Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\n
We wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\n
Throughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\n
We wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
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\r\n\tThe importance of education and care in the early stages of life has long been debated and documented. However, in a world that faces ongoing crises and challenges, early childhood education is in a constant quest for pedagogies that respond to acute problems such as:
\r\n
\r\n\ta. Environmental crises which result in food & water shortages \r\n\tb. The growth of digital environments which can educate and empower as well as exploit and destroy (mobile learning, STEM education, tablets, etc.). \r\n\tc. Social, racial, class, and gender-based discriminations that restrict the developmental potential and the prosperity perspectives \r\n\td. Health hazards and illnesses such as the laters COVID-19 pandemic. \r\n\te. Armed conflicts with casualties and displacements of populations seeking refuge \r\n\tf. Lack of physical spaces that will support and nourish development and learning, etc.
\r\n
\r\n\tEducation in the post-modern era strives to address the above issues and develop policies, curricula, methodologies, and strategies to contribute to an environmentally and socially sustainable future. It embraces multiple perspectives and worldviews and seeks to touch on inequalities and discriminations in favor of equity. In this direction, children’s s agency lies at the heart of democratic approaches. Educational processes adopt forms of interactions that actualize learning as “becoming” and place it in a continuum between past, present, and future. This book intends to feature innovative approaches that employ transformative elements (targets, methods, materials, ideas, etc.) and embrace the concept of child development as “becoming” in an ever-changing and challenging world.
\r\n
\r\n\tWe invite authors to contribute original research or research review papers that present innovative approaches addressing personal and social transformation. All aspects of early childhood education will be considered, including research methodology for the early years.
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1. Introduction
Common factors linked to osteoarthritis (OA) occurrence are increasing age (>55 years) and obesity [1]. The gender also seems to play a major role, where the majority of OA patients are women and higher prevalence has been liked to menopause. Radiological evidence suggests that about 70% of women above the age of 65 years are affected by OA [2, 3]. Other factors such as genetic predisposition, extrinsic environmental factors, nutrition, and lack of exercise are reasons for the increased prevalence of OA. It has been reported by the World Health Organization (WHO) that 10–15% of the populations aged >60 years exhibit a certain degree of OA [4]. It has been reported by the National Health Portal of India that 22–39% of the Indian population are affected by OA. As reported by the United Nations Organization (UNO), 130 million people will be affected by OA with over 40 million people with severe disability due to disease progression [3].
The etiology of OA is believed to be multifactorial. Some of the main reasons include the biomechanical disease progression due to the narrowing of space in the joints, bone hypertrophy, and formation of new osteophytes in the articular margins causing stiffness and pain in the joints. In addition, an imbalance in the synthesis and release of cytokines by chondrocytes in the disease state could be the main reason for the continual inflammatory state in the joint. During the initial stages of OA, catabolic interleukins (IL) such as IL-1α and IL-1β and tumor necrosis factor α (TNFα) increase inflammation affecting cartilage metabolism and homeostasis. TNFα is a proinflammatory cytokine implicated in the degradation of matrix proteins synthesized by chondrocytes and synoviocytes [5]. Further, increase in the levels of interferon γ (IFNγ) in the joint worsens the inflammatory state and structure of the joint leading to degradation of proteoglycans such as sulfated glycosaminoglycans (sGAG) [5, 6].
2. Current treatment options for osteoarthritis
Currently, pain in OA is pharmacologically managed using nonsteroidal anti-inflammatory drugs (NSAIDS), opioids, and analgesics. Corticosteroid injections have also been used for relieving severe pain in OA patients. Recent attempts have been made to use TNFα blockers as recent studies have proven the significant role of TNFα in contribution to the pathogenesis of OA [7]. Research by several groups has implicated the role of nerve growth factor (NGF) and its binding to tropomyosin receptor kinase A (trk A) which leads to downstream signaling and activation of peripheral and central pain molecules causing severe pain. The therapeutic efficiency of anti-NGF antibodies to block NGF or its antagonists has been studied by several groups for relieving pain. The pain-relieving effects of anti-NGF antibodies fasinumab and fulranumab manufactured by Regeneron Pharmaceuticals and Janssen Pharmaceutica, respectively, have been evaluated in phase III clinical trials [8]. In addition to pain relief, efforts have been made to halt further cartilage damage using slow-acting symptomatic drugs such as chondroitin sulfate and glucosamine sulfate. Orally administered chondroitin and glucosamine have shown to relieve joint pain equivalently compared to NSAIDs. These molecules, intact or broken, could be absorbed into the matrix of the joint and prevent cartilage degeneration. Although glucosamine and chondroitin sulfate have been clinically proven to be safe, their therapeutic efficacy in protecting the cartilage matrix was found to the variable [9]. In grade 4 OA (Kellgren and Lawrence classifications), patients are advised to opt for total knee replacement surgery [10]. Alternatively, autologous chondrocyte implantation (ACI) has been suggested and reported to be successful. In the ACI method, the chondrocytes from patients are taken, culture-expanded in vitro, and then implanted back into the knees of patients. This procedure is invasive and has a lesser success rate than total knee replacement surgeries [11].
Apart from ACI, the efficacy of autologous platelet-rich plasma (PRP) in providing pain relief and promoting cartilage regeneration has been recently investigated by several groups [12]. The PRP is rich in platelets that secrete several growth factors and cytokines such as platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), insulin-like growth factor 1 (IGF-1), vascular endothelial growth factor (VEGF), and prostaglandin E2 (PGE-2) [13]. Several research groups have reported that intra-articular injections of PRP primarily reduced inflammation mediated by PGE-2, HGF, and IGF-1. IGF-1 synthesized and secreted by platelets is shown to prevent leukocyte infiltration into the joint space, thereby reducing the levels of IL-1β and TNFα in the synovial fluid [13]. Overall intra-articular injection of PRP has been shown to maintain joint homeostasis. However, clinical trial data suggest that the effect of PRP seems to last for only 3 weeks and thereafter reduces. The symptoms of OA were seen to relapse after a period of 1 year. Although promising results were observed using PRP in the hydrogel, chitosan, or hyaluronic acid (HA) scaffolds [14], efficacy is yet to be shown in elaborate randomized clinical trials (RCTs).
3. Mesenchymal stromal cells
The history of mesenchymal stromal/stem cells (MSCs) dates back to 1960 when seminal studies conducted by Friedenstein showed the isolation of MSCs from bone marrow (BM) which were capable of forming ectopic bone in vivo. This was found to be a non-hematopoietic fibroblast-like, colony-forming cell which primarily supported hematopoietic stem cells in the perivascular niche [15]. Owen and Friedenstein discovered that these cells were capable of differentiating into the osteogenic lineage [16]. Subsequently, the multipotent plasticity of that bone marrow MSCs (BMMSCs) was identified and shown that they were capable of differentiating into osteocytes, chondrocytes, and adipocytes in vitro [17]. In addition to the abovementioned three lineages, Caplan and colleagues demonstrated that these cells were capable of differentiating into cells of the muscle, tendons/ligaments, and connective tissue after which he coined the term “mesenchymal stem cells” [18]. Bianco and Gehron Robey deduced that cbfa1 gene was the master regulator for directing the osteogenic fate of MSCs. Because of the ability of MSCs to form osteocytes, they named them skeletal stem cells [19]. In 2006, the International Society for Cellular Therapy (ISCT) proposed the name multipotent mesenchymal stromal cells and defined that MSCs must adhere to the criteria of being plastic adherent; express surface markers CD105, CD73, and CD90; lack the expression of hematopoietic markers CD45, CD34, CD14 or CD11b, CD79α or CD19, and HLA-DR; and differentiate into osteoblasts, chondrocytes, and adipocytes under suitable conditions in vitro [20]. In addition to their differentiation capacity, MSCs have been shown to elicit immunosuppressive and immunomodulatory effects on T lymphocytes, B cells, dendritic cells (DC), and natural killer (NK) cells either by cell-cell interactions or by secretion of anti-inflammatory molecules such as indoleamine 2,3-dioxygenase (IDO) and prostaglandin E2 (PGE-2), interleukin-4 (IL-4), interleukin-10 (IL-10), and transforming growth factor β (TGFβ) making them ideal cell types for treatment of diseases [21, 22, 23]. Because of their ability to differentiate into chondrocytes in vitro and with their anti-inflammatory and immunomodulatory functions, they were believed to be candidate cell type to treat diseases such as OA. MSCs have been isolated from over 18 different tissue sources. The most commonly used tissue sources for isolating MSCs apart from bone marrow are the adipose tissue, umbilical cord, placenta, and dental pulp. However, autologous or allogeneic BMMSCs are currently the most widely used cell type in clinical trials for various disease indications. They are considered the “gold standard” MSC type because of their extensive characterization that took place for over 5 decades.
4. Possible mechanism of action (MoA) of BMMSCs for treatment of osteoarthritis
The pathophysiology of OA is characterized by degradation of hyaline cartilage causing narrowing of joint space leading to subchondral sclerosis, subchondral cysts, hypertrophic chondrocytes, and formation of osteophytes. The friction caused by the rubbing of joints results in chronic pain in OA patients [24]. Degeneration of cartilage extracellular matrix (ECM) may be caused due to the increase in the levels of proteolytic enzymes such as matrix metalloproteases (MMPs) and aggrecanases mediated by IL-1β and TNFα [25]. BMMSCs express a wide range of properties that are anticipated to be beneficial for treating genetic, mechanical, and age-related degeneration in diseases such as OA. In our previous publication, we have in detail attempted to deduce the possible mechanism of action (MoA) of allogeneic pooled BMMSC population [25]. Briefly, BMMSCs are known to be immunomodulatory in nature, primarily because of their potential to significantly suppress the proliferation of inflammatory T cells, monocytes, and dendritic cells either by direct cell-to-cell contact. In addition, they secrete a wide range of anti-inflammatory molecules such as PGE-2, IDO, IL1Ra, and IL-10 [26, 27]. BMMSCs influence the local osteoarthritic microenvironment by stimulating resident chondrogenic progenitor cells and promote their differentiation into mature chondrocytes mediated by secretion of bone morphogenetic proteins (BMPs) and TGFβ1 [28]. BMMSCs are known to differentiate into chondrocytes in vitro using differentiation cues such as BMP-7 and TGFβ1. A similar mechanism could be involved in the differentiation of BMMSCs in vivo. With the increase in the levels of BMP-7 and TGFβ1 in the local joint milieu, mediated by a change in expression of master regulatory genes such as Sox9, HoxA, HoxD, and Gli3, BMMSCs could differentiate into chondrogenic progenitor cells (CPCs) in vivo. The CPCs further differentiate into chondroblasts characterized by definitive upregulation of collagen types II B, IX, and XI. Subsequently, the CPCs differentiate into mature chondrocytes regulated by balanced expression of collagen X (Col X) and synthesize the secretion of collagen II which is made of sGAG building blocks which maintain the structural integrity of hyaline cartilage [25]. Very high expression of collagen X has been linked to hypertrophy of chondrocytes and formation of fibrous cartilage, and thus a regulated expression of Col X would likely result in deposition of hyaline cartilage [29]. From the above-described multimodal MoA, it is clear that BMMSCs are an ideal cell population which could contribute significantly for an effective treatment of OA.
