\r\n\tThe human microbiota consists of a wide variety of bacteria, viruses, fungi, and other single-celled animals that live in the body while microbiome is the name given to all of the genes inside these microbial cells. Recently, there has been renewed interest in the role played by microbiota and microbiome in both human health and human disease. A correct equilibrium between the human host and their microorganisms is important for an appropriate physiological function. \r\n\tMicroorganisms have evolved alongside humans and form an integral part of life, carrying out a range of vital functions. They are implicated in both health and disease, and research has found links between bacterial populations, whether normal or disturbed, and the following diseases: asthma, cancer, diabetes, obesity, heart disease and, neurological and neurodegenerative diseases. \r\n\tThe chapters of this book aim to present outstanding research on biochemical, genetics, clinical, molecular and behavioral fields about microbiota-gut-brain axis with emphasis in how neuropeptides such as brain derived factor (BDNF), substance P, calcitonin gene-related peptide and neuropeptide Y (NPY), vasoactive intestinal polypeptide, somatostatin and corticotropin-releasing factor are also likely to play a role in the bidirectional gut-brain communication. In this capacity they may influence the activity of the gastrointestinal microbiota and its interaction with the gut-brain axis. \r\n\tIt will be shown evidence that neuropeptides represents a challenge in understanding the complex interactions between gut and brain. Although their precise role in the microbiota-gut-brain axis has not yet been defined, neuropeptides play an important role in this respect. For instance, a growing field of work is implicating the microbiota-microbiome in a variety of psychological processes and neuropsychiatric disorders. These include mood and anxiety disorders, neurodevelopmental disorders such as autism spectrum disorder and schizophrenia, and even neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. These brain disturbances have been linked to molecular and biochemical alterations in the course of neurodevelopment so, the research in this area has established different approaches (nutritional, immunological, energy homeostasis), to find the role played by the gut microbiota-microbiome in the etiology of the aforementioned brain disorders.
",isbn:null,printIsbn:"979-953-307-X-X",pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"2c441b6a49e0eba12af16fcb6ad8b887",bookSignature:"Dr. Sandra Morales-Mulia",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/8940.jpg",keywords:"Gut-Microbiota, Neurodevelopment, Synaptic plasticity, Neurogenesis, Neuroimmune system, Neuropeptide Y, Brain-derived neurotrophic factor (BDNF), Peptide YY, Cholecystokinin (CCK), Corticotropin-releasing factor (CRF), Substance P, Neuropeptide Y (NPY), Oxytocin",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 24th 2019",dateEndSecondStepPublish:"June 14th 2019",dateEndThirdStepPublish:"August 13th 2019",dateEndFourthStepPublish:"November 1st 2019",dateEndFifthStepPublish:"December 31st 2019",remainingDaysToSecondStep:"2 years",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"287114",title:"Dr.",name:"Sandra",middleName:null,surname:"Morales-Mulia",slug:"sandra-morales-mulia",fullName:"Sandra Morales-Mulia",profilePictureURL:"https://mts.intechopen.com/storage/users/287114/images/system/287114.jpeg",biography:"EDUCATION AND DEGREES \n1988-1991. National Autonomous University of Mexico (UNAM). School of Sciences. B. S. in Biology. \n1995-1997. National Autonomous University of Mexico (UNAM). Cell Physiology Institute. Master in Basic Biomedical Sciences Research\n1998-2000. National Autonomous University of Mexico (UNAM). Cell Physiology Institute. PhD in Biomedical Sciences (Neuroscience) \n2002-2004. Postdoctoral Fellow. Laboratory of Cell Biology: Mitosis, Ciliogenesis, Intracellular Transport and Motor Protein Functions. University of California, Davis- Dept. of Molecular & Cellular Biology, One Shields Ave. Davis, CA 95616. \n2005-2008. Postdoctoral Fellow. Laboratory of Neuropharmacology. National Institute of Psychiatry “Ramón de La Fuente Muñiz”. Calzada México-Xochimilco #101, Col. San Lorenzo Huipulco, CP 14370 México City, México. \n2009-present. Teaching Professor in Biochemistry. Bachelor in Biology Program. School of Sciences. National Autonomous University of Mexico (UNAM). Av. Insurgentes Sur 3000, Circuito Exterior. Ciudad Universitaria, Mexico D.F. C.P. 04510.\n2006-present. Consultant and Assessor Researcher. \nLaboratory of Psychiatric and Neurodegenerative Diseases. National Institute of Genomic Medicine (INMEGEN-SAP). Periferico Sur 4809, Arenal Tepepan, 14610 México City, México.\nLaboratory of Molecular Basis of Addictions. National Institute of Psychiatry RFM, Mexico City, Mexico.",institutionString:"National Autonomous University of Mexico",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Autonomous University of Mexico",institutionURL:null,country:{name:"Mexico"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"18",title:"Neuroscience",slug:"life-sciences-neuroscience"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"301331",firstName:"Mia",lastName:"Vulovic",middleName:null,title:"Mrs.",imageUrl:"https://mts.intechopen.com/storage/users/301331/images/8498_n.jpg",email:"mia.v@intechopen.com",biography:"As an Author Service Manager, my responsibilities include monitoring and facilitating all publishing activities for authors and editors. 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\n\n\n
Key Points
\n
Evidence shows that PRP infusion directly into the endometrium enhances lining development in patients suffering from chronically refractive or underdeveloped endometrium. Chemical pregnancy in patients that underwent PRP infusion with frozen embryo transfer was 50% (108/216) in comparison to 17.1% (16/93) in patients that did not receive PRP treatment.
\n\n
\n
\n
1. Introduction
\n
The overall objective of this review was to determine if platelet-rich plasma (PRP) infusions are viable alternatives to current treatments for thin endometrial lining, and to distinguish if PRP infusions increase endometrial thickness and implantation in patients that underwent treatment in eight different case studies.
\n
Platelet-rich plasma is prepared from autologous whole blood collected from a patient’s peripheral vein, mixed with an acid citrate dextrose solution A (ACD-A) anticoagulant, and processed to separate platelets from remaining blood components [1]. Platelet-rich plasma is recognized as plasma from autologous blood with 4–5 times the concentration of normal platelet levels; these high concentrations of PRP contain cytokines and growth factors including: vascular endothelial growth factor (VEGF), transforming growth factor (TGF), platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) [2, 3]. Because of the expression of several regenerative growth factors, PRP is being used in several fields of medicine to promote wound regeneration including: arthritis, nerve injury, tendinitis, bone regeneration, cardiac muscle repair, alopecia, and plastic and oral surgery recovery [4, 5]. When the body is injured, a natural healing process occurs that floods the wound site with activated platelets that instantly promote cell regeneration and proliferation. It is theorized that PRP may be used to promote the same growth and proliferation in endometrium that have previous suboptimal growth patterns. Similar research, such as endometrial scratching, has been studied to promote the generation of growth factors to increase implantation; however, the concentration of platelet levels within direct PRP infusion into the endometrium is vastly superior to the natural, localized endometrial healing process that occurs with the scratching method.
