoprotection, cyclodextrin and thermal analysis.",institutionString:null,institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"334285",title:"Ph.D. Student",name:"Sameer",middleName:"Kumar",surname:"Jagirdar",slug:"sameer-jagirdar",fullName:"Sameer Jagirdar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334285/images/14691_n.jpg",biography:"I\\'m a graduate student at the center for biosystems science and engineering at the Indian Institute of Science, Bangalore, India. I am interested in studying host-pathogen interactions at the biomaterial interface.",institutionString:null,institution:{name:"Indian Institute of Science Bangalore",country:{name:"India"}}},{id:"329795",title:"Dr.",name:"Mohd Aftab",middleName:"Aftab",surname:"Siddiqui",slug:"mohd-aftab-siddiqui",fullName:"Mohd Aftab Siddiqui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329795/images/15648_n.jpg",biography:"Dr. Mohd Aftab Siddiqui is currently working as Assistant Professor in the Faculty of Pharmacy, Integral University, Lucknow for the last 6 years. He has completed his Doctor in Philosophy (Pharmacology) in 2020 from Integral University, Lucknow. He completed his Bachelor in Pharmacy in 2013 and Master in Pharmacy (Pharmacology) in 2015 from Integral University, Lucknow. He is the gold medalist in Bachelor and Master degree. He qualified GPAT -2013, GPAT -2014, and GPAT 2015. His area of research is Pharmacological screening of herbal drugs/ natural products in liver and cardiac diseases. He has guided many M. Pharm. research projects. He has many national and international publications.",institutionString:"Integral University",institution:null},{id:"255360",title:"Dr.",name:"Usama",middleName:null,surname:"Ahmad",slug:"usama-ahmad",fullName:"Usama Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255360/images/system/255360.png",biography:"Dr. Usama Ahmad holds a specialization in Pharmaceutics from Amity University, Lucknow, India. He received his Ph.D. degree from Integral University. Currently, he’s working as an Assistant Professor of Pharmaceutics in the Faculty of Pharmacy, Integral University. From 2013 to 2014 he worked on a research project funded by SERB-DST, Government of India. He has a rich publication record with more than 32 original articles published in reputed journals, 3 edited books, 5 book chapters, and a number of scientific articles published in ‘Ingredients South Asia Magazine’ and ‘QualPharma Magazine’. He is a member of the American Association for Cancer Research, International Association for the Study of Lung Cancer, and the British Society for Nanomedicine. Dr. Ahmad’s research focus is on the development of nanoformulations to facilitate the delivery of drugs that aim to provide practical solutions to current healthcare problems.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"30568",title:"Prof.",name:"Madhu",middleName:null,surname:"Khullar",slug:"madhu-khullar",fullName:"Madhu Khullar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/30568/images/system/30568.jpg",biography:"Dr. Madhu Khullar is a Professor of Experimental Medicine and Biotechnology at the Post Graduate Institute of Medical Education and Research, Chandigarh, India. She completed her Post Doctorate in hypertension research at the Henry Ford Hospital, Detroit, USA in 1985. She is an editor and reviewer of several international journals, and a fellow and member of several cardiovascular research societies. Dr. Khullar has a keen research interest in genetics of hypertension, and is currently studying pharmacogenetics of hypertension.",institutionString:"Post Graduate Institute of Medical Education and Research",institution:{name:"Post Graduate Institute of Medical Education and Research",country:{name:"India"}}},{id:"223233",title:"Prof.",name:"Xianquan",middleName:null,surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/223233/images/system/223233.png",biography:"Xianquan Zhan received his MD and Ph.D. in Preventive Medicine at West China University of Medical Sciences. He received his post-doctoral training in oncology and cancer proteomics at the Central South University, China, and the University of Tennessee Health Science Center (UTHSC), USA. He worked at UTHSC and the Cleveland Clinic in 2001–2012 and achieved the rank of associate professor at UTHSC. Currently, he is a full professor at Central South University and Shandong First Medical University, and an advisor to MS/PhD students and postdoctoral fellows. He is also a fellow of the Royal Society of Medicine and European Association for Predictive Preventive Personalized Medicine (EPMA), a national representative of EPMA, and a member of the American Society of Clinical Oncology (ASCO) and the American Association for the Advancement of Sciences (AAAS). He is also the editor in chief of International Journal of Chronic Diseases & Therapy, an associate editor of EPMA Journal, Frontiers in Endocrinology, and BMC Medical Genomics, and a guest editor of Mass Spectrometry Reviews, Frontiers in Endocrinology, EPMA Journal, and Oxidative Medicine and Cellular Longevity. He has published more than 148 articles, 28 book chapters, 6 books, and 2 US patents in the field of clinical proteomics and biomarkers.",institutionString:"Shandong First Medical University",institution:{name:"Affiliated Hospital of Shandong Academy of Medical Sciences",country:{name:"China"}}},{id:"297507",title:"Dr.",name:"Charles",middleName:"Elias",surname:"Assmann",slug:"charles-assmann",fullName:"Charles