5. Advantages of using a pooled human BMMSC (phBMMSC, Stempeucel®) product for treating osteoarthritis
In the current therapeutic scenario, the common practice is to screen several individual donors, isolate MSCs, and characterize them based on their key characteristics such as their surface marker expression, tri-lineage differentiation potential, and immunomodulatory and paracrine properties [30, 31, 32]. It is inevitable that a product that is manufactured using a master cell bank (MCB) made from a single donor will result in exhaustion. Successively, a product that is made using another single donor MSC bank, although presumably similar in basic characteristics qualifying the identity and safety criteria, may not have the same functional attributes which may lead to varied therapeutic outcomes. Eminent scientific groups have demonstrated donor-to-donor variability in properties of MSCs such as their clonogenicity, growth kinetics, and differentiation potential [33]. A comparative analysis of five different BMMSC populations showed significant variation in the proteomic profile of these cells. Only 13% similarity in the proteomic profile which included transcriptional and translational regulators, kinases, receptor proteins, and cytokines between the five BMMSC populations was found. A maximum of 72% similarity in the proteome was observed between two of the five analyzed cell populations [34]. Disparities in clinical trial outcomes have been reported where BMMSCs derived from single donors have been used. A steroid-refractory acute graft-versus-host disease (SR-aGvHD) clinical trial conducted in both children (n = 25) and adults (n = 30) using BMMSC products derived from 92 HLA-matched and HLA-mismatched donors resulted in only 50% overall durable complete response, while the remaining patients did not respond or partially responded to the treatment [35]. Similar variations with limited response rates were observed in a phase III GvHD trial conducted by Osiris Therapeutics using Prochymal® with only 35% complete response rate compared to 30% in the placebo arm [36]. It has been suggested that improper selection of a BM donor and making a single donor-derived cell product could lead to substantial variations in therapeutic outcomes [37]. In order to challenge this issue, some scientific groups have suggested pooling of BMMSCs from two or more donors in order to compensate for the variation and balance the properties between different donor cell populations. Samuelsson et al. showed that a two- or three-donor pooled BMMSC product could optimize the immunosuppressive properties of these cells in vitro [38]. Later, Kuçi et al. showed substantial variability in the immunosuppressive properties of individual donor-derived BMMSCs (n = 8). On the contrary, a mesenchymal end product (MEP) made by pooling BMMNCs from eight donors resulted in a cell population that consistently suppressed an MLR in vitro [39]. Subsequently, they went on to conduct a multicentric SR-aGvHD clinical trial in 51 children and 18 adults using MEP/MSC Frankfurt am Main (MSC-FFM, Obnitix®) cells and observed 83% overall response (complete response, 32%; partial response, 51%) [40]. At Stempeutics Research Pvt. Ltd., we were the first group to develop an allogeneic pooled human BMMSC product called Stempeucel® using an established, robust pooling protocol and a two-tier manufacturing and banking system as previously described [41, 42]. Recently, we have published our comprehensive studies including in vitro chondrogenic properties and preclinical and clinical findings establishing the efficacy and safety of using Stempeucel® for the treatment of OA of the knee joint [43]. In this study, we found that several manufactured batches of Stempeucel®, when differentiated into the chondrocyte lineage, downregulated the expression of the gene Sox9 and upregulated the expression of collagen type 2A (Col2A) gene confirming their differentiation into the chondrogenic lineage. The same Stempeucel® batches synthesized substantial levels of sGAG (30 ± 1.8 μg/μg GAG/DNA) which were estimated using a dimethylmethylene blue-based biochemical assay kit (Figure 1). These properties indicate that Stempeucel® could be a potential treatment option for treating OA.
Figure 1.
Chondrogenic potency assessment using quantification of sGAG in 16 batches of Stempeucel® cryopreserved in PlasmaLyte A-based cryopreservation solution and 4 batches of Stempeucel® cryopreserved in CS 5.
6. Development of a potency assay for Stempeucel® intended to treat osteoarthritis
The US Food and Drug Administration (USFDA) describes potency assays as “The specific ability or capacity of the product, as indicated by appropriate laboratory tests or by adequately controlled clinical data obtained through the administration of the product in the manner intended, to effect a given result” (US-FDA, 21 CFR 600). For any cell therapy product (CTP) intended to be used for a particular indication, a specific, quantifiable, potency test or array must be developed. The development of a potency assay must begin with in vitro and preclinical studies based on the MoA of the CTP. The confirmation of the assay or the identified marker must be evaluated in every large-scale manufactured batch of the CTP during the progress of the phase I and phase II clinical studies. A quantifiable range for the potency test must be defined and implemented during the course of phase III clinical trial [44]. In order to predict the efficacy of a CTP, either in vitro biochemical assays or biological assays or in vivo biological assessment could be implemented. For example, a company called TiGenix (Leuven, Belgium) has developed and adopted an assay matrix where an ex vivo polymerase chain reaction (PCR) array for autologous chondrocytes (ChondroCelect) is performed and ectopic cartilage formation is correlated to the histology sections of an orthotopic goat model where ChondroCelect is implanted [45, 46]. Jeong et al. have demonstrated that thrombospondin-2 (TSP-2) could be an effective marker to predict the chondrogenic efficiency of umbilical cord-derived MSCs (UC-MSCs). They demonstrated that UC-MSCs, through the TSP-2 secretion, can promote chondrogenesis via PKCa, ERK, P38/MAPK, and Notch signaling pathways [47]. Recently, another group estimated the levels of TSP-2 to evaluate the chondrogenic potency of a UC-MSC product (Cellistem®OA, Cells for Cells, Brazil) intended to be used in phase I/phase II RCT for knee OA [48]. Other scientific groups have shown that autologous culture-expanded chondrocytes could be embedded in collagen-1 and injected subcutaneously in nude mice to predict the potency of several bioactive molecules in promoting chondrogenesis [49]. For the first time, we have developed a chondrogenic potency assay for an allogeneic pooled bone marrow-derived MSC product (phBMMSCs, Stempeucel®). Preliminarily, we culture-expanded and differentiated several Stempeucel® batches into the chondrogenic lineage using commercially available differentiation assay kits (Thermo Fisher Scientific, USA). To confirm the differentiation, we evaluated the Col2A mRNA expression in differentiated cells and compared them with the undifferentiated control cells. After observing a significant increase in the Col2A expression of differentiated cells, we enzymatically digested both the differentiated and undifferentiated cells to quantify the levels of sGAG synthesized by these cells using a 1,9-dimethylmethylene blue (DMMB)-based assay kit (Blyscan, Biocolor, UK). We further normalized the levels of sGAG with the amount of DNA from the same number of cells. We evaluated the sGAG levels in 20 batches of Stempeucel® of which 16 batches were cryopreserved in our older formulation (10% dimethyl sulfoxide (DMSO), 5% human serum albumin (HSA) and PlasmaLyte A) and also four batches of Stempeucel® cryopreserved in a new cGMP grade CryoStor 5 solution (CS5, BioLife Solutions). We observed a significant and consistent increase in the levels of sGAG in the differentiated cells compared to the undifferentiated cells (undifferentiated, 11.9 ± 4.6 GAG/DNA (μg/μg); differentiated, 31 ± 8.6 GAG/DNA (μg/μg; P < 0.0001; n = 20)) (Figure 1). Based on our results, we propose that the sGAG assay is a simple, quantifiable, and robust potency assay which could also be a part of a bigger potency assay matrix to predict the chondrogenic potency of therapeutic cells intended to treat cartilage defects.
7. Preclinical efficacy studies in OA
Many studies have demonstrated that MSCs are nontoxic and non-tumorigenic when tested in various animal models [50, 51]. Prior to evaluating the efficacy of Stempeucel® in an appropriate preclinical model of OA, we had earlier evaluated the preclinical safety and toxicity of Stempeucel® in rodent and non-rodent models. In the same study, we evaluated the feasibility of multiple routes of cell injection. Tumorigenic analysis in severe combined immunodeficient (SCID) mice showed that Stempeucel® is non-tumorigenic. In addition, the biodistribution kinetics of CM-DiI labeled Stempeucel® in the systemic circulation and also in muscle tissue were studied in both rats and mice [51].
It is important to demonstrate the efficacy of any cell therapy product in an animal model of disease before administrating the product in humans with the same disease. It is imperative to determine the suitability of using animal stem cells in animals or human stem cells in immunocompromised/immunocompetent animals. A common regulatory requirement is to have animal data for the same test product that is intended to be tested in humans. In our recently published work, we evaluated the efficacy of Stempeucel® in a monosodium iodoacetate (MIA)-induced OA model in Wistar rats. We demonstrated the dose-dependent efficacy of two Stempeucel® doses of 0.65 × 106 (25 × 106 human equivalent dose, HED) and 1.3 × 106 (50 × 106 HED) followed by an injection of hyaluronic acid (HA). A significant dose-dependent reduction in pain scores was observed in both low and high Stempeucel® doses compared to the HA alone and disease control group. Histological evaluation of joint tissue sections in all study groups showed significant improvement in proteoglycan staining in both low and high Stempeucel® administered groups indicating significant regeneration of the cartilage in both groups compared to the HA alone and disease control groups [43].
Similar to the animal model we used, other scientific groups have created articular cartilage defects in small animals, such as mice [52], rats [43, 53, 54], and rabbits [55, 56]. Smaller animal models are cost-effective and easy to house, and rodents are available in a variety of genetically modified strains with minimal biological variability [57, 58]. However, the small joint size, thin cartilage, altered biomechanics, and increased spontaneous intrinsic healing hamper the study of the regenerative capacity of stem cells and these mechanisms of healing which cannot be fully extrapolated to human cartilage repair [59, 60]. Rodents have mainly been used to assess the chondrogenesis of cell-based therapies by subcutaneous, intramuscular, and intra-articular implantations of cells [60]. Of all small animals, the rabbit model is the most utilized model in cartilage regeneration studies because of the slightly larger knee joint size than rodents [55, 56]. Despite their limited translational capacity, small animals can be very useful as a proof-of-principle study and to assess therapy safety before moving on to preclinical studies using larger animals [60].
Large animal models play a more substantial role in translational research because of a larger joint size and thicker cartilage; however, their preclinical use is often hindered by high costs and difficulties in animal handling. A variety of large animal models have been used to investigate cartilage repair strategies, including horses [61], dogs [62], sheep [63, 64], goats [65], and pigs [66], each with their own strengths and limitations. We have listed some relevant published studies which have used autologous, allogeneic, or xenogeneic BMMSCs to treat OA induced by various methods (Table 1).
Based on the positive efficacy outcomes of our preclinical study, subsequently, we demonstrated the safety and optimal dose for efficacy in a phBMMSC product, Stempeucel®, in a randomized, double-blind, placebo-controlled dose-finding phase II clinical trial in Indian patients [43].