\n
Other treatment strategies for thin endometrial lining have varied throughout recent years, but have been inclusive of extended use of exogenous estradiol, low-dose aspirin, vitamin E supplementation, and use of granulocyte colony stimulation factor (G-CSF), but not all have been proven effective [6, 7, 8, 9]. The minimal endometrial thickness suggested for successful implantation at embryo transfer is 7 mm [10], however, there are those that argue endometrial lining is a poor indicator for pregnancy outcomes and therefore should not be heavily considered [11]. During typical HRT cycles, estradiol administration is regulated from day 2 or day 3 of an average 28 day cycle and continues until the endometrial lining reaches optimal thickness for transfer (typically >7 mm) at which time progesterone administration then occurs [12]. This model is utilized in IVF clinics globally; however, patients who fail to reach the recommended endometrial thickness often undergo canceled cycles in which they have wasted valuable time, medications, and expenses without receiving an embryo transfer.
\n
Thin endometrial lining or suboptimal endometrial growth is a problem that affects up to 5% of the patients undergoing IVF treatment [13]. These patients often experience the emotionally and physically traumatizing effects of canceled cycles or repeated implantation failure (RIF). It is proven that growth factors expressed in the endometrium of women with RIF are less than those expressed in normal fertile women [14]. These growth factors can be stimulated by infusion of autologous PRP into the endometrium in conjunction with HRT prior to embryo transfer. However, many factors are involved in successful embryonic implantation, not limited to embryo quality, but also a synchrony between the embryo and the endometrium in addition to any immunological factors [15]. Without optimal endometrial growth, this synchrony becomes far less likely as the endometrium does not express the adequate genes nor growth factors involved in embryonic implantation [16, 17].
\n
\n
\n
2. PRP collection and infusion
\n
Through multiple studies, PRP processing was performed similarly. On the 10th day of HRT, Chang and coworkers drew 15 ml of autologous blood into a tube with 5 ml of Acid Citrate A Anticoagulant (ACD-A) and centrifuged; separating red blood cells, a gel buffy coat, and cellular plasma. The plasma and buffy coat were then transferred to a second tube and centrifuged again, yielding 0.5–1 ml of PRP [18]. Both Zadehmodarres and Nazari and their colleagues drew 17.5 ml of blood on day 9 or 10 of HRT into 2.5 ml of ACD-A and similarly centrifuged twice to obtain 0.5 ml of PRP [19, 20]. Tandulwadkar et al. used 10 ml of autologous blood into an unspecified amount of ACD-A; which was centrifuged sequentially utilizing first a soft spin for 15 minutes, followed by a hard spin for 6 minutes, again yielding between 0.5 and 0.8 ml of PRP [21]. Eftekhar and others used an alternative approach, collecting PRP on the 13th day of HRT by drawing 8.5 ml of peripheral venous blood into a syringe containing 1.5 ml of ACD-A that was then centrifuged for 10 minutes; following first centrifugation, the buffy coat and plasma layer were then removed and centrifuged again, yielding 1.5 ml of PRP [22]. Meanwhile, Hounyoung et al. collected 18 ml of venous blood in a 30 ml syringe prepared with 2 CC of ACD-A and then centrifuged twice to obtain 0.7–1.0 ml of PRP [23]. Nazari and coworkers performed a follow-up study utilizing a double-blinded trial in which 30 patients underwent PRP infusion, prepared in the same manner as the initial pilot study [19], and 30 patients underwent placebo PRP infusions [24]. Chang et al. performed a secondary study as well, involving a larger cohort of patients compared against a control group, and performed PRP collection as previously reported [18, 25]. All studies transfused the PRP into the endometrium using an IUI catheter, and then repeated intravaginal ultrasound 48 hours later to measure endometrial growth; patients who did not reach the desired lining thickness (>7 mm deemed adequate in all studies) were then treated with a second round of PRP infusion [18, 19, 20, 21, 22, 23, 24, 25].
\n
\n
2.1 Hormone replacement therapy
\n
In the past, IVF clinics allowed for natural cycle frozen embryo transfer in which they permitted endometrial lining to develop on its own, but it resulted in many timing issues with need for frequent monitoring and cancelation due to anovulation and poor development of the endometrium. Today, most clinics have moved fully to HRT protocols that allow for artificial stimulation of the endometrium that can be easily tracked utilizing blood serum and ultrasound assessment to time an embryo transfer concordant with a receptive endometrium. In humans, estrogen stimulates endometrial growth and induces progesterone receptors as it moves naturally through the menstrual cycle. After ovulation, the endometrium is exposed to progesterone which induces morphological and biochemical changes that alter the endometrium from the proliferative phase to the secretory phase [17]. In HRT cycles, estradiol administration (typically Estradiol Valerate) occurs until the lining has reached a thickness of greater than 7 mm, at which time progesterone is then administered for the number of days proportional to the embryo being transferred (i.e., a day 6 blastocyst will receive progesterone for 6 days) and then the embryo is transferred to a supposedly receptive endometrium [26, 27]. In these HRT cycles, patients receive estradiol during the follicular phase that inhibits gonadotropin secretion and prevents follicular development and ovulation. The start of the luteal phase can be exactly pinpointed, as it starts when progesterone is added to estradiol dosages.
\n
\n
\n
2.2 Methodology
\n
HRT allows for artificial stimulation of endometrial growth via hormone administration orally, transdermally, intramuscularly, vaginally, subcutaneously, or a combination of both. Most clinics administer estradiol for several days until the endometrial lining has reach a point of optimal growth, at which time they will then administer progesterone to induce the secretory phase of cycle that promotes embryo implantation [21]. Each of the studies examined in this review conducted HRT protocols concordant with physician recommendation as follows:
\n
Chang et al.: In the pilot study, Estradiol Valerate (E2V) started at 3 mg/d on day 3 of menses and increased every 4 days up to a max of 12 mg/d; and in the cohort study, E2V started at 6 mg/d and subsequently increased to 12 mg/d [18, 25]. The pilot study included five patients suffering from chronically non-responsive thin endometrium (5.9–6.6 mm) who underwent PRP infusion on the 10th day of HRT and lining was measured via transvaginal ultrasound. In the cohort study, platelet-rich plasma infusion was also performed on the 10th day of HRT, and endometrial thickness was measured in both the control group and study group.
\n
Zadehmodarres et al.: Estradiol Valerate started at 6 mg/d on day 3 of menses, and increased to 8–9 mg/d. Suppository progesterone was started when endometrial thickness reached >7 mm and continued for 2 weeks after ET [19]. PRP infusion was administered on the 11th or 12th day of cycle and assessed 48 hours later.
\n
Nazari et al.: Estradiol Valerate started on day 2 or 3 of menses at 6 mg/d and was increased to 8 mg/d if lining did not reach >7 mm. When thickness reached 7 mm, progesterone suppositories, 4000 mg, were started twice daily [20, 24]. In the pilot study, 0.5 ml of PRP was infused into the endometrium of patients 48 hours prior to frozen embryo transfer in conjunction with an HRT cycle. In the follow-up RCT, PRP infusion or mock infusion was performed on day 11 or 12 of HRT cycle, modified from the initial pilot study, and lining was measured using transvaginal ultrasonography.
\n
Tandulwadkar et al.: Estradiol Valerate started at 6–8 mg/d concordant with baseline endometrial vascularity as measured by Power Doppler on day 1 of menses and increased to 12 mg/d if growth was not seen. Transvaginal ultrasounds were performed starting on day 7/8 [21]. Day of PRP infusion was not given in the initial study.
\n
Eftekhar et al.: In this study, the case group was treated with PRP and increased HRT, and the control group was just treated with increased HRT. For all women, E2V was started at 6 mg/d, then increased to 10 mg/d [22]. PRP infusion occurred on the 13th day of cycle and endometrial lining was measured transvaginally.
\n
Hounyoung et al.: Patients treated within this study began E2V administration on the second day of menses, starting at 4-6 mg/d and followed by PRP infusion on cycle day 10 [23]. PRP infusion was administered via IUI catheter and repeated 2–3 times in 3 day intervals until optimal endometrial thickness was achieved (>7 mm).
\n
\n
\n
\n
3. Sample size and selection of samples
\n
Eight clinical trials were selected, all of which were inclusive of a total of 346 patients that underwent HRT in conjunction with PRP infusion. Of 346 patients, 313 underwent embryo transfer at either cleavage or blastocyst stage. The remaining 33 patients dropped out of the studies prior to embryo transfer due to persistently poor endometrial development [18, 19, 20, 21, 22, 23, 24, 25].
\n
\n
3.1 Inclusion criteria
\n
Inclusion criteria remained relatively constant through all eight studies. All patients had a history of thin endometrial lining, repeat implantation failure, or two or more canceled cycles due to poor endometrial growth. All patients were between the ages of 18–42 years old and all had a normal BMI of <30%; donor egg cycles were not included due to the potential to skew the results. All patients that underwent embryo transfer post-PRP infusion reached an endometrial thickness of >7 mm, as deemed acceptable by the performing physicians.
\n
\n
\n
3.2 Exclusion criteria
\n
All patients with hematological and immunological disorders, hormonal disorders, chromosomal and genetic abnormalities and uterine abnormalities were excluded from the studies. All patients who did not reach optimal endometrial thickness post-PRP infusion were excluded from embryo transfer. Any patient of advanced maternal age (>42 years old) or increased BMI (>30%) was excluded from the studies.
\n
\n
\n
\n
4. Results and data analysis
\n
Five patients were included in the initial pilot study by Chang et al. [18]. 48–72 hours post PRP, all five patients reached a minimum lining of 7 mm (7.0–8.0). All patients underwent frozen embryo transfer, and all five patients were pregnant (5/5) with an ongoing pregnancy rate of 80% (4/5).
\n
Zadehmodarres and colleagues [19] performed their study on 10 patients with previous canceled cycles due to thin endometrial development, four of which were diagnosed with Asherman’s Syndrome. All 10 patients reached adequate lining thickness for embryo transfer (7.0–7.5). All patients underwent frozen embryo transfer resulting in chemical pregnancy in 50% of patients (5/10) with an ongoing pregnancy rate of 40% (4/10).
\n
The pilot study by Nazari and coworkers [20] was based upon a study group of 20 patients suffering from RIF due to thin endometrial lining. All patients received a blastocyst stage transfer of one to two embryos that were graded morphologically normal. Chemical pregnancy was reported in 90% of patients (18/20) with an ongoing pregnancy rate of 80% (16/20).
\n
Tandulwadkar et al. [21] assessed not only endometrial thickness, but endometrial vascularity as well post PRP infusion as measured by serial transvaginal ultrasound. Of the 68 patients included in the study, 64 went on to achieve optimal lining thickness for frozen embryo transfer. Average mean lining thickness before PRP infusion was 5 mm, and 7.22 mm after PRP infusion. Of the 64 patients that received a frozen embryo transfer, endometrial vascularity increased in all patients. 60.1% (39/64) reported chemical pregnancy with an ongoing pregnancy rate of 45.3% (26/64).
\n
A randomized control trial was performed by Eftekhar and others [22] in which 83 women participated; 40 were allocated to the study group and received PRP infusion, while 43 were placed in the control group and did not receive PRP. Prior to PRP infusion on the 13th day of cycle, there were no significant differences in endometrial lining as measured between the two groups; however, after PRP infusion, significant differences were noted (8.80 vs. 8.04 mm). Of the 40 women in the study group, 7 did not receive an embryo transfer due to persistently thin endometrium, whereas 10 women in the control group were excluded from frozen embryo transfer for the same reason. Thirty-three women in the study group and 33 women in the control group underwent cleavage stage frozen embryo transfer. In the study group, chemical pregnancy was reported in 42.2% (14/33) in comparison to the control group, which recorded chemical pregnancy in only 24.2% (8/33) of patients. Ongoing pregnancy rates were 33.3% (11/33) versus 18.2% (6/33), respectively.
\n
Hounyoung and colleagues [23] performed a pilot study on 24 patients with a history of refractory endometrium. Of the 24 patients initially included in the study, two patients were canceled, and two were lost to follow-up. Data was collected for the remaining 20 patients, all of whom received a frozen embryo transfer of 2–3 day 3 cleavage stage embryos. Among the study group, a chemical pregnancy rate of 30% (6/20) was reported with an ongoing pregnancy rate of 20% (4/20).
\n
After an initial pilot study, Nazari et al. [24] performed a follow-up double blinded randomized control trial to validate their previous findings. Sixty patients were selected for inclusion in the study; 30 were randomly assigned to the study group to receive PRP infusion, and 30 were aliquoted to the control group in which a sham-catheter was utilized for mock PRP infusion. In the PRP group, lining increased to 7.21 ± 0.18 mm respectively, and in the mock infusion group, lining reached 5.76 ± 0.97 mm. Of the 30 patients in the study group, all patients received a frozen embryo transfer in comparison to just 6 that reached optimal lining (>7 mm) for frozen embryo transfer in the control group. Chemical pregnancy was recorded in 40% (12/30) of cases in the study group, and in 6.7% (2/30) in the control group. Ongoing pregnancy rate was 33.3% (10/30) in the PRP group, and 3.3% (1/30) in the control group.
\n
Chang and others [25] performed a follow-up randomized control trial to their initial pilot study as well, assigning 34 patients to the PRP infusion group and 30 patients to the control group, which received only HRT without PRP. In the study group, endometrial thickness reached an average of 7.65 ± 0.22 mm versus 6.52 ± 0.31 mm in the control group. The cycle cancelation rate was 19.0% in the study group, and 41.2% in the control group, which was statistically significant. All patients that reached optimal endometrial thickness received a frozen blastocyst transfer of one or two morphologically good blastocyst stage embryos. In the PRP group, clinical pregnancy was reported as 44.1% (15/34), and 20% (6/30) in the control group.
\n
All patients within study groups that underwent embryo transfer reached optimal lining thickness (>7 mm) after one or multiple rounds of PRP infusion. Patients that underwent PRP infusion in the study groups reached an average endometrial thickness of 7.36 mm with an average increase of 1.68 mm post PRP infusion. In the control groups presented by studies performing RCT, the control patients reached an average endometrial thickness of 6.77 mm with an average increase of 0.91 mm after HRT. Among patients within study groups, the overall chemical pregnancy rate was 50% (108/216) in contrast to 17.1% (16/93) following conventional HRT without PRP infusion.
\n
\n
\n
5. Discussion
\n
Platelet-rich plasma infusion is a novel approach to endometrium enhancement. This autologous therapy strives to increase endometrial thickness among patients with histories of canceled cycles and repeat implantation failure due to chronically refractive endometrium. While there is no universally agreed upon treatment for this patient population, the search to find an effective solution for non-reactive endometrial lining should be at the forefront of clinical researchers within the ART industry. Platelet-rich plasma is easily attained, cost-effective, minimally invasive, rich in cytokines and growth factors, and carries very little risk of disease or infection transmission as the patient uses their own blood to attain PRP. Infusion into the endometrium takes place in conjunction with traditional HRT and therefore can be administered during the average cycle while patients are already present for serial ultrasounds and serum hormone level measurements.
\n
In the eight studies discussed above, PRP infusion into the endometrium proved effective when administered on various days of an HRT cycle as well as in variable quantities. While the majority of studies reviewed were clinical applications, which presents a weakness in the data as there was no comparative control group, the randomized controlled trials that were performed offered arguably conclusive, supportive evidence of PRP effectiveness. All the patients that underwent PRP infusion experienced a significantly marked increase in endometrial thickness, allowing for frozen embryo transfer. In the studies that did utilize a study population versus a control population, results among the study participants were significantly improved with greater cycle completion. Although most studies utilized frozen blastocyst transfers, there were some that elected to use frozen cleavage stage embryo transfers, which can also be considered a limiting factor among the data. The studies here agreed upon 7 mm as the minimal lining thickness for embryo implantation success, but some physicians argue that endometrial thickness is a poor marker for transfer outcome. While this argument can be made and supported, as it was by Griesinger and colleagues [11], there is a wide consensus that endometrial thickness does play a vital role in receptivity (Table 1).
\n
Table 1.
Eight studies were compared for the measurement of endometrial thickness before and after PRP infusion in study groups vs. control groups. Clinical pregnancy outcomes are included following PRP treatment.
\n
The patient populations presented in these studies, including those among the study group and those in the control group, were all patients that had suffered two or more failed previous cycles due to poor lining development. The inclusion criteria for these studies were consistent through all eight trials and provided an unbiased patient group in order to obtain reliable results. The data conclusively shows that endometrial thickness among patients with chronically poor endometrial development is greatly increased with PRP infusion therapy in comparison to traditional HRT alone. The primary outcome of each study was satisfied by the significant increase in endometrial lining development with the secondary satisfaction of improved clinical pregnancy outcomes in the PRP group versus the control group.
\n
Another diagnostic tool to be considered in patients with a history of suboptimal endometrial development and repeat implantation failure is the use of the Endometrial Receptivity Array (ERA). The ERA is a customized array that allows to test for 248 different genes expressed during the endometrial cycle and works concordantly with a computational algorithm that identifies the receptivity status of an endometrial biopsy to diagnose a personalized window of implantation [28]. ERA is performed with a mock embryo transfer cycle. Utilizing the ERA, Ruiz-Alonso and colleagues were able to validate conclusively that 25% of RIF patients had a displaced window of implantation and went on to coin the phrase “personalized embryo transfer” (pET) to increase the chance of a successful pregnancy in women suffering from mistimed endometrial receptivity [29]. Potentially, ERA can be utilized in conjunction with PRP infusion to determine receptivity of the endometrium in PRP patients. In the study by Tandulwadkar et al. [21], not only was lining thickness assessed, but endometrial vascularity was observed as well utilizing 3D Doppler ultrasound. Blood flow to the endometrium as well as the uterine biophysical profile can be measured via a combination between abdominal and transvaginal ultrasound. Greater blood flow to the uterus has been associated with higher implantation rates and can be seen in color utilizing Doppler ultrasound methods [27]. PRP infusion has the potential to increase lining development as well as endometrial vascularity as proven by Tandulwadkar, and future studies should observe an increase in vascularity concordant with lining and uterine biophysical profile. Utilizing the ERA and 3D Doppler system in conjunction with PRP in future studies can be therefore linked to the immune, genetic, and biophysical pathways of the endometrium.
\n
While the use of PRP infusion into the endometrium to increase lining growth and vascularity is a relatively new area of research, the initial trials show encouraging results. The patients that were included within these studies are patients who had suffered from multiple failed or canceled cycles and would not have received embryo transfers otherwise. In a patient population that has had multiple failures, PRP infusion into the endometrium provides a suitable solution that effectively allows for embryo transfer, giving these patients a chance at pregnancy that they otherwise would not have had utilizing traditional HRT alone. Although the data is still new and there is need for additional research and much larger randomized controlled trials, the initial use of PRP as a universal means of treating poor responders to HRT shows a promising treatment method for the future.
\n
\n
\n
6. Conclusion
\n
The review of the initial data presented in these eight early studies of PRP infusion into the endometrium in conjunction with traditional HRT reveals statistically significant outcomes. Patients with previous failures that did not reach the minimal lining thickness needed to perform embryo transfer (>7 mm) underwent PRP infusion into the endometrium and reached an average endometrial thickness of 7.36 mm in comparison to the control group, which reached an average of only 6.77 mm. Clinical pregnancy rates within the study group were also significantly higher than the control group, 50% (108/216) versus 17.1% (16/93), respectively. For patients that have had multiple failures and canceled cycles, offering an absolute solution that at minimum guarantees them an embryo transfer can potentially increase the success of frozen embryo transfers in clinics globally, while decreasing patient stress and costs, and reducing the potential for embryo wastage.
\n
\n
Acknowledgments
\n
The author would like to acknowledge and recognize the support of her co-authors and their institutions, the Eastern Virginia Medical School and Ovation Fertility-Newport Beach.
\n
Conflict of interests
The author declares no conflict of interest.
\n',keywords:"cytokines, embryo transfer, endometrial lining, endometrium, growth factors, hormone replacement therapy, infusion, platelet-rich plasma, suboptimal lining",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/70544.pdf",chapterXML:"https://mts.intechopen.com/source/xml/70544.xml",downloadPdfUrl:"/chapter/pdf-download/70544",previewPdfUrl:"/chapter/pdf-preview/70544",totalDownloads:208,totalViews:0,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,dateSubmitted:"September 30th 2019",dateReviewed:"November 26th 2019",datePrePublished:"December 20th 2019",datePublished:"May 6th 2020",dateFinished:null,readingETA:"0",abstract:"Over the past decade, platelet-rich plasma (PRP) has been used in several fields of medicine to promote cell growth and expedite wound healing for the treatment of arthritis, nerve injury, tendinitis, bone regeneration, cardiac muscle repair, and oral & plastic surgery. Recently, researchers have been applying autologous PRP to bolster the growth of endometrial lining in patients with a history of endometrium-related failed embryo transfers. Evidence reveals that PRP is a rich source of active cytokines and various growth factors, which come from an autologous source that can be easily attained from peripheral blood without risk of disease transmission to the patient. In this review, several studies were analyzed that involved patients 18–42 years of age undergoing hormone replacement therapy (HRT) in preparation for embryo transfer and serial transvaginal ultrasound in conjunction with PRP infusions into the endometrium via an intrauterine insemination (IUI) catheter. Exclusion criteria included patients with endometritis, polyps, or adhesions. Embryo transfers (ET) were performed when the endometrial lining achieved a thickness of >7 mm. The database indicates that PRP infusion therapy is a promising low-cost treatment for HRT patients that significantly increases endometrial thickness and improves pregnancy success in a previous suboptimal ET patient population.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/70544",risUrl:"/chapter/ris/70544",book:{slug:"innovations-in-assisted-reproduction-technology"},signatures:"Casey Zeffiro, Silvina Bocca, Helena Russell and Mitchel C. Schiewe",authors:[{id:"255618",title:"Ph.D.",name:"Mitchel",middleName:"C.",surname:"Schiewe",fullName:"Mitchel Schiewe",slug:"mitchel-schiewe",email:"mschiewe@ovationfertility.com",position:null,institution:null},{id:"312738",title:"MSc.",name:"Casey",middleName:null,surname:"Zeffiro",fullName:"Casey Zeffiro",slug:"casey-zeffiro",email:"czeffiro@ovationfertility.com",position:null,institution:{name:"Ovation Fertility",institutionURL:null,country:{name:"United States of America"}}},{id:"315468",title:"Dr.",name:"Silvina",middleName:null,surname:"Bocca",fullName:"Silvina Bocca",slug:"silvina-bocca",email:"boccas@evms.edu",position:null,institution:null},{id:"315469",title:"MSc.",name:"Helena",middleName:null,surname:"Russell",fullName:"Helena Russell",slug:"helena-russell",email:"russellhi@evms.edu",position:null,institution:null}],sections:[{id:"sec_1",title:"",level:"1"},{id:"sec_2",title:"1. Introduction",level:"1"},{id:"sec_3",title:"2. PRP collection and infusion",level:"1"},{id:"sec_3_2",title:"2.1 Hormone replacement therapy",level:"2"},{id:"sec_4_2",title:"2.2 Methodology",level:"2"},{id:"sec_6",title:"3. Sample size and selection of samples",level:"1"},{id:"sec_6_2",title:"3.1 Inclusion criteria",level:"2"},{id:"sec_7_2",title:"3.2 Exclusion criteria",level:"2"},{id:"sec_9",title:"4. Results and data analysis",level:"1"},{id:"sec_10",title:"5. Discussion",level:"1"},{id:"sec_11",title:"6. Conclusion",level:"1"},{id:"sec_12",title:"Acknowledgments",level:"1"},{id:"sec_15",title:"Conflict of interests",level:"1"}],chapterReferences:[{id:"B1",body:'\nAmable PR, Carias RB, Teixeira MV, da Cruz Pacheco I, Correa do Amaral RJ, Granjeiro JM, et al. Platelet-rich plasma preparation for regenerative medicine: Optimization and quantification of cytokines and growth factors. Stem Cell Research & Therapy. 2013;4:67\n'},{id:"B2",body:'\nLee JW, Kwon OH, Kim TK, Cho YK, Choi KY, Chung HY, et al. Platelet rich plasma: Quantitative assessment of growth factor levels and comparative analysis of activated and inactivated groups. Archives of Plastic Surgery. 2013;40:530-535\n'},{id:"B3",body:'\nChristgau M, Moder D, Hiller KA, Dada A, Schmitz G, Schmalz G. Growth factors and cytokines in autologous platelet concentrate and their correlation to periodontal regeneration outcomes. Journal of Clinical Periodontology. 2006;33:837-845\n'},{id:"B4",body:'\nBarrione P, Gianfrancesco AD, Pereira MT, Pigozzi F. Platelet-rich plasma in muscle healing. American Journal of Physical Medicine & Rehabilitation. 2010;89:854-861\n'},{id:"B5",body:'\nPatel AN, Slezman CH, Kumpati GS, McKellar SH, Bull DA. Evaluation of autologous platelet rich plasma for cardiac surgery: Outcome analysis of 2000 patients. Journal of Cardiothoracic Surgery. 2016;11:62\n'},{id:"B6",body:'\nChen MJ, Yang JH, Peng FH, Chen SU, Ho HN, Yang YS. Extended estrogen administration for women with thin endometrium in frozen-thawed in-vitro fertilization programs. Journal of Assisted Reproduction and Genetics. 2006;23:337-342\n'},{id:"B7",body:'\nKhiaru M, Banerjee K, El-Touhky T, Coomarasamy A, Khalaf Y. Aspirin in women undergoing in vitro fertilization treatment; a systemic review and meta-analysis. Fertility and Sterility. 2007;88:822-831\n'},{id:"B8",body:'\nTakasaki A, Tamura H, Miwa I, Taketani T, Shimamura K, Sugino N. Endometrial growth and uterine blood flow: A pilot study for improving endometrial thickness in the patients with a thin endometrium. Fertility and Sterility. 2010;93:1851-1858\n'},{id:"B9",body:'\nGleicher N, Vidali A, Barad DH. Successful treatment of unresponsive thin endometrium. Fertility and Sterility. 2011;95(6):2123.e13-2123.e17\n'},{id:"B10",body:'\nKhalifa E, Brzyski RG, Oehninger S, Acosta AA, Muasher SJ. Sonographic appearance of the endometrium: The predictive value for the outcome of in-vitro fertilization in stimulated cycles. Human Reproduction. 1992;7:677-680\n'},{id:"B11",body:'\nGriesinger G, Trevisan S, Cometti B. Endometrial thickness on the day of embryo transfer is a poor predictor of IVF treatment outcome. Human Reproduction Open. 2018;1:1-8\n'},{id:"B12",body:'\nZawar MP, Deshpande NM, Gadgil PA, Mahanta AA. Histopathological study of endometrium in infertility. Indian Journal of Pathology & Microbiology. 2003;46:630-633\n'},{id:"B13",body:'\nMahajan N, Sharma S. The endometrium in assisted reproductive technology: How thin is thin? Journal of Human Reproductive Sciences. 2016;9(1):3-8\n'},{id:"B14",body:'\nSak ME, Gul T, Evsen MS, Soydinc HE, Sak S, Ozler A, et al. Fibroblast growth factor-1 expression in the endometrium of patients with repeated implantation failure after in vitro fertilization. European Review for Medical and Pharmacological Sciences. 2013;17:398-402\n'},{id:"B15",body:'\nGreen CJ, Fraser ST, Day ML. Insulin-like growth factor 1 increases apical fibronectin in blastocysts to increase blastocyst attachment to endometrial epithelial cells in vitro. Human Reproduction. 2015;30:284-298\n'},{id:"B16",body:'\nCasper RF, Yanushpolsky EH. Optimal endometrial preparation for frozen embryo transfer cycles: Window of implantation and progesterone support. Fertility and Sterility. 2016;105:867-872\n'},{id:"B17",body:'\nLessey BA, Killam AP, Metzger DA, Haney AF, Greene GL, McCarty KS Jr. Immunohistochemical analysis of human uterine estrogen and progesterone receptors throughout the menstrual cycle. The Journal of Clinical Endocrinology and Metabolism. 1988;67:334-340\n'},{id:"B18",body:'\nChang Y, Li J, Chen Y, Wei L, Pang J, Liang X. Autologous platelet-rich plasma promotes endometrial growth and improves pregnancy outcome during in-vitro fertilization. International Journal of Clinical and Experimental Medicine. 2015;8(1):1286-1290\n'},{id:"B19",body:'\nZadehmodarres S, Salehpour S, Saharkhiz N, Nazari L. Treatment of thin endometrium with autologous platelet-rich plasma: A pilot study. JBRA Assisted Reproduction. 2017;21:54-56\n'},{id:"B20",body:'\nNazari L, Salehpour S, Hoseini S, Zadehmodarres S, Ajori L. Effects of autologous platelet-rich plasma on implantation and pregnancy in repeated implantation failure: A pilot study. International Journal of Reproductive BioMedicine. 2016;14:625-628\n'},{id:"B21",body:'\nTandulwadkar SR, Naralkar MV, Surana AD, Slevakarthick M, Kharat AH. Autologous intrauterine platelet-rich plasma instillation for suboptimal endometrium in frozen embryo transfer cycles: A pilot study. Journal of Human Reproductive Sciences. 2017;10:208-212\n'},{id:"B22",body:'\nEftekhar M, Neghab N, Naghshineg E, Khani P. Can autologous platelet rich plasma expand endometrial thickness and improve pregnancy rate during frozen-thawed embryo transfer cycle? A randomized clinical trial. Taiwanese Journal of Obstetrics & Gynecology. 2018;57:810-813\n'},{id:"B23",body:'\nHounyoung K, Eun Shin J, Seon Koo H, Kwon H, Choi DH, Kim JH. Effect of autologous platelet-rich plasma treatment on refractory thin endometrium during the frozen embryo transfer cycle: A pilot study. Frontiers in Endocrinology. 2019;10:61\n'},{id:"B24",body:'\nNazari L, Salehpour S, Hoseini S, Zadehmodarres S, Azargashb E. Effects of autologous platelet-rich plasma on endometrial expansion in patients undergoing frozen-thawed embryo transfer: A double-blind RCT. International Journal of Reproductive BioMedicine. 2019;17(6):443-448\n'},{id:"B25",body:'\nChang Y, Li J, Wei L, Pang J, Chen J, Liang X. Autologous platelet-rich plasma infusion improves clinical pregnancy rate in frozen embryo transfer cycles for women with thin endometrium. Medicine (Baltimore). 2019;98(3):140-162\n'},{id:"B26",body:'\nPaulson RJ. Hormonal induction of endometrial receptivity. Fertility and Sterility. 2011;96:530-535\n'},{id:"B27",body:'\nMalhorta N, Malhorta J, Malhorta N, Rao JP, Mishra N. Endometrial receptivity and scoring for prediction of implantation and newer markers. Donald School Journal of Ultrasound in Obstetrics and Gynecology. 2010;4(4):439-446\n'},{id:"B28",body:'\nDiaz-Gimeno P, Horcajadas JA, Marinez-Conejero JA, Esteban FJ, Alma P, Pelicer A. A genomic diagnostic tool for human endometrial receptivity based on the transcriptomic signature. Fertility and Sterility. 2011;95:50-60\n'},{id:"B29",body:'\nRuiz-Alonso M, Belsa D, Diaz-Gimeno P, Gomez E. The endometrial receptivity array for diagnosis and personalized embryo transfer as a treatment for patients with repeated implantation failure. Fertility and Sterility. 2013;100:818-824\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Casey Zeffiro",address:"czeffiro@ovationfertility.com",affiliation:'
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\n
1. Introduction
\n
Terrorism is the use of internationally indiscriminate ferocity as a means to create panic in public; or fear to gain some political, financial, or religious objective. During the French Revolution, the terrorism and terrorist invented but increased popularity in the 1970s in news reports, research papers, and magazines covering the dispute and/or conflicts in the Basque, Palestine, and North Ireland.
\n
There is no doubt that there are many definitions of terrorism. Terrorism is a charged term. It is usually used with the connotation of something that is “ethically and morally wrong”. According to the Global Terrorism Database [1], from 2000 to 2014, almost 61,000 incidents of non-state terrorism, resulting in at least 140,000 deaths.
\n
Terrorism can occur in different places to create fear in the public and build pressure on governmental bodies for the aim of financial, religious, or any other benefits (\nFigure 1\n). The National Advisory Committee on Criminal Justice Standard and Goals highlighted six fundamental types of terrorism:
\n
Figure 1.
The Mumbai attack in 2008.
\n
\n
1.1 Civil disorder
\n
This is a violent form of protest, which usually held against the sitting government and mostly time supported by opposition parties. The objective is to show the unhappiness of people, but they sometimes result in large riots in which public and private property is burned/broken and civilians are injured.
\n
\n
\n
1.2 Political terrorism
\n
This type of terrorism is used by one political group to threaten another political group. In fact, government leaders are the ones who are intended to receive the ultimate message and citizens are the ones who are targeted with violent attacks.
\n
\n
\n
1.3 Quasi terrorism
\n
This is a violent act that utilizes the same methods, which employed by terrorists, but does not have the same factors of motivating. Usually, these cases involve an armed criminal who is trying to escape from law enforcement utilizing civilians as a hostage to help them escape. The lawbreaker is acting in a similar manner to a terrorist, but terrorism is not the goal.
\n
\n
\n
1.4 Nonpolitical terrorism
\n
This type of terrorism is not for gaining any political purpose, but most times is connected with religious nature.
\n
\n
\n
1.5 State terrorism
\n
This type of terrorism is totally supported by the government. In state terrorism, the government uses its military forces for their illegal objectives. The state terrorism is well-known for Indian governmental activities in Kashmir, which is also the violation of human rights. In addition, one more example of state terrorism can be noticed in Palestine.
\n
\n
\n
1.6 Limited political terrorism
\n
These acts are usually one time only plots to make an ideological statement. In this type of terrorism, the key objective is not to change the government, but to show the unhappiness against the governmental policy.
\n
\n
\n
\n
2. Cases of terrorism in developing countries
\n
During 2014, a terrorist group attack on the APS (Army Public School), which is located in the Peshawar capital city of Khyber Pakhtunkhwa Province of Pakistan. All militants were foreigner including Chechen, Afghanis, and Arabs. They entered the school and killed 132 school children and 17 school teacher and staff. During the incidents, a rescue operation was launched by the great Pak Army, who killed all the terrorists and rescued more than 950 people (\nFigure 2\n).
\n
Figure 2.
The Army Public School attack in 2014.
\n
In 2019, during the celebration of Easter festival in Sri Lanka, three churches and three hotels were targeted by the terrorist. In the suicide bombings, approximately 258 people were died including 45 foreigners, while the number of injured people was around 500. As per the official agencies, the terrorist was Sri Lankan national and was associated with a local militant group (\nFigures 3\n and \n4\n).
\n
Figure 3.
Attack on churches in Sri Lanka.
\n
Figure 4.
Suicide bombing on Easter day in Sri Lanka.
\n
During May 2019, Afghan Taliban attack in Kabul and killed five people and 24 people were injured. According to the Afghan government, four terrorists were also killed by the security forces and more than 200 people were rescued (\nFigure 5\n).
\n
Figure 5.
Smokes rises after a terrorist attack in Kabul.
\n
In April 2019, two suicide bomb attack in the northeastern Nigerian city of Maiduguri. The national news confirmed the death of 3 people and 30 were hospitalized. According to the governmental reports, two female bombers detonated their explosives among a crowd in Muna Dalti on the outskirts of Borno state capital Maiduguri, the birthplace of the Boko Haram jihadist group (\nFigure 6\n).
\n
Figure 6.
Boko Haram fighters in Nigeria.
\n
In February 2019, around 42 Indian soldiers have been killed in a suicide attack in the disputed area of Kashmir. After the suicide attack, the Indian government put their failure on Pakistani forces and blamed that the attackers were sent from Pakistan (\nFigures 7\n and \n8\n). On the other hand, Pakistani officials clearly denied the Indian officials statement. In addition, the Pakistani government spokesman said: “It is Indian habit to blame Pakistan.” Further, the spokesman offers that we are willing to investigate the case with the Indian government for better regional peace and prosperity.
\n
Figure 7.
Disputed area of Kashmir between Pakistan-Indian.
\n
Figure 8.
A suicide bombing last week in southern Kashmir killed at least 40 Indian soldiers.
\n
\n
\n
3. Terrorism in developing countries and economic growth
\n
Since the last couple of decades, the developing world is significantly facing the problem of terrorism, which slowdown to the economic growth of those countries. The table displays the list of seven developing countries that experienced terrorism incidents and lost their economic growth (\nTable 1\n).
\n
\n
\n
\n
\n
\n
\n\n
\n
S. no.
\n
Country
\n
Domestic
\n
International
\n
Total incidents
\n
\n\n\n
\n
1
\n
India
\n
2229
\n
78
\n
2438
\n
\n
\n
2
\n
Thailand
\n
985
\n
21
\n
1027
\n
\n
\n
3
\n
Philippines
\n
621
\n
51
\n
702
\n
\n
\n
4
\n
Israel
\n
482
\n
42
\n
546
\n
\n
\n
5
\n
Colombia
\n
540
\n
37
\n
620
\n
\n
\n
6
\n
Nigeria
\n
712
\n
92
\n
842
\n
\n
\n
7
\n
Nepal
\n
282
\n
27
\n
323
\n
\n\n
Table 1.
The developing countries with greater terrorism activities.
\n
In 2004, Blomberg et al. [2] conducted a study to examine the effect of terrorism on economic viability in the sample of time series data during the period of 1968 to 2000. Their findings show that terrorism has a significant and negative effect on economic growth. In addition, greater terrorist activities lose the interest of investors and mostly time’s countries face some international sanctions. In a similar way, Gaibulloev and Sandler [3] formulated a comparative analysis between developed and developing countries; they collected the data from 52 and 7 developing and developed countries, respectively. The findings were little surprising, as terrorism has no adverse effect on economic growth in developed countries, while the emerging countries economy are badly affected and destroyed by terrorism. There are myriads of other costs like brain drain, destruction of transportation and trade-related infrastructure, and diversion of funds to counterterrorism (compared to funding on social welfare including subsidies on medicines and free education).
\n
Unquestionably, foreign direct investment is fuel for economic growth, but without political stability and terror-free country, it is almost impossible. In developing countries, raising terrorism is creating an alarming situation for their economic viability [4]. A study published by Bandyopadhyay et al. [5] emphasized on a sample of 78 developing nations and they found that 1% increase in terrorism will reduce the foreign direct investment inflows by $323.6 million approximately.
\n
On the other hand, terrorism also raises the cost of doing business such as shipping cost will rise if shippers have to buy insurance to mitigate their risk of possible damages in the ports of terrorism-prone nations. In the results, the costs transferred to the consumers in terms of expensive products, which will not only reduce both imports and exports of terror-affected countries. Nitsch and Schumacher [6] claimed that during the period of 1960 to 1993, an increasing number of terrorist incidents reduced the bilateral trade among 200 countries. The multiplier effect of terrorism is not only dragged economic activities but sometimes pull countries into circular debt problems.
\n
\n
\n
4. Conclusion
\n
This chapter mainly discussed the types of terrorism and their impact on the economic growth of the countries. In addition, authors also provided cases of different terrorist attack in developing countries, particularly in Pakistan, India, Sri Lanka, and Nigeria. Authors discussed and explored with the support of previously published articles that terrorism is strongly and negatively associated with economic growth in developing countries, while in some developed countries there is no relationship between terrorism and economic growth. As developing countries economy is not well sustained as compare to developed countries and due to a single attack can leak and shake to the economic and trade activities.
\n
\n
Acknowledgments
\n
Apart from the efforts of us, the success of any project depends largely on the encouragement and guidelines of many others. I take this opportunity to express my gratitude to our research team members.
\n
Conflict of interest
There is no conflict of interest.
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School of Economics and Management, Tsinghua University, China
School of Economics and Management, Chang’an University, China
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The company was founded in Vienna in 2004 by Alex Lazinica and Vedran Kordic, two PhD students researching robotics. While completing our PhDs, we found it difficult to access the research we needed. So, we decided to create a new Open Access publisher. A better one, where researchers like us could find the information they needed easily. The result is IntechOpen, an Open Access publisher that puts the academic needs of the researchers before the business interests of publishers.
",metaTitle:"Our story",metaDescription:"The company was founded in Vienna in 2004 by Alex Lazinica and Vedran Kordic, two PhD students researching robotics. While completing our PhDs, we found it difficult to access the research we needed. So, we decided to create a new Open Access publisher. A better one, where researchers like us could find the information they needed easily. The result is IntechOpen, an Open Access publisher that puts the academic needs of the researchers before the business interests of publishers.",metaKeywords:null,canonicalURL:"/page/our-story",contentRaw:'[{"type":"htmlEditorComponent","content":"
We started by publishing journals and books from the fields of science we were most familiar with - AI, robotics, manufacturing and operations research. Through our growing network of institutions and authors, we soon expanded into related fields like environmental engineering, nanotechnology, computer science, renewable energy and electrical engineering, Today, we are the world’s largest Open Access publisher of scientific research, with over 4,200 books and 54,000 scientific works including peer-reviewed content from more than 116,000 scientists spanning 161 countries. Our authors range from globally-renowned Nobel Prize winners to up-and-coming researchers at the cutting edge of scientific discovery.
\\n\\n
In the same year that IntechOpen was founded, we launched what was at the time the first ever Open Access, peer-reviewed journal in its field: the International Journal of Advanced Robotic Systems (IJARS).
\\n\\n
The IntechOpen timeline
\\n\\n
2004
\\n\\n
\\n\\t
Intech Open is founded in Vienna, Austria, by Alex Lazinica and Vedran Kordic, two PhD students, and their first Open Access journals and books are published.
\\n\\t
Alex and Vedran launch the first Open Access, peer-reviewed robotics journal and IntechOpen’s flagship publication, the International Journal of Advanced Robotic Systems (IJARS).
\\n
\\n\\n
2005
\\n\\n
\\n\\t
IntechOpen publishes its first Open Access book: Cutting Edge Robotics.
\\n
\\n\\n
2006
\\n\\n
\\n\\t
IntechOpen publishes a special issue of IJARS, featuring contributions from NASA scientists regarding the Mars Exploration Rover missions.
\\n
\\n\\n
2008
\\n\\n
\\n\\t
Downloads milestone: 200,000 downloads reached
\\n
\\n\\n
2009
\\n\\n
\\n\\t
Publishing milestone: the first 100 Open Access STM books are published
\\n
\\n\\n
2010
\\n\\n
\\n\\t
Downloads milestone: one million downloads reached
\\n\\t
IntechOpen expands its book publishing into a new field: medicine.
\\n
\\n\\n
2011
\\n\\n
\\n\\t
Publishing milestone: More than five million downloads reached
\\n\\t
IntechOpen publishes 1996 Nobel Prize in Chemistry winner Harold W. Kroto’s “Strategies to Successfully Cross-Link Carbon Nanotubes”. Find it here.
\\n\\t
IntechOpen and TBI collaborate on a project to explore the changing needs of researchers and the evolving ways that they discover, publish and exchange information. The result is the survey “Author Attitudes Towards Open Access Publishing: A Market Research Program”.
\\n\\t
IntechOpen hosts SHOW - Share Open Access Worldwide; a series of lectures, debates, round-tables and events to bring people together in discussion of open source principles, intellectual property, content licensing innovations, remixed and shared culture and free knowledge.
\\n
\\n\\n
2012
\\n\\n
\\n\\t
Publishing milestone: 10 million downloads reached
\\n\\t
IntechOpen holds Interact2012, a free series of workshops held by figureheads of the scientific community including Professor Hiroshi Ishiguro, director of the Intelligent Robotics Laboratory, who took the audience through some of the most impressive human-robot interactions observed in his lab.
\\n
\\n\\n
2013
\\n\\n
\\n\\t
IntechOpen joins the Committee on Publication Ethics (COPE) as part of a commitment to guaranteeing the highest standards of publishing.
\\n
\\n\\n
2014
\\n\\n
\\n\\t
IntechOpen turns 10, with more than 30 million downloads to date.
\\n\\t
IntechOpen appoints its first Regional Representatives - members of the team situated around the world dedicated to increasing the visibility of our authors’ published work within their local scientific communities.
\\n
\\n\\n
2015
\\n\\n
\\n\\t
Downloads milestone: More than 70 million downloads reached, more than doubling since the previous year.
\\n\\t
Publishing milestone: IntechOpen publishes its 2,500th book and 40,000th Open Access chapter, reaching 20,000 citations in Thomson Reuters ISI Web of Science.
\\n\\t
40 IntechOpen authors are included in the top one per cent of the world’s most-cited researchers.
\\n\\t
Thomson Reuters’ ISI Web of Science Book Citation Index begins indexing IntechOpen’s books in its database.
\\n
\\n\\n
2016
\\n\\n
\\n\\t
IntechOpen is identified as a world leader in Simba Information’s Open Access Book Publishing 2016-2020 report and forecast. IntechOpen came in as the world’s largest Open Access book publisher by title count.
\\n
\\n\\n
2017
\\n\\n
\\n\\t
Downloads milestone: IntechOpen reaches more than 100 million downloads
\\n\\t
Publishing milestone: IntechOpen publishes its 3,000th Open Access book, making it the largest Open Access book collection in the world
We started by publishing journals and books from the fields of science we were most familiar with - AI, robotics, manufacturing and operations research. Through our growing network of institutions and authors, we soon expanded into related fields like environmental engineering, nanotechnology, computer science, renewable energy and electrical engineering, Today, we are the world’s largest Open Access publisher of scientific research, with over 4,200 books and 54,000 scientific works including peer-reviewed content from more than 116,000 scientists spanning 161 countries. Our authors range from globally-renowned Nobel Prize winners to up-and-coming researchers at the cutting edge of scientific discovery.
\n\n
In the same year that IntechOpen was founded, we launched what was at the time the first ever Open Access, peer-reviewed journal in its field: the International Journal of Advanced Robotic Systems (IJARS).
\n\n
The IntechOpen timeline
\n\n
2004
\n\n
\n\t
Intech Open is founded in Vienna, Austria, by Alex Lazinica and Vedran Kordic, two PhD students, and their first Open Access journals and books are published.
\n\t
Alex and Vedran launch the first Open Access, peer-reviewed robotics journal and IntechOpen’s flagship publication, the International Journal of Advanced Robotic Systems (IJARS).
\n
\n\n
2005
\n\n
\n\t
IntechOpen publishes its first Open Access book: Cutting Edge Robotics.
\n
\n\n
2006
\n\n
\n\t
IntechOpen publishes a special issue of IJARS, featuring contributions from NASA scientists regarding the Mars Exploration Rover missions.
\n
\n\n
2008
\n\n
\n\t
Downloads milestone: 200,000 downloads reached
\n
\n\n
2009
\n\n
\n\t
Publishing milestone: the first 100 Open Access STM books are published
\n
\n\n
2010
\n\n
\n\t
Downloads milestone: one million downloads reached
\n\t
IntechOpen expands its book publishing into a new field: medicine.
\n
\n\n
2011
\n\n
\n\t
Publishing milestone: More than five million downloads reached
\n\t
IntechOpen publishes 1996 Nobel Prize in Chemistry winner Harold W. Kroto’s “Strategies to Successfully Cross-Link Carbon Nanotubes”. Find it here.
\n\t
IntechOpen and TBI collaborate on a project to explore the changing needs of researchers and the evolving ways that they discover, publish and exchange information. The result is the survey “Author Attitudes Towards Open Access Publishing: A Market Research Program”.
\n\t
IntechOpen hosts SHOW - Share Open Access Worldwide; a series of lectures, debates, round-tables and events to bring people together in discussion of open source principles, intellectual property, content licensing innovations, remixed and shared culture and free knowledge.
\n
\n\n
2012
\n\n
\n\t
Publishing milestone: 10 million downloads reached
\n\t
IntechOpen holds Interact2012, a free series of workshops held by figureheads of the scientific community including Professor Hiroshi Ishiguro, director of the Intelligent Robotics Laboratory, who took the audience through some of the most impressive human-robot interactions observed in his lab.
\n
\n\n
2013
\n\n
\n\t
IntechOpen joins the Committee on Publication Ethics (COPE) as part of a commitment to guaranteeing the highest standards of publishing.
\n
\n\n
2014
\n\n
\n\t
IntechOpen turns 10, with more than 30 million downloads to date.
\n\t
IntechOpen appoints its first Regional Representatives - members of the team situated around the world dedicated to increasing the visibility of our authors’ published work within their local scientific communities.
\n
\n\n
2015
\n\n
\n\t
Downloads milestone: More than 70 million downloads reached, more than doubling since the previous year.
\n\t
Publishing milestone: IntechOpen publishes its 2,500th book and 40,000th Open Access chapter, reaching 20,000 citations in Thomson Reuters ISI Web of Science.
\n\t
40 IntechOpen authors are included in the top one per cent of the world’s most-cited researchers.
\n\t
Thomson Reuters’ ISI Web of Science Book Citation Index begins indexing IntechOpen’s books in its database.
\n
\n\n
2016
\n\n
\n\t
IntechOpen is identified as a world leader in Simba Information’s Open Access Book Publishing 2016-2020 report and forecast. IntechOpen came in as the world’s largest Open Access book publisher by title count.
\n
\n\n
2017
\n\n
\n\t
Downloads milestone: IntechOpen reaches more than 100 million downloads
\n\t
Publishing milestone: IntechOpen publishes its 3,000th Open Access book, making it the largest Open Access book collection in the world
\n
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