Assmann",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/297507/images/system/297507.jpg",biography:"Charles Elias Assmann is a biologist from Federal University of Santa Maria (UFSM, Brazil), who spent some time abroad at the Ludwig-Maximilians-Universität München (LMU, Germany). He has Masters Degree in Biochemistry (UFSM), and is currently a PhD student at Biochemistry at the Department of Biochemistry and Molecular Biology of the UFSM. His areas of expertise include: Biochemistry, Molecular Biology, Enzymology, Genetics and Toxicology. He is currently working on the following subjects: Aluminium toxicity, Neuroinflammation, Oxidative stress and Purinergic system. Since 2011 he has presented more than 80 abstracts in scientific proceedings of national and international meetings. Since 2014, he has published more than 20 peer reviewed papers (including 4 reviews, 3 in Portuguese) and 2 book chapters. He has also been a reviewer of international journals and ad hoc reviewer of scientific committees from Brazilian Universities.",institutionString:"Universidade Federal de Santa Maria",institution:{name:"Universidade Federal de Santa Maria",country:{name:"Brazil"}}},{id:"217850",title:"Dr.",name:"Margarete Dulce",middleName:null,surname:"Bagatini",slug:"margarete-dulce-bagatini",fullName:"Margarete Dulce Bagatini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217850/images/system/217850.jpeg",biography:"Dr. Margarete Dulce Bagatini is an associate professor at the Federal University of Fronteira Sul/Brazil. She has a degree in Pharmacy and a PhD in Biological Sciences: Toxicological Biochemistry. She is a member of the UFFS Research Advisory Committee\nand a member of the Biovitta Research Institute. She is currently:\nthe leader of the research group: Biological and Clinical Studies\nin Human Pathologies, professor of postgraduate program in\nBiochemistry at UFSC and postgraduate program in Science and Food Technology at\nUFFS. She has experience in the area of pharmacy and clinical analysis, acting mainly\non the following topics: oxidative stress, the purinergic system and human pathologies, being a reviewer of several international journals and books.",institutionString:"Universidade Federal da Fronteira Sul",institution:{name:"Universidade Federal da Fronteira Sul",country:{name:"Brazil"}}},{id:"226275",title:"Ph.D.",name:"Metin",middleName:null,surname:"Budak",slug:"metin-budak",fullName:"Metin Budak",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226275/images/system/226275.jfif",biography:"Metin Budak, MSc, PhD is an Assistant Professor at Trakya University, Faculty of Medicine. He has been Head of the Molecular Research Lab at Prof. Mirko Tos Ear and Hearing Research Center since 2018. His specializations are biophysics, epigenetics, genetics, and methylation mechanisms. He has published around 25 peer-reviewed papers, 2 book chapters, and 28 abstracts. He is a member of the Clinical Research Ethics Committee and Quantification and Consideration Committee of Medicine Faculty. His research area is the role of methylation during gene transcription, chromatin packages DNA within the cell and DNA repair, replication, recombination, and gene transcription. His research focuses on how the cell overcomes chromatin structure and methylation to allow access to the underlying DNA and enable normal cellular function.",institutionString:"Trakya University",institution:{name:"Trakya University",country:{name:"Turkey"}}},{id:"243049",title:"Dr.",name:"Anca",middleName:null,surname:"Pantea Stoian",slug:"anca-pantea-stoian",fullName:"Anca Pantea Stoian",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243049/images/system/243049.jpg",biography:"Anca Pantea Stoian is a specialist in diabetes, nutrition, and metabolic diseases as well as health food hygiene. She also has competency in general ultrasonography.\n\nShe is an associate professor in the Diabetes, Nutrition and Metabolic Diseases Department, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania. She has been chief of the Hygiene Department, Faculty of Dentistry, at the same university since 2019. Her interests include micro and macrovascular complications in diabetes and new therapies. Her research activities focus on nutritional intervention in chronic pathology, as well as cardio-renal-metabolic risk assessment, and diabetes in cancer. She is currently engaged in developing new therapies and technological tools for screening, prevention, and patient education in diabetes. \n\nShe is a member of the European Association for the Study of Diabetes, Cardiometabolic Academy, CEDA, Romanian Society of Diabetes, Nutrition and Metabolic Diseases, Romanian Diabetes Federation, and Association for Renal Metabolic and Nutrition studies. She has authored or co-authored 160 papers in national and international peer-reviewed journals.",institutionString:null,institution:{name:"Carol Davila University of Medicine and Pharmacy",country:{name:"Romania"}}},{id:"279792",title:"Dr.",name:"João",middleName:null,surname:"Cotas",slug:"joao-cotas",fullName:"João Cotas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/279792/images/system/279792.jpg",biography:"Graduate and master in Biology from the University of Coimbra.\n\nI am a research fellow at the Macroalgae Laboratory Unit, in the MARE-UC – Marine and Environmental Sciences Centre of the University of Coimbra. My principal function is the collection, extraction and purification of macroalgae compounds, chemical and bioactive characterization of the compounds and algae extracts and development of new methodologies in marine biotechnology area. \nI am associated in two projects: one consists on discovery of natural compounds for oncobiology. The other project is the about the natural compounds/products for agricultural area.\n\nPublications:\nCotas, J.; Figueirinha, A.; Pereira, L.; Batista, T. 2018. An analysis of the effects of salinity on Fucus ceranoides (Ochrophyta, Phaeophyceae), in the Mondego River (Portugal). Journal of Oceanology and Limnology. in press. DOI: 10.1007/s00343-019-8111-3",institutionString:"Faculty of Sciences and Technology of University of Coimbra",institution:null},{id:"279788",title:"Dr.",name:"Leonel",middleName:null,surname:"Pereira",slug:"leonel-pereira",fullName:"Leonel Pereira",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/279788/images/system/279788.jpg",biography:"Leonel Pereira has an undergraduate degree in Biology, a Ph.D. in Biology (specialty in Cell Biology), and a Habilitation degree in Biosciences (specialization in Biotechnology) from the Faculty of Science and Technology, University of Coimbra, Portugal, where he is currently a professor. In addition to teaching at this university, he is an integrated researcher at the Marine and Environmental Sciences Center (MARE), Portugal. His interests include marine biodiversity (algae), marine biotechnology (algae bioactive compounds), and marine ecology (environmental assessment). Since 2008, he has been the author and editor of the electronic publication MACOI – Portuguese Seaweeds Website (www.seaweeds.uc.pt). He is also a member of the editorial boards of several scientific journals. Dr. Pereira has edited or authored more than 20 books, 100 journal articles, and 45 book chapters. He has given more than 100 lectures and oral communications at various national and international scientific events. He is the coordinator of several national and international research projects. In 1998, he received the Francisco de Holanda Award (Honorable Mention) and, more recently, the Mar Rei D. Carlos award (18th edition). He is also a winner of the 2016 CHOICE Award for an outstanding academic title for his book Edible Seaweeds of the World. In 2020, Dr. Pereira received an Honorable Mention for the Impact of International Publications from the Web of Science",institutionString:"University of Coimbra",institution:{name:"University of Coimbra",country:{name:"Portugal"}}},{id:"61946",title:"Dr.",name:"Carol",middleName:null,surname:"Bernstein",slug:"carol-bernstein",fullName:"Carol Bernstein",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/61946/images/system/61946.jpg",biography:"Carol Bernstein received her PhD in Genetics from the University of California (Davis). She was a faculty member at the University of Arizona College of Medicine for 43 years, retiring in 2011. Her research interests focus on DNA damage and its underlying role in sex, aging and in the early steps of initiation and progression to cancer. In her research, she had used organisms including bacteriophage T4, Neurospora crassa, Schizosaccharomyces pombe and mice, as well as human cells and tissues. She authored or co-authored more than 140 scientific publications, including articles in major peer reviewed journals, book chapters, invited reviews and one book.",institutionString:"University of Arizona",institution:{name:"University of Arizona",country:{name:"United States of America"}}},{id:"182258",title:"Dr.",name:"Ademar",middleName:"Pereira",surname:"Serra",slug:"ademar-serra",fullName:"Ademar Serra",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/182258/images/system/182258.jpeg",biography:"Dr. Serra studied Agronomy on Universidade Federal de Mato Grosso do Sul (UFMS) (2005). He received master degree in Agronomy, Crop Science (Soil fertility and plant nutrition) (2007) by Universidade Federal da Grande Dourados (UFGD), and PhD in agronomy (Soil fertility and plant nutrition) (2011) from Universidade Federal da Grande Dourados / Escola Superior de Agricultura Luiz de Queiroz (UFGD/ESALQ-USP). Dr. Serra is currently working at Brazilian Agricultural Research Corporation (EMBRAPA). His research focus is on mineral nutrition of plants, crop science and soil science. Dr. Serra\\'s current projects are soil organic matter, soil phosphorus fractions, compositional nutrient diagnosis (CND) and isometric log ratio (ilr) transformation in compositional data analysis.",institutionString:"Brazilian Agricultural Research Corporation",institution:{name:"Brazilian Agricultural Research Corporation",country:{name:"Brazil"}}}]}},subseries:{item:{id:"9",type:"subseries",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering",keywords:"Biotechnology, Biosensors, Biomaterials, Tissue Engineering",scope:"The Biotechnology - Biosensors, Biomaterials and Tissue Engineering topic within the Biomedical Engineering Series aims to rapidly publish contributions on all aspects of biotechnology, biosensors, biomaterial and tissue engineering. We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",hasOnlineFirst:!1,hasPublishedBooks:!0,annualVolume:11405,editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",slug:"luis-villarreal-gomez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",biography:"Dr. Luis Villarreal is a research professor from the Facultad de Ciencias de la Ingeniería y Tecnología, Universidad Autónoma de Baja California, Tijuana, Baja California, México. 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