8. Clinical trials in osteoarthritis of the knee joint
8.1 Safety of mesenchymal stromal cells in clinical trials
Lalu MM et al. conducted a systematic review of clinical trials that examined the use of MSCs to evaluate their safety [68]. A total of 36 studies having 1012 participants with different clinical conditions was evaluated. Eight studies were randomized control trials (RCTs) and enrolled 321 participants. Only prospective clinical trials that used the intravenous or intra-arterial route of administration in different age groups were analyzed. Meta-analysis did not detect an association with MSC administration and acute infusional toxicity, organ system complications, infection, and death. There was a significant association between MSCs and transient fever at or shortly after MSC administration which was not associated with long-term sequelae. Most importantly, the meta-analysis showed no serious adverse event due to the administration of MSCs and specifically found no association between MSCs and tumor formation. In another study, Peeters et al. [69] did a systemic review of the safety of intra-articular administration of culture-expanded stem cells. A total of 844 procedures (mean follow-up of 21 months) was analyzed. Four SAEs were reported—one infection following bone marrow aspiration (BMA) that resolved with antibiotics, one pulmonary embolism after 2 weeks of BMA, and two adverse events not related to the therapy. Other adverse events documented were increased pain/swelling and dehydration after BMA. In another review, a recent analysis of adverse events (AEs) in 2372 orthopedic patients treated with autologous stem cell therapies and followed up for 2.2 years has been published [70]. The common AEs reported included post-procedure pain and pain due to progressive degenerative joint disease in under 4% of the population. Hence, we can conclude that the systemic administration of MSC including intra-articular administration is safe.
8.2 Efficacy of stem cells including mesenchymal stromal cells in clinical trials of osteoarthritis of the knee joint
Several clinical trials have been conducted using bone marrow mononuclear cells, adipose tissue-derived stromal vascular fraction (AD-SVF), adipose tissue-derived mesenchymal stromal cells (AD-MSCs), or bone marrow-derived mesenchymal stromal cells (BMMSCs) in OA of the knee joint. The list of the published clinical trials in chronological order is given in Table 2. Administration of the cells has been fairly standardized, with the cells being administered either directly intra-articularly or under ultrasound guidance. Few trials have been conducted using the arthroscopic method of administration with direct implantation of the cells alone or with a scaffold at the site of cartilage injury.
Author/year
Sample size
Study design
Grade of OA
Cell type and dose
Control group
Outcome measures
Outcomes
Follow-up period
Reference
Wakitani (2002)
24
A single-arm control study
Stage I to stage II Ahlback changes
Auto BMMSC, 13 × 106 cells embedded in soluble collagen (n = 12)
High tibial osteotomy (n = 12)
Hospital for Special Surgery knee rating scale, arthroscopy and histology
No significant difference in clinical evaluations between the two groups, arthroscopy and histology showed partially hyaline cartilage-like tissue
VAS pain score, time to walk and number of stairs to climb to produce pain, the resting time to induce the gelling pain, ROM and patellae crepitus
Walking time for the pain to appear improved for three patient, VAS pain score and number of stairs to climb improved for all patients, improvement in crepitus
Lysholm score, Tegner activity scale, and VAS scores
The clinical scores preoperatively were significantly poorer than those of the control group but at the last follow-up visit were similar and not significantly different between the two groups
IKDC score, Tegner activity scale, and cartilage repair assessed using ICRS grading
IKDC and Tegner activity scale scores significantly improved, ICRS grades showed 2 of the 37 lesions (5%) were grade I (normal) and 7 (19%) were grade II (near normal)
Lysholm score, KOOS, VAS score, MRI, cartilage repair tissue scoring system, arthroscopy and histology
MRI, better signal intensity for repair tissue in group 1 (80%) as compared to 72.5% in group 2; KOOS pain and symptom subscores, significantly greater for group 1; arthroscopy and histology, no significant difference
Allo BMMSC + HA, four doses (25, 50, 75, 150 × 106 cells)
n = 20 (placebo + HA)
Safety, VAS, ICOAP, WOMAC, MRI, WORMS score
Safety established; AE were predominant in the higher-dose groups; VAS, ICOAP, and WOMAC scores best in the lowest dose; MRI, no significant difference
Safety, KOOS, VAS, MRI, second-look arthroscopy, histology
No SUSAR; KOOS and VAS scores improved significantly; MRI, showed complete filling of the defect; arthroscopy, effective defect fill, and integration in the surrounding tissue; histology, positive staining for both type I and type II collagen and proteoglycan
3 groups, 20 each; first group (AAPBSC + PRP + G-CSF+ HA + MCS); second group (AAPBSC + PRP + HA + MCS); third group (control) (all given weekly × 3 injections)
20 patients, IA, HA alone
Avoidance of TKA intervention and WOMAC scores
TKA done in three patients in the control group but not in the cell group; WOMAC, all groups reached statistically significant improvements within the individual (intra) groups
ICRS cartilage repair, VAS, IKDC, MRI, histological findings
VAS and IKDC improved at 24 weeks and stable till 7 years; histology at 1 year showed hyaline-like cartilage; MRI at 3 years showed the persistence of regenerated cartilage
15 patients; AM + Auto AD (SVF + PRP; 107 SVF cells/ml)
15 patients, AM
Safety, WOMAC, Lysholm, and modified VAS scores, MRI
Safety established, WOMAC scores not significant between two arms at 6 and 12 months but significant at 18 months; increased Lysholm and VAS scores in the treatment group compared with the placebo; MRI, MRI demonstrated cartilage layer was thicker in the treatment group
Randomized 4:1; Progenza (PRG) (Allo AD-MSC + culture supernatant); 2 groups, 8 pts. each, 3.9 or 6.7 million cells
4 patients, placebo administered
Safety, WOMAC, VAS, AQoL-4D, biomarkers (urine, C2C and CTX-II; serum, MIF and CTX-I; MRI, MOAKS score)
All patients experienced at least one TEAE; VAS and WOMAC, statistically significant within-group reduction from baseline in PRG group, no statistically significant differences at any time point between placebo and PRG groups; MRI, no decrease in lateral tibial cartilage volume while the placebo group showed a statistically significant cartilage loss
RCT, phase I/phase II, placebo-controlled, triple-blind
KL grade 2 to grade 4
Auto BMMSC, 40 × 106 cells (n = 19)
5 ml normal saline (placebo) (n = 24)
VAS, WOMAC, walking distance, painless walking distance, standing time and knee flexion compared
WOMAC, significant improvements in total score, pain, and physical function subscales and improvement in painless walking distance compared with placebo
VAS, KOOS, knee flexion range of motion (ROM), MRI
No SAEs; significant knee ROM improvement at 2 and 24 weeks; VAS, no change; KOOS, improvement till 8 weeks; MRI, chondral thickness improved in about 10% of the total knee joint area AT 24 weeks
Chronological list of publications of stem cell application for cartilage repair.
AAPBSC, autologous activated peripheral blood stem cells; AD-MSCs, adipose tissue-derived mesenchymal stromal cells; AEs, adverse events; Auto, autologous; Allo, allogeneic; AM, arthroscopic microfracture; AQoL-4D, assessment of quality of life 4D questionnaire; BMAC, bone marrow aspirate concentrate; BMMSCs, bone marrow-derived mesenchymal stromal cells; C2C, type II collagen C2C peptide; CTX-1, C-terminal telopeptide of type I collagen; CTX-II, C-terminal telopeptide of type II collagen; dGEMRIC, delayed gadolinium-enhanced magnetic resonance imaging of cartilage; FRI, functional rating index; HA, hyaluronic acid; G-CSF, granulocyte colony-stimulating factor; IA, intra-articular; ICOAP, Intermittent and Constant Osteoarthritis Pain; ICRS, International Cartilage Repair Society Cartilage Injury Evaluation Package; IKDC, International Knee Documentation Committee Subjective Knee Evaluation Form; JKOM, Japanese Knee Osteoarthritis Measure; KL grade, Kellgren and Lawrence grade; KOOS, Knee Injury and Osteoarthritis Outcome Scores; KSS, Knee Society clinical rating system; MIF, macrophage migration inhibitory factor; MOAKS, MRI Osteoarthritis Knee Score; MOCART, magnetic resonance observation of cartilage repair tissue; MCS, mesenchymal cell stimulation; MRI, magnetic resonance imaging; NC, nucleated cells; PCI, poor cartilage index; PBPC, peripheral blood progenitor cells; PGA, patient global assessment; PR-FG, platelet-rich fibrin glue; PRP, platelet-rich plasma; QOL, quality of life; RCT, randomized controlled trial; RHSSK, Revised Hospital for Special Surgery knee scores; ROM, range of motion; SAE, serious adverse event; SAS, Short Arthritis Assessment Scale; SF-36, Short Form-36 quality of life questionnaire; SUSAR, suspected unexpected serious adverse reaction; SVF, stromal vascular fraction; TEAE, treatment emergent adverse event; TKA, total knee arthroplasty; TUG, timed up and go; UC-MSC, umbilical cord-derived MSC; VAS, visual analog pain score; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index; WORMS, whole-organ magnetic resonance imaging score.
The first clinical study has been published way back in 2002 by Wakitani et al. [71]. In this study of 12 patients who underwent high tibial osteotomy, BMMSCs at a dose of 13 million cells were embedded in collagen gel and transplanted into the cartilage defect and covered with autologous periosteum. The clinical improvement was not significantly different from the control group, but the arthroscopic and histological evidence was better in the transplanted group than the control arm. Since then many studies have been published, but still many contentious issues regarding cell therapy in OA are being discussed. We will try to discuss a few burning issues in this chapter:
Level of evidence regarding the use of MSC therapy in OA: Jevotovsky et al. [106] did a systemic review of 61 studies to look at the study evidence level, MSC protocol, treatment results, and AEs. The levels of evidence were defined by Marx et al. stating the level of evidence as level 1, randomized controlled trial; level II, prospective cohort study or observational study with dramatic effects; level III, retrospective cohort study or case–control study; level IV, case series; and level V, mechanism-based reasoning [107]. These levels of evidence help physicians to come to clinical decisions. In this review, a total of 2390 patients in 61 studies was identified. Most of the studies used adipose-derived stem cells (ADSCs) (n = 29) or bone marrow-derived stem cells (BMSCs) (n = 30). The majority of the studies (57%) were level IV evidence which consists of therapeutic case series without comparative groups. Only five and nine studies were level I and level II evidence, respectively, in a total of 288 patients. Additionally, 11% were level III retrospective cohort studies, and 8% were level V single-patient case reports. The published data highlights the need for more level I and level II evidence to evaluate the role of MSC treatment in OA patients. However, the majority of the studies have reported positive results and an association between MSC therapy and symptomatic and radiologic improvement in these patients.
Best source of MSC for treatment of OA: Many studies have been published using different sources of MSCs, and there is no consensus as to which MSC type is the most effective in treating OA. Recently few studies have been published using SVF, bone marrow aspirate concentrate, and micro-fragmented adipose tissue, which further adds to the variability of this issue. The most common problem affecting the clinical outcome in OA is the tendency of MSCs to differentiate into fibrous-like tissue instead of hyaline cartilage [108]. To eliminate or reduce chondrogenesis of the injected MSCs, one school of thought is to identify new sources of MSCs for cartilage repair. Recently synovium-derived stem cells have been used for OA study as it is believed that epigenetic memory may play a role and impact the specific lineage differentiation of MSCs [109]. Hence, the use of synovium stem cells predicts a better outcome as chondrogenic differentiation is expected as it belongs to the same lineage. Fetal stem cells have higher plasticity and proliferation ability than adult stem cells. Hence, fetal tissue-derived stem cells, especially derived from the fetal cartilage, may show higher chondrogenic activity [110] and may be the ideal source of cells for OA. More controlled clinical trials are required to come to a conclusion as to which cell type may be the best choice for the effective treatment of OA.
Autologous or allogeneic source of MSCs: Most of the published trials used autologous MSCs to minimize immune response, which may lead to best clinical outcomes. Six of the studies in Table 2 attempted to investigate the potential application of allogeneic MSCs [43, 48, 93, 96, 103, 105] in OA. Recently in the last 2–3 years, most of the studies have attempted to use an allogeneic source of MSCs due to the ease of application. Further, no observed serious adverse effects indicate the safety of allogeneic cells in OA. Around 3000 patients have been administered allogeneic MSCs for different conditions, and no immune response has been reported to date [111]. In a recently published trial using allogeneic umbilical cord-derived MSCs (UC-MSC) in knee OA, patients were randomized to receive hyaluronic acid at baseline and 6 months (HA, n = 8), single-dose (20 × 106) UC-MSC at baseline (MSC-1, n = 9), or repeated UC-MSC doses at baseline and 6 months (20 × 106 × 2; MSC-2, n = 9). No serious adverse events were reported. At 12 months of follow-up, MSC-2-treated group had significantly lower levels of pain [visual analog score (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), total score, and pain subscale] than HA group [48]. Hence, it can be safely concluded that the use of allogeneic MSCs is safe and may be efficacious in OA.
The optimal dose of MSCs for best efficacy in OA: MSCs have been used in different doses in several clinical trials of OA (Table 2). The dose varied from as low as 1.18 million cells [79] to as high as 150 million cells [43]. In a study by Koh et al. [79], 18 patients were given intra-articular injections with adipose tissue-derived MSCs in a mean dose of 1.18 million cells and platelet-rich plasma. At 26 months of follow-up, patients had significant improvement in VAS, Lysholm, and WOMAC scores. Magnetic resonance imaging (MRI) was evaluated using WORMS score and showed statistically significant improvement in the total and cartilage scores. In another dose-finding study, Pers et al. [90] recruited 18 patients who were treated with autologous AD-MSCs in three different doses: low dose (2 × 106 cells), medium dose (10 × 106 cells), and high dose (50 × 106 cells). After 6 months of follow-up, the procedure was found to be safe, and no serious adverse events were reported. Patients in the low dose had significant improvement in pain levels and functions as compared to baseline. In a dose-finding study conducted by Gupta et al. [43], four different doses (25, 50, 75 and 150 million cells) of allogeneic BMMSCs were used in a total of 60 patients. At 1 year of follow-up, the lower doses of 25 million had shown improvement in pain levels and function as compared to placebo and baseline. However in a study by Jo et al. [101], 18 patients were injected with autologous AD-MSCs in three different doses: 10, 50, and 100 million cells. At 2 years of follow-up, significant improvement in the Knee Society clinical rating system (KSS), Knee Injury and Osteoarthritis Outcome Score (KOOS), and VAS scores was seen in the highest dose of 100 million cells. As can be seen, most of the studies are single-arm studies without any control arm. Hence, to determine the most efficacious dose in OA, more randomized controlled, dose-finding clinical trials are required.
Selection of endpoints for the conduct of clinical trial: The FDA 2018 draft guidance document for OA regarding the development of structural endpoints for the development of drugs, devices, and biological products for treatment states that approvals for OA to date have been based on patient-reported outcome measures that assess pain and function. For the development of new product in OA, the goal of treatment should be inhibition of structural damage or targeting the underlying pathophysiology associated with OA or significantly delay the complications of joint failure and the need for joint replacement and also to reduce the deterioration of function and worsening of pain. All of the above may be taken into consideration for the development of endpoints for the study in OA [112].
Recently a meta-analysis was done to evaluate the different endpoints used to see the therapeutic efficacy and safety of MSCs for the treatment of patients with knee osteoarthritis [113]. Five hundred eighty-two patients in 11 randomized controlled trials were included in this meta-analysis. It showed that MSC treatment significantly improved VAS and International Knee Documentation Committee (IKDC) scores after 24 months of follow-up compared to controls. MSC therapy also showed significant improvement in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Lequesne algofunctional indices (Lequesne), Lysholm knee scale (Lysholm), and Tegner activity scale (Tegner) at 12 or 24 months of follow-up. Hence, all the endpoints used currently for evaluation of efficacy in OA have shown significant improvement in different clinical trials:
MRI to evaluate cartilage regeneration: MRI has emerged as the leading method of imaging soft tissue structures around joints. An ideal MRI study for the cartilage should provide an accurate assessment of cartilage thickness and volume, show morphologic changes of the cartilage surface, show internal cartilage signal changes, and allow evaluation of the subchondral bone for signal abnormalities. Also, it would be desirable for MRI to provide an evaluation of the underlying cartilage physiology, including providing information about the status of the glycosaminoglycan (GAG) and collagen matrices [114]. But, in actual, there is an absence of a standard system by MRI to evaluate cartilage regeneration. Many studies as given in Table 2 that have used MRI to evaluate cartilage regeneration are only qualitative. It is recommended to use validated imaging outcomes for cartilage regeneration for scientifically validating cell-based therapies, thus advancing the field. The most common parameters used for evaluation of cartilage regeneration by MRI are cartilage thickness in different points in all the compartments of the joint [97], cartilage volume [101], whole-organ magnetic resonance imaging score (WORMS) [43, 48], T2 relaxation time mapping [78, 83, 85, 95, 98], MRI Osteoarthritis Knee Score (MOAKS) score [88, 103], magnetic resonance observation of cartilage repair tissue (MOCART) score [88], and contrast-enhanced imaging technique known as delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) [90]. Among all the parameters, T2 mapping and WORMS seem to be the most commonly used qualitative parameters used for evaluation of cartilage regeneration as it is sensitive to both changes in cartilage hydration and collagen fibril orientation. In a study by Orozco et al. [78], T2 relaxation measurements demonstrated a highly significant decrease of poor cartilage areas (on average, 27%), with the improvement of cartilage quality in 11 of the 12 patients. In another study by Rich et al. [83], a total of 50 patients was evaluated by T2 mapping at 12 months of follow-up after administration of autologous BMMSCs. The mean poor cartilage index (PCI) significantly decreased in 37 of 50 patients (74%), 10 remained the same (20%), and 3 worsened between 7 and 10% (6%). Hence, cartilage T2 mapping may be a sensitive marker for monitoring cartilage quality in subjects with knee OA as it allows us to accurately determine the grade of disorganization of the extracellular matrix.
Use of MSC alone or MSC with a scaffold for intra-articular injection in OA: When MSCs are injected intra-articularly alone, MSCs scatter widely in the joint, making it impossible to obtain consistent local concentration at the site of cartilage defect. Hence, with a hope to enhance their efficacy in cartilage regeneration, MSC implantation using scaffolds is being attempted in different clinical trials so that the cells are delivered to the site of interest. Compared to direct intra-articular injection, MSC delivery via a scaffold affords more control of proliferation, matrix production, and self-renewal which may help in the regeneration/repair of degenerated or damaged articular cartilage. Different scaffolds have been designed as the delivery system for the repair of articular cartilage. The different scaffolds which can be used are either made of poly-lactic-co-glycolic acids (PLGA) [115], collagen [116], gelatin [117], tricalcium (TCP) [118], poly-lactic acid (PLA) [115], hyaluronic acid (HA) [119], poly-glycolic acid (PGA), or fibrin glue [120]. HA has been used frequently for implantation of MSCs into the joint. Many clinical studies (Table 2) have used HA as scaffold along with MSCs for implantation of the cells. Cartistem®, an approved drug by the Korean FDA for knee OA, is a combination of human umbilical cord blood-derived MSCs and sodium hyaluronate which is directly implanted at the site of cartilage injury into the joint by arthroscopy [96, 121]. Hence, cells with scaffold are the ideal combination for intra-articular delivery for cartilage degeneration. However, further studies are necessary to find optimal implantation vehicles that can result in the regeneration of articular cartilage.
8.3 Clinical trials in India
Few clinical trials using autologous or allogeneic MSCs or mononuclear stem cells in OA have been conducted in India. The trials registered in the Clinical Trials Registry of India are the two trials done by Stempeutics (one phase II trial completed and the other phase III trial ongoing). However, one published trial by Bansal et al. [122] for the single-arm study was done in India in which a total of 10 patients were treated with AD-MSCs. The patients were evaluated for safety, WOMAC, 6-minute walk test (6MWT), and MRI for cartilage thickness. The patients were followed up for 2 years. The total WOMAC and its subscale scores and 6MWT were significantly improved at all-time points till 2 years of follow-up. Cartilage thickness as determined by MRI improved by at least 0.2 mm in six patients, was unchanged in two patients, and decreased by at least 0.2 mm in two patients. The authors concluded that the procedure demonstrated a strong safety profile with no severe adverse events or complications reported.
8.4 Stempeutics Research experience in osteoarthritis of the knee joint
The off-the-shelf allogeneic, pooled BMMSC product developed by Stempeutics has completed one phase II clinical trial [43] and currently ongoing phase III trial in knee OA. In our completed phase II trial, we included patients of idiopathic OA in grade 2 or 3 of Kellgren and Lawrence radiographic criteria; patients who had self-reported difficulty in at least one of the following activities attributed to knee pain, lifting and carrying groceries, walking 400 m, getting in and out of a chair, or going up and down stairs; and patients who had been on stable medication, including nonsteroidal anti-inflammatory drugs/opioid analgesics for the past 3 months and in the age group of 40–70 years. All the criteria have to be present before being included in the study [43].
8.4.1 Phase II study in patients with osteoarthritis of the knee joint
The phase II results of Stempeucel® in OA patients have been published [43]. Briefly, it was a double-blind, randomized, placebo-controlled, dose-finding study. In this study, 60 OA patients were randomized to receive different doses of Stempeucel®, 25, 50, 75, and 150 million cells or placebo. Stempeucel® was administered intra-articularly (IA) to the knee joint followed by 2 ml of hyaluronic acid (20 mg). The subjects were followed up for 2 years and were evaluated for safety parameters including AEs, and for efficacy parameters, VAS for pain, Intermittent and Constant Osteoarthritis Pain (ICOAP), WOMAC (total score and its subscales), and MRI were done to evaluate the WORMS score. The intra-articular administration of Stempeucel® was safe with knee pain and swelling as the most common AEs. Clinically relevant improvement in a persistent manner was seen in 25 million dose group in all subjective parameters (VAS, ICOAP, and WOMAC scores) (Figures 2–4). WORMS of MRI knee did not reveal any difference from the baseline and placebo group. It was concluded that intra-articular administration of Stempeucel® is safe and 25 million dose may be the most effective among the doses tested.
Figure 2.
Visual analog scale values. Data presented as mean value ± SD; C1 = cohort 1; C2 = cohort 2; 25M, 50M, 75M, 150M = 25, 50, 75, 150 million cells, respectively; 1M, 3M, 6M, 12M = 1, 3, 6, 12 months, respectively.
Figure 3.
WOMAC results. WOMAC: (A, B) composite; (C, D) pain; (E, F) stiffness; and (G, H) physical function. Data presented as mean value ± SD; C1 = cohort 1; C2 = cohort 2; 25M, 50M, 75M, 150M = 25, 50, 75, 150 million cells, respectively; 1M, 3M, 6M, 12M = 1, 3, 6, 12 months, respectively; WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index.
Figure 4.
ICOAP results. ICOAP: (A, B) total; (C, D) continuous pain; and (E, F) intermittent pain. Data presented as mean value ± SD; C1 = cohort 1; C2 = cohort 2; 25M, 50M, 75M, 150M = 25, 50, 75, 150 million cells, respectively; 1M, 3M, 6M, 12M = 1, 3, 6, 12 months, respectively; ICOAP = Intermittent and Constant Osteoarthritis Pain.
Currently, we are conducting a phase III trial in OA of the knee joint. This is a randomized, double-blind, multicentric, placebo-controlled study assessing the efficacy and safety of intra-articular administration of Stempeucel® in patients with osteoarthritis of the knee joint. One hundred and forty-six patients will be randomized to stem cell and placebo arm in a ratio of 1:1. Seventy-three patients will receive Stempeucel® (25 million) followed by 2 ml of hyaluronan, and 73 patients will receive only intra-articular injection of 2 ml of placebo followed by 2 ml of hyaluronan. The patients will be followed up for a total of 2 years after IMP administration. The details of the study are found in the Clinical Trials Registry of India (CTRI/2018/09/015785).
9. Conclusion
Osteoarthritis is a common disorder involving damage to synovial joint tissues particularly the cartilage and bone. Current treatments are mostly targeted at end-stage disease, but biological therapies including stem cell therapy show a promise for earlier intervention with a more prolonged benefit. With all the published clinical trial data, it is reasonable to expect that MSCs may prove to be an important therapy for OA. Pooled BMMSCs with their enhanced anti-inflammatory potential, immunomodulatory properties, and secretion of paracrine factors create the optimum environment for a controlled reparative pathway in the affected joint. Pooled BMMSC treatment, perhaps combined with other modalities like a scaffold, would be advantageous in providing treatment in early OA to slow disease progression, thus delaying or avoiding total joint replacement.
Acknowledgments
We thank Stempeutics Research Pvt. Ltd. and Mr. BN Manohar for proving the required funding for the relevant studies. We would like to thank Dr. Anish S Majumdar and Dr. Sudha Balasubramanian for their critical scientific inputs for potency assay development, preclinical studies, and clinical studies conducted by Stempeutics Research. We also thank Dr. Anoop Chullikana for his valuable inputs in the clinical studies.
Conflict of interest
The authors declare no conflict of interests.
\n',keywords:"osteoarthritis, pooled human bone marrow-derived mesenchymal stromal cells, potency assay, preclinical studies, clinical studies",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/67252.pdf",chapterXML:"https://mts.intechopen.com/source/xml/67252.xml",downloadPdfUrl:"/chapter/pdf-download/67252",previewPdfUrl:"/chapter/pdf-preview/67252",totalDownloads:1015,totalViews:0,totalCrossrefCites:0,dateSubmitted:"September 17th 2018",dateReviewed:"March 25th 2019",datePrePublished:"May 21st 2019",datePublished:"April 22nd 2020",dateFinished:"May 21st 2019",readingETA:"0",abstract:"Osteoarthritis (OA) is one of the most common chronic, inflammatory, and degenerative diseases affecting the synovial joints, the hip, and the knee. OA is commonly managed clinically by treating pain with anti-inflammatory medicines using nonsteroidal anti-inflammatory drugs (NSAIDS) or analgesics. In severe OA patients, invasive knee replacement surgery is the last option. Treatment of OA using mesenchymal stromal cells (MSCs) has been widely explored due to their anti-inflammatory properties and chondrogenic differentiation potential. In this chapter, we comprehensively discuss in detail the in vitro OA potency development, OA preclinical studies, and clinical trials conducted using MSCs.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/67252",risUrl:"/chapter/ris/67252",signatures:"Charan Thej and Pawan Kumar Gupta",book:{id:"8026",type:"book",title:"Update on Mesenchymal and Induced Pluripotent Stem Cells",subtitle:null,fullTitle:"Update on Mesenchymal and Induced Pluripotent Stem Cells",slug:"update-on-mesenchymal-and-induced-pluripotent-stem-cells",publishedDate:"April 22nd 2020",bookSignature:"Khalid Ahmed Al-Anazi",coverURL:"https://cdn.intechopen.com/books/images_new/8026.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-78923-808-2",printIsbn:"978-1-78923-807-5",pdfIsbn:"978-1-83880-526-5",isAvailableForWebshopOrdering:!0,editors:[{id:"37255",title:"Dr.",name:"Khalid",middleName:"Ahmed",surname:"Al-Anazi",slug:"khalid-al-anazi",fullName:"Khalid Al-Anazi"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Current treatment options for osteoarthritis",level:"1"},{id:"sec_3",title:"3. Mesenchymal stromal cells",level:"1"},{id:"sec_4",title:"4. Possible mechanism of action (MoA) of BMMSCs for treatment of osteoarthritis",level:"1"},{id:"sec_5",title:"5. Advantages of using a pooled human BMMSC (phBMMSC, Stempeucel®) product for treating osteoarthritis",level:"1"},{id:"sec_6",title:"6. Development of a potency assay for Stempeucel® intended to treat osteoarthritis",level:"1"},{id:"sec_7",title:"7. Preclinical efficacy studies in OA",level:"1"},{id:"sec_8",title:"8. Clinical trials in osteoarthritis of the knee joint",level:"1"},{id:"sec_8_2",title:"8.1 Safety of mesenchymal stromal cells in clinical trials",level:"2"},{id:"sec_9_2",title:"8.2 Efficacy of stem cells including mesenchymal stromal cells in clinical trials of osteoarthritis of the knee joint",level:"2"},{id:"sec_10_2",title:"8.3 Clinical trials in India",level:"2"},{id:"sec_11_2",title:"8.4 Stempeutics Research experience in osteoarthritis of the knee joint",level:"2"},{id:"sec_11_3",title:"8.4.1 Phase II study in patients with osteoarthritis of the knee joint",level:"3"},{id:"sec_14",title:"9. Conclusion",level:"1"},{id:"sec_15",title:"Acknowledgments",level:"1"},{id:"sec_18",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Yucesoy B, Charles LE, Baker B, Burchfiel CM. Occupational and genetic risk factors for osteoarthritis: A review. Work [Internet]. 2015;50(2):261-273. 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The clinical use of human culture-expanded autologous bone marrow mesenchymal stem cells transplanted on platelet-rich fibrin glue in the treatment of articular cartilage defects: A pilot study and preliminary results. Cartilage. 2010;1(4):253-261'},{id:"B74",body:'Nejadnik H, Hui JH, Feng Choong EP, Tai B-C, Lee EH. Autologous bone marrow-derived mesenchymal stem cells versus autologous chondrocyte implantation: An observational cohort study. The American Journal of Sports Medicine. 2010;38(6):1110-1116'},{id:"B75",body:'Davatchi F, Abdollahi BS, Mohyeddin M, Shahram F, Nikbin B. Mesenchymal stem cell therapy for knee osteoarthritis. Preliminary report of four patients. International Journal of Rheumatic Diseases. 2011;14(2):211-215'},{id:"B76",body:'Saw K-Y, Anz A, Merican S, Tay Y-G, Ragavanaidu K, Jee CSY, et al. 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Avoidance of total knee arthroplasty in early osteoarthritis of the knee with intra-articular implantation of autologous activated peripheral blood stem cells versus hyaluronic acid: A randomized controlled trial with differential effects of growth factor. Stem Cells International. 2017;2017:8925132'},{id:"B95",body:'Shapiro SA, Kazmerchak SE, Heckman MG, Zubair AC, O’Connor MI. A prospective, single-blind, placebo-controlled trial of bone marrow aspirate concentrate for knee osteoarthritis. The American Journal of Sports Medicine. 2017;45(1):82-90'},{id:"B96",body:'Park Y-B, Ha C-W, Lee C-H, Yoon YC, Park Y-G. Cartilage regeneration in osteoarthritic patients by a composite of allogeneic umbilical cord blood-derived mesenchymal stem cells and hyaluronate hydrogel: Results from a clinical trial for safety and proof-of-concept with 7 years of extended follow-up. 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Safety, tolerability and efficacy of intra-articular Progenza in knee osteoarthritis: A randomized double-blind placebo-controlled single ascending dose study. Journal of Translational Medicine. 2018;16(1):49'},{id:"B104",body:'Emadedin M, Labibzadeh N, Liastani MG, Karimi A, Jaroughi N, Bolurieh T, et al. Intra-articular implantation of autologous bone marrow-derived mesenchymal stromal cells to treat knee osteoarthritis: A randomized, triple-blind, placebo-controlled phase 1/2 clinical trial. Cytotherapy. 2018;20(10):1238-1246'},{id:"B105",body:'Khalifeh Soltani S, Forogh B, Ahmadbeigi N, Hadizadeh Kharazi H, Fallahzadeh K, Kashani L, et al. Safety and efficacy of allogenic placental mesenchymal stem cells for treating knee osteoarthritis: A pilot study. Cytotherapy. 2019;21(1):54-63'},{id:"B106",body:'Jevotovsky DS, Alfonso AR, Einhorn TA, Chiu ES. Osteoarthritis and stem cell therapy in humans: A systematic review. 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Available from: http://www.ncbi.nlm.nih.gov/pubmed/29556366'},{id:"B119",body:'Mohammadi F, Mohammadi Samani S, Tanideh N, Ahmadi F. Hybrid scaffolds of hyaluronic acid and collagen loaded with prednisolone: An interesting system for osteoarthritis. Advanced Pharmaceutical Bulletin [Internet]. 2018;8(1):11-19. Availablee from: http://www.ncbi.nlm.nih.gov/pubmed/29670834'},{id:"B120",body:'de Barros CN, Miluzzi Yamada AL, Junior RSF, Barraviera B, Hussni CA, de Souza JB, et al. A new heterologous fibrin sealant as a scaffold to cartilage repair—Experimental study and preliminary results. Experimental Biology and Medicine (Maywood, N.J.) [Internet]. 2016;241(13):1410-1415. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26264444'},{id:"B121",body:'https://clinicaltrials.gov/ct2/show/NCT03800810'},{id:"B122",body:'Bansal H, Comella K, Leon J, Verma P, Agrawal D, Koka P, et al. Intra-articular injection in the knee of adipose derived stromal cells (stromal vascular fraction) and platelet rich plasma for osteoarthritis. Journal of Translational Medicine. 2017;15(1):141'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Charan Thej",address:null,affiliation:'
Stempeutics Research Pvt. Ltd., Manipal Hospitals Whitefield Pvt. Ltd., Bengaluru, India
Stempeutics Research Pvt. Ltd., Manipal Hospitals Whitefield Pvt. Ltd., Bengaluru, India
'}],corrections:null},book:{id:"8026",type:"book",title:"Update on Mesenchymal and Induced Pluripotent Stem Cells",subtitle:null,fullTitle:"Update on Mesenchymal and Induced Pluripotent Stem Cells",slug:"update-on-mesenchymal-and-induced-pluripotent-stem-cells",publishedDate:"April 22nd 2020",bookSignature:"Khalid Ahmed Al-Anazi",coverURL:"https://cdn.intechopen.com/books/images_new/8026.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-78923-808-2",printIsbn:"978-1-78923-807-5",pdfIsbn:"978-1-83880-526-5",isAvailableForWebshopOrdering:!0,editors:[{id:"37255",title:"Dr.",name:"Khalid",middleName:"Ahmed",surname:"Al-Anazi",slug:"khalid-al-anazi",fullName:"Khalid Al-Anazi"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},profile:{item:{id:"53197",title:"Prof.",name:"Masaki",middleName:null,surname:"Fujioka",email:"inazumahayato7@gmail.com",fullName:"Masaki Fujioka",slug:"masaki-fujioka",position:null,biography:"Prof. Masaki Fujioka graduated from the Jichi Medical School-Six Year Medical Program in 1985. In 1998 he earned his Ph.D. degree from Nagasaki University, Graduate School of Medicine, Specialized in Plastic and Reconstructive Surgery. \n\nFrom 2005 to 2010 he served as a Senior Assistant Professor of Plastic Surgery at Nagasaki University and from 2003 to 2011 as a research fellow at the Clinical Research Center, National Nagasaki Medical Center. Since 2011 he has been serving as a Clinical Professor of Department of Plastic and Reconstructive Surgery, Nagasaki University and Director of Department of Surgical Therapeutics, Division of Functional Reconstructive Surgery at the National Hospital Organization Nagasaki Medical Center. Since 2003 he is also a Director of the Department of Plastic and Reconstructive Surgery, National Nagasaki Medical Center.\n\nHe is a member of the Japanese Society of Burn Injuries, Japan Society of Plastic and Reconstructive Surgery, Japan Society of Craniomaxillofacial Surgery, American Association for the Advancement of Science, Japan Society of pressure Ulcer, Japan Society of Wound Surgery, Wound healing Society.\n\nHis research interests include: Clinical research of skin substitute, Clinical treatment of compromised wound healing, Treatment of severe burn injury, Repair of maxillofacial deformity, Microsurgery\n \nIn 1989\the received the First Prize of Investigators Award, Japan Community Medicine Association, in 1996 First Prize of Investigators Award, Japan Community Medicine Association, in 2008 Best Investigator Award, the Japanese Society of Pressure Ulcer, Oura Award, in 2010 Ohtsuka Award, the Japanese Society of Pressure Ulcer, and in 2011 Speaker’s Award: An appreciation for the best oral presentation-Clinics. First International Symposium. Pediatric Wound Care.",institutionString:"National Hospital Organization Nagasaki Medical Center",profilePictureURL:"https://mts.intechopen.com/storage/users/53197/images/system/53197.png",totalCites:0,totalChapterViews:"0",outsideEditionCount:0,totalAuthoredChapters:"7",totalEditedBooks:"1",personalWebsiteURL:null,twitterURL:null,linkedinURL:null,institution:null},booksEdited:[{id:"7975",type:"book",slug:"limb-amputation",title:"Limb Amputation",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7975.jpg",abstract:"Patients often need to have limbs amputated to save them from advanced malignant neoplasms and severe limb infections, or due to the failure to repair severe limb trauma. However, efforts should be made to maintain limbs where possible, and to minimize loss of function if amputation is required. We provide the latest developments in limb amputation for this purpose. This book provides expert commentary on the following issues: cutting to prevent large-scale amputations in peripheral arterial disease and diabetes, optimal wound treatment in severe trauma, troubles of prostheses due to stump overgrowth in amputation in children.We hope this book will help physicians dealing with limb illness and trauma, and all amputee patients.",editors:[{id:"53197",title:"Prof.",name:"Masaki",surname:"Fujioka",slug:"masaki-fujioka",fullName:"Masaki Fujioka"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",title:"Edited Volume"}}],chaptersAuthored:[{id:"24616",title:"Complex Wounds in Patients Receiving Hemodialysis",slug:"complex-wounds-in-patients-receiving-hemodialysis",abstract:null,signatures:"Masaki Fujioka",authors:[{id:"53197",title:"Prof.",name:"Masaki",surname:"Fujioka",fullName:"Masaki Fujioka",slug:"masaki-fujioka",email:"inazumahayato7@gmail.com"}],book:{id:"1377",title:"Technical Problems in Patients on Hemodialysis",slug:"technical-problems-in-patients-on-hemodialysis",productType:{id:"1",title:"Edited Volume"}}},{id:"41865",title:"More than Half of Patients Receiving Hemodialysis with Leg Ulcer Require Amputation",slug:"more-than-half-of-patients-receiving-hemodialysis-with-leg-ulcer-require-amputation",abstract:null,signatures:"Masaki Fujioka",authors:[{id:"53197",title:"Prof.",name:"Masaki",surname:"Fujioka",fullName:"Masaki Fujioka",slug:"masaki-fujioka",email:"inazumahayato7@gmail.com"}],book:{id:"3267",title:"Hemodialysis",slug:"hemodialysis",productType:{id:"1",title:"Edited Volume"}}},{id:"55847",title:"Application of Free Flow‐Through Anterolateral Thigh Flap for the Reconstruction of an Extremity Soft Tissue Defect Requiring Vascularization",slug:"application-of-free-flow-through-anterolateral-thigh-flap-for-the-reconstruction-of-an-extremity-sof",abstract:"Patients with severe injury or vasculopathy of the extremities often require resurfacing of tissue defects as well as preservation of functional blood flow to distal areas. In conventional free flap transfer, the recipient vessel is sacrificed to facilitate pedicle anastomosis. On the other hand, a flow‐through flap can provide blood flow to distal tissues. In this chapter, we present cases of successful salvage and reconstruction of the extremities using free flow‐through flaps and highlight their advantages and applications. Free flow‐through flap use should be a good option in the following cases: (1) Gustilo‐Anderson IIIC type open fracture, (2) chronic ulcer resurfacing in the less vascularized extremities, and (3) additional blood supply for an ischemic flap. This flap facilitates not only the reconstruction of soft tissue defects, but also restores the functional vascular anatomy and maintains the original blood flow by interposing the T‐portion of the vessel. This technique enables both vascular and soft tissue reconstructions simultaneously with minimal donor site problems. The anterolateral thigh flap is recommended as a free flow‐through‐type flap due to its advantages, including the variety of flap sizes, adequate calibers of the vascular pedicle, and the lack of a need for position changing.",signatures:"Masaki Fujioka",authors:[{id:"53197",title:"Prof.",name:"Masaki",surname:"Fujioka",fullName:"Masaki Fujioka",slug:"masaki-fujioka",email:"inazumahayato7@gmail.com"}],book:{id:"5927",title:"Issues in Flap Surgery",slug:"issues-in-flap-surgery",productType:{id:"1",title:"Edited Volume"}}},{id:"56466",title:"Emergent or Early Flap Resurfacing Is Required for Bone- Exposing Wounds of Gustilo-Anderson IIIB and IIIC Fractures",slug:"emergent-or-early-flap-resurfacing-is-required-for-bone-exposing-wounds-of-gustilo-anderson-iiib-and",abstract:"Background: The wound treatment has progressed owing to the development of new medicine, instruments. Following these trends, can the bone-exposing wounds of severe open fractures be resurfaced without using flaps but only skin grafting? We evaluated a new medicine and instrument, for the resurfacing of bone-exposing complex wounds of Gustilo-Anderson IIIB and C fractures. Patients and methods: Patients with Gustilo-Anderson IIIB (five cases) and C (two cases) open fractures who underwent open reduction and external fixation were evaluated. Bone-exposing wounds were resurfaced with artificial dermis, and basic fibroblast growth factor was sprayed. We investigated the course and outcome. Result: In all of seven cases, abundant granulation tissue did not develop on the bone-exposing wound surface during 2–5 weeks, and 4 patients developed osteomyelitis. Subsequently, all cases required flap surgery to resurface the wound. All patients could walk; however, required a longer period for the complete union of bones. Conclusion: This study showed that it was impossible to prepare a favorable wound bed on the bone when the fracture was severe. Thus, early flap surgery was a recommendable resurfacing option. Furthermore, emergent bone resurfacing with flap, while performing rigid bone fixation with an internal fixation plate, was an ideal procedure.",signatures:"Masaki Fujioka",authors:[{id:"53197",title:"Prof.",name:"Masaki",surname:"Fujioka",fullName:"Masaki Fujioka",slug:"masaki-fujioka",email:"inazumahayato7@gmail.com"}],book:{id:"5927",title:"Issues in Flap Surgery",slug:"issues-in-flap-surgery",productType:{id:"1",title:"Edited Volume"}}},{id:"65001",title:"Stoma Revision on the Flaps in Cases of Abdominal Wall Defect with Digestive Tract Rupture",slug:"stoma-revision-on-the-flaps-in-cases-of-abdominal-wall-defect-with-digestive-tract-rupture",abstract:"Several surgical methods are performed for the reconstruction of abdominal wall defects after abdominoperineal resection, involving re-suture and free skin grafting. In the complex surgical cases with large abdominal wall defects, the treatment of intestinal fistula and wound infection is challenging. In many cases, they also have had the problems of the control and reposition of a stoma, which has been already present due to the previous unsuccessful surgical procedures. Especially, the case of larger abdominal wall defects with intestinal fistulation, which drains digestive juice into the wound, requires repairing the abdominal wall while fashioning a stoma. This is because a ruptured digestive tract causes infection and inflammation that results in adhesion of the digestive tract, which limits the mobility of both the abdominal wall and bowel. The only method to solve this complex problem is abdominal wall reconstruction with a large vascularized flap and creation of a new stoma on it to separate the wound from drained digestive juice. We present several cases of a large abdominal wall defect, which was reconstructed successfully. Especially, surgical methods using free and perforator flaps are highlighted. These are optimal methods to reconstruct severe abdominal wall defects that involve complications.",signatures:"Masaki Fujioka",authors:[{id:"53197",title:"Prof.",name:"Masaki",surname:"Fujioka",fullName:"Masaki Fujioka",slug:"masaki-fujioka",email:"inazumahayato7@gmail.com"}],book:{id:"8443",title:"Gastrointestinal Stomas",slug:"gastrointestinal-stomas",productType:{id:"1",title:"Edited Volume"}}},{id:"65986",title:"Introductory Chapter: General Remarks Regarding Limb Amputations",slug:"introductory-chapter-general-remarks-regarding-limb-amputations",abstract:null,signatures:"Masaki Fujioka",authors:[{id:"53197",title:"Prof.",name:"Masaki",surname:"Fujioka",fullName:"Masaki Fujioka",slug:"masaki-fujioka",email:"inazumahayato7@gmail.com"}],book:{id:"7975",title:"Limb Amputation",slug:"limb-amputation",productType:{id:"1",title:"Edited Volume"}}},{id:"68374",title:"A Retrospective Analysis of Amputation Risk Due to Diabetic Foot and Angioplasty and Free Flap Transfer to Reduce Major Amputation",slug:"a-retrospective-analysis-of-amputation-risk-due-to-diabetic-foot-and-angioplasty-and-free-flap-trans",abstract:"Foot ulceration in persons with diabetes is the most frequent precursor to amputation, which impairs their activities. The aim of this chapter is to describe factors that lead to amputation of a diabetic foot, and propose a management strategy to prevent major amputation. I analyzed 233 patients who were admitted at the National Nagasaki Medical Center between 2008 and 2017 with foot ulcer and/or infection. We divided them into two groups: 152 patients with diabetes mellitus (DM) and 81 without DM. We analyzed their laboratory data, and evaluated the wound severity, complications of peripheral artery disease (PAD) and renal failure, and infection. Patients with DM ulcer were significantly more likely to receive amputation. Patients with DM were significantly more likely to develop infection, and tended to undergo emergency debridement. Among the patients with DM, the amputation group (85) showed significantly higher levels of CRP and WBC, and was more likely to develop infection, PAD, and renal failure. My results suggest that risk factors leading to leg amputation are severe infection and reduction of arterial blood flow. Early debridement to reduce infectious inflammation and angioplasty following free flap transfer are recommended to preserve legs.",signatures:"Masaki Fujioka",authors:[{id:"53197",title:"Prof.",name:"Masaki",surname:"Fujioka",fullName:"Masaki Fujioka",slug:"masaki-fujioka",email:"inazumahayato7@gmail.com"}],book:{id:"7975",title:"Limb Amputation",slug:"limb-amputation",productType:{id:"1",title:"Edited Volume"}}}],collaborators:[{id:"44541",title:"Dr.",name:"Mary",surname:"Hammes",slug:"mary-hammes",fullName:"Mary Hammes",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"48397",title:"Dr.",name:"Lucian Florin",surname:"Dorobantu",slug:"lucian-florin-dorobantu",fullName:"Lucian Florin Dorobantu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"49421",title:"Prof.",name:"Eirini",surname:"Grapsa",slug:"eirini-grapsa",fullName:"Eirini Grapsa",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"50757",title:"Prof.",name:"Elmer",surname:"Fernandez",slug:"elmer-fernandez",fullName:"Elmer Fernandez",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Catholic University of Cordoba",institutionURL:null,country:{name:"Argentina"}}},{id:"59434",title:"Prof.",name:"Monica",surname:"Balzarini",slug:"monica-balzarini",fullName:"Monica Balzarini",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:"MSc in Biometry\nPh D in Applied Statistics\nProf. At the University of Córdoba, Argentina\nCONICET Researcher",institutionString:null,institution:{name:"National University of Córdoba",institutionURL:null,country:{name:"Argentina"}}},{id:"59435",title:"Prof.",name:"Rodolfo",surname:"Valtuille",slug:"rodolfo-valtuille",fullName:"Rodolfo Valtuille",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"110315",title:"Dr.",name:"Ovidiu",surname:"Stiru",slug:"ovidiu-stiru",fullName:"Ovidiu Stiru",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"110317",title:"Dr.",name:"Cristian",surname:"Bulescu",slug:"cristian-bulescu",fullName:"Cristian Bulescu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"110318",title:"Dr.",name:"Serban",surname:"Bubenek",slug:"serban-bubenek",fullName:"Serban Bubenek",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"110319",title:"Prof.",name:"Vlad Anton",surname:"Iliescu",slug:"vlad-anton-iliescu",fullName:"Vlad Anton Iliescu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null}]},generic:{page:{slug:"OA-publishing-fees",title:"Open Access Publishing Fees",intro:"
The Open Access model is applied to all of our publications and is designed to eliminate subscriptions and pay-per-view fees. This approach ensures free, immediate access to full text versions of your research.
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To explore funding opportunities and learn more about how you can finance your IntechOpen publication, go to our Open Access Funding page. IntechOpen offers expert assistance to all of its Authors. We can support you in approaching funding bodies and institutions in relation to publishing fees by providing information about compliance with the Open Access policies of your funder or institution. We can also assist with communicating the benefits of Open Access in order to support and strengthen your funding request and provide personal guidance through your application process. You can contact us at funders@intechopen.com for further details or assistance.
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For Authors who are still unable to obtain funding from their institutions or research funding bodies for individual projects, IntechOpen does offer the possibility of applying for a Waiver to offset some or all processing feed. Details regarding our Waiver Policy can be found here.
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Indexing and listing across major repositories, see details ...
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Dissemination and Promotion
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Proven world leader in Open Access book publishing with over 10 years experience
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+5,700 OA books published
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Most competitive prices in the market
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As a gold Open Access publisher, an Open Access Publishing Fee is payable on acceptance following peer review of the manuscript. In return, we provide high quality publishing services and exclusive benefits for all contributors. IntechOpen is the trusted publishing partner of over 140,000 international scientists and researchers.
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The Open Access Publishing Fee (OAPF) is payable only after your book chapter, monograph or journal article is accepted for publication.
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OAPF Publishing Options
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1,400 GBP Chapter - Edited Volume
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850 GBP Chapter - Book Series Topic (Annual Volume)
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10,000 GBP Monograph - Long Form
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4,000 GBP Compacts Monograph - Short Form
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850 GBP Journal Article (Across Portfolio)
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During the launching phase journals do not charge an APC, rather they will be funded by IntechOpen.
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*These prices do not include Value-Added Tax (VAT). Residents of European Union countries need to add VAT based on the specific rate in their country of residence. Institutions and companies registered as VAT taxable entities in their own EU member state will not pay VAT as long as provision of the VAT registration number is made during the application process. This is made possible by the EU reverse charge method.
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Services included are:
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An online manuscript tracking system to facilitate your work
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Personal contact and support throughout the publishing process from your dedicated Author Service Manager
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Assurance that your manuscript meets the highest publishing standards
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English language copyediting and proofreading, including the correction of grammatical, spelling, and other common errors
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XML Typesetting and pagination - web (PDF, HTML) and print files preparation
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Discoverability - electronic citation and linking via DOI
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Permanent and unrestricted online access to your work
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What isn't covered by the Open Access Publishing Fee?
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If your manuscript:
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Exceeds the number of pages defined by the publishing guidelines, an additional fee per page may be required
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If a manuscript requires Heavy Editing or Language Polishing, this will incur additional fees.
\n
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Your Author Service Manager will inform you of any items not covered by the OAPF and provide exact information regarding those additional costs before proceeding.
\n\n
Open Access Funding
\n\n
To explore funding opportunities and learn more about how you can finance your IntechOpen publication, go to our Open Access Funding page. IntechOpen offers expert assistance to all of its Authors. We can support you in approaching funding bodies and institutions in relation to publishing fees by providing information about compliance with the Open Access policies of your funder or institution. We can also assist with communicating the benefits of Open Access in order to support and strengthen your funding request and provide personal guidance through your application process. You can contact us at funders@intechopen.com for further details or assistance.
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For Authors who are still unable to obtain funding from their institutions or research funding bodies for individual projects, IntechOpen does offer the possibility of applying for a Waiver to offset some or all processing feed. Details regarding our Waiver Policy can be found here.
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Added Value of Publishing with IntechOpen
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Choosing to publish with IntechOpen ensures the following benefits:
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Indexing and listing across major repositories, see details ...
\n\t
Long-term archiving
\n\t
Visibility on the world's strongest OA platform
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Live Performance Metrics to track readership and the impact of your chapter
\n\t
Dissemination and Promotion
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Proven world leader in Open Access book publishing with over 10 years experience
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+5,700 OA books published
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Optimized processes that assure your research is made available to the scientific community without delay
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Personal support during every step of the publication process
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+184,650 citations in Web of Science databases
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Currently strongest OA platform with over 175 million downloads
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He has both an MS and Ph.D. in Biomedical Engineering. He was previously a research scientist at the University of California Los Angeles (UCLA) and visiting professor and researcher at the University of North Dakota. He is currently working in artificial intelligence and its applications in medical signal processing. In addition, he is using digital signal processing in medical imaging and speech processing. Dr. Asadpour has developed brain-computer interfacing algorithms and has published books, book chapters, and several journal and conference papers in this field and other areas of intelligent signal processing. He has also designed medical devices, including a laser Doppler monitoring system.",institutionString:"Kaiser Permanente Southern California",institution:null},{id:"169608",title:"Prof.",name:"Marian",middleName:null,surname:"Găiceanu",slug:"marian-gaiceanu",fullName:"Marian Găiceanu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/169608/images/system/169608.png",biography:"Prof. Dr. Marian Gaiceanu graduated from the Naval and Electrical Engineering Faculty, Dunarea de Jos University of Galati, Romania, in 1997. He received a Ph.D. (Magna Cum Laude) in Electrical Engineering in 2002. Since 2017, Dr. Gaiceanu has been a Ph.D. supervisor for students in Electrical Engineering. He has been employed at Dunarea de Jos University of Galati since 1996, where he is currently a professor. Dr. Gaiceanu is a member of the National Council for Attesting Titles, Diplomas and Certificates, an expert of the Executive Agency for Higher Education, Research Funding, and a member of the Senate of the Dunarea de Jos University of Galati. He has been the head of the Integrated Energy Conversion Systems and Advanced Control of Complex Processes Research Center, Romania, since 2016. He has conducted several projects in power converter systems for electrical drives, power quality, PEM and SOFC fuel cell power converters for utilities, electric vehicles, and marine applications with the Department of Regulation and Control, SIEI S.pA. (2002–2004) and the Polytechnic University of Turin, Italy (2002–2004, 2006–2007). He is a member of the Institute of Electrical and Electronics Engineers (IEEE) and cofounder-member of the IEEE Power Electronics Romanian Chapter. He is a guest editor at Energies and an academic book editor for IntechOpen. He is also a member of the editorial boards of the Journal of Electrical Engineering, Electronics, Control and Computer Science and Sustainability. Dr. Gaiceanu has been General Chairman of the IEEE International Symposium on Electrical and Electronics Engineering in the last six editions.",institutionString:'"Dunarea de Jos" University of Galati',institution:{name:'"Dunarea de Jos" University of Galati',country:{name:"Romania"}}},{id:"4519",title:"Prof.",name:"Jaydip",middleName:null,surname:"Sen",slug:"jaydip-sen",fullName:"Jaydip Sen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/4519/images/system/4519.jpeg",biography:"Jaydip Sen is associated with Praxis Business School, Kolkata, India, as a professor in the Department of Data Science. His research areas include security and privacy issues in computing and communication, intrusion detection systems, machine learning, deep learning, and artificial intelligence in the financial domain. He has more than 200 publications in reputed international journals, refereed conference proceedings, and 20 book chapters in books published by internationally renowned publishing houses, such as Springer, CRC press, IGI Global, etc. Currently, he is serving on the editorial board of the prestigious journal Frontiers in Communications and Networks and in the technical program committees of a number of high-ranked international conferences organized by the IEEE, USA, and the ACM, USA. He has been listed among the top 2% of scientists in the world for the last three consecutive years, 2019 to 2021 as per studies conducted by the Stanford University, USA.",institutionString:"Praxis Business School",institution:null},{id:"320071",title:"Dr.",name:"Sidra",middleName:null,surname:"Mehtab",slug:"sidra-mehtab",fullName:"Sidra Mehtab",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00002v6KHoQAM/Profile_Picture_1584512086360",biography:"Sidra Mehtab has completed her BS with honors in Physics from Calcutta University, India in 2018. She has done MS in Data Science and Analytics from Maulana Abul Kalam Azad University of Technology (MAKAUT), Kolkata, India in 2020. Her research areas include Econometrics, Time Series Analysis, Machine Learning, Deep Learning, Artificial Intelligence, and Computer and Network Security with a particular focus on Cyber Security Analytics. Ms. Mehtab has published seven papers in international conferences and one of her papers has been accepted for publication in a reputable international journal. She has won the best paper awards in two prestigious international conferences – BAICONF 2019, and ICADCML 2021, organized in the Indian Institute of Management, Bangalore, India in December 2019, and SOA University, Bhubaneswar, India in January 2021. Besides, Ms. Mehtab has also published two book chapters in two books. Seven of her book chapters will be published in a volume shortly in 2021 by Cambridge Scholars’ Press, UK. Currently, she is working as the joint editor of two edited volumes on Time Series Analysis and Forecasting to be published in the first half of 2021 by an international house. Currently, she is working as a Data Scientist with an MNC in Delhi, India.",institutionString:"NSHM College of Management and Technology",institution:null},{id:"226240",title:"Dr.",name:"Andri Irfan",middleName:null,surname:"Rifai",slug:"andri-irfan-rifai",fullName:"Andri Irfan Rifai",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226240/images/7412_n.jpg",biography:"Andri IRFAN is a Senior Lecturer of Civil Engineering and Planning. He completed the PhD at the Universitas Indonesia & Universidade do Minho with Sandwich Program Scholarship from the Directorate General of Higher Education and LPDP scholarship. He has been teaching for more than 19 years and much active to applied his knowledge in the project construction in Indonesia. His research interest ranges from pavement management system to advanced data mining techniques for transportation engineering. He has published more than 50 papers in journals and 2 books.",institutionString:null,institution:{name:"Universitas Internasional Batam",country:{name:"Indonesia"}}},{id:"314576",title:"Dr.",name:"Ibai",middleName:null,surname:"Laña",slug:"ibai-lana",fullName:"Ibai Laña",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314576/images/system/314576.jpg",biography:"Dr. Ibai Laña works at TECNALIA as a data analyst. He received his Ph.D. in Artificial Intelligence from the University of the Basque Country (UPV/EHU), Spain, in 2018. He is currently a senior researcher at TECNALIA. His research interests fall within the intersection of intelligent transportation systems, machine learning, traffic data analysis, and data science. He has dealt with urban traffic forecasting problems, applying machine learning models and evolutionary algorithms. He has experience in origin-destination matrix estimation or point of interest and trajectory detection. Working with large volumes of data has given him a good command of big data processing tools and NoSQL databases. He has also been a visiting scholar at the Knowledge Engineering and Discovery Research Institute, Auckland University of Technology.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"314575",title:"Dr.",name:"Jesus",middleName:null,surname:"L. Lobo",slug:"jesus-l.-lobo",fullName:"Jesus L. Lobo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314575/images/system/314575.png",biography:"Dr. Jesús López is currently based in Bilbao (Spain) working at TECNALIA as Artificial Intelligence Research Scientist. In most cases, a project idea or a new research line needs to be investigated to see if it is good enough to take into production or to focus on it. That is exactly what he does, diving into Machine Learning algorithms and technologies to help TECNALIA to decide whether something is great in theory or will actually impact on the product or processes of its projects. So, he is expert at framing experiments, developing hypotheses, and proving whether they’re true or not, in order to investigate fundamental problems with a longer time horizon. He is also able to design and develop PoCs and system prototypes in simulation. He has participated in several national and internacional R&D projects.\n\nAs another relevant part of his everyday research work, he usually publishes his findings in reputed scientific refereed journals and international conferences, occasionally acting as reviewer and Programme Commitee member. Concretely, since 2018 he has published 9 JCR (8 Q1) journal papers, 9 conference papers (e.g. ECML PKDD 2021), and he has co-edited a book. He is also active in popular science writing data science stories for reputed blogs (KDNuggets, TowardsDataScience, Naukas). Besides, he has recently embarked on mentoring programmes as mentor, and has also worked as data science trainer.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"103779",title:"Prof.",name:"Yalcin",middleName:null,surname:"Isler",slug:"yalcin-isler",fullName:"Yalcin Isler",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQ8QAK/Profile_Picture_1628834958734",biography:"Yalcin Isler (1971 - Burdur / Turkey) received the B.Sc. degree in the Department of Electrical and Electronics Engineering from Anadolu University, Eskisehir, Turkey, in 1993, the M.Sc. degree from the Department of Electronics and Communication Engineering, Suleyman Demirel University, Isparta, Turkey, in 1996, the Ph.D. degree from the Department of Electrical and Electronics Engineering, Dokuz Eylul University, Izmir, Turkey, in 2009, and the Competence of Associate Professorship from the Turkish Interuniversity Council in 2019.\n\nHe was Lecturer at Burdur Vocational School in Suleyman Demirel University (1993-2000, Burdur / Turkey), Software Engineer (2000-2002, Izmir / Turkey), Research Assistant in Bulent Ecevit University (2002-2003, Zonguldak / Turkey), Research Assistant in Dokuz Eylul University (2003-2010, Izmir / Turkey), Assistant Professor at the Department of Electrical and Electronics Engineering in Bulent Ecevit University (2010-2012, Zonguldak / Turkey), Assistant Professor at the Department of Biomedical Engineering in Izmir Katip Celebi University (2012-2019, Izmir / Turkey). He is an Associate Professor at the Department of Biomedical Engineering at Izmir Katip Celebi University, Izmir / Turkey, since 2019. In addition to academics, he has also founded Islerya Medical and Information Technologies Company, Izmir / Turkey, since 2017.\n\nHis main research interests cover biomedical signal processing, pattern recognition, medical device design, programming, and embedded systems. He has many scientific papers and participated in several projects in these study fields. He was an IEEE Student Member (2009-2011) and IEEE Member (2011-2014) and has been IEEE Senior Member since 2014.",institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"339677",title:"Dr.",name:"Mrinmoy",middleName:null,surname:"Roy",slug:"mrinmoy-roy",fullName:"Mrinmoy Roy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/339677/images/16768_n.jpg",biography:"An accomplished Sales & Marketing professional with 12 years of cross-functional experience in well-known organisations such as CIPLA, LUPIN, GLENMARK, ASTRAZENECA across different segment of Sales & Marketing, International Business, Institutional Business, Product Management, Strategic Marketing of HIV, Oncology, Derma, Respiratory, Anti-Diabetic, Nutraceutical & Stomatological Product Portfolio and Generic as well as Chronic Critical Care Portfolio. A First Class MBA in International Business & Strategic Marketing, B.Pharm, D.Pharm, Google Certified Digital Marketing Professional. Qualified PhD Candidate in Operations and Management with special focus on Artificial Intelligence and Machine Learning adoption, analysis and use in Healthcare, Hospital & Pharma Domain. Seasoned with diverse therapy area of Pharmaceutical Sales & Marketing ranging from generating revenue through generating prescriptions, launching new products, and making them big brands with continuous strategy execution at the Physician and Patients level. Moved from Sales to Marketing and Business Development for 3.5 years in South East Asian Market operating from Manila, Philippines. Came back to India and handled and developed Brands such as Gluconorm, Lupisulin, Supracal, Absolut Woman, Hemozink, Fabiflu (For COVID 19), and many more. In my previous assignment I used to develop and execute strategies on Sales & Marketing, Commercialization & Business Development for Institution and Corporate Hospital Business portfolio of Oncology Therapy Area for AstraZeneca Pharma India Ltd. Being a Research Scholar and Student of ‘Operations Research & Management: Artificial Intelligence’ I published several pioneer research papers and book chapters on the same in Internationally reputed journals and Books indexed in Scopus, Springer and Ei Compendex, Google Scholar etc. Currently, I am launching PGDM Pharmaceutical Management Program in IIHMR Bangalore and spearheading the course curriculum and structure of the same. I am interested in Collaboration for Healthcare Innovation, Pharma AI Innovation, Future trend in Marketing and Management with incubation on Healthcare, Healthcare IT startups, AI-ML Modelling and Healthcare Algorithm based training module development. I am also an affiliated member of the Institute of Management Consultant of India, looking forward to Healthcare, Healthcare IT and Innovation, Pharma and Hospital Management Consulting works.",institutionString:null,institution:{name:"Lovely Professional University",country:{name:"India"}}},{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1063/images/system/1063.png",biography:"Prof. Dr. Constantin Voloşencu graduated as an engineer from\nPolitehnica University of Timișoara, Romania, where he also\nobtained a doctorate degree. He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. He has developed automation equipment for machine tools, spooling\nmachines, high-power ultrasound processes, and more.",institutionString:"Polytechnic University of Timişoara",institution:{name:"Polytechnic University of Timişoara",country:{name:"Romania"}}},{id:"221364",title:"Dr.",name:"Eneko",middleName:null,surname:"Osaba",slug:"eneko-osaba",fullName:"Eneko Osaba",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/221364/images/system/221364.jpg",biography:"Dr. Eneko Osaba works at TECNALIA as a senior researcher. He obtained his Ph.D. in Artificial Intelligence in 2015. He has participated in more than twenty-five local and European research projects, and in the publication of more than 130 papers. He has performed several stays at universities in the United Kingdom, Italy, and Malta. Dr. Osaba has served as a program committee member in more than forty international conferences and participated in organizing activities in more than ten international conferences. He is a member of the editorial board of the International Journal of Artificial Intelligence, Data in Brief, and Journal of Advanced Transportation. He is also a guest editor for the Journal of Computational Science, Neurocomputing, Swarm, and Evolutionary Computation and IEEE ITS Magazine.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"275829",title:"Dr.",name:"Esther",middleName:null,surname:"Villar-Rodriguez",slug:"esther-villar-rodriguez",fullName:"Esther Villar-Rodriguez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/275829/images/system/275829.jpg",biography:"Dr. Esther Villar obtained a Ph.D. in Information and Communication Technologies from the University of Alcalá, Spain, in 2015. She obtained a degree in Computer Science from the University of Deusto, Spain, in 2010, and an MSc in Computer Languages and Systems from the National University of Distance Education, Spain, in 2012. Her areas of interest and knowledge include natural language processing (NLP), detection of impersonation in social networks, semantic web, and machine learning. Dr. Esther Villar made several contributions at conferences and publishing in various journals in those fields. Currently, she is working within the OPTIMA (Optimization Modeling & Analytics) business of TECNALIA’s ICT Division as a data scientist in projects related to the prediction and optimization of management and industrial processes (resource planning, energy efficiency, etc).",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. He is a Senior Member of the IEEE, and a recipient of the Biscay Talent prize for his academic career.",institutionString:"Tecnalia Research & Innovation",institution:null},{id:"278948",title:"Dr.",name:"Carlos Pedro",middleName:null,surname:"Gonçalves",slug:"carlos-pedro-goncalves",fullName:"Carlos Pedro Gonçalves",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRcmyQAC/Profile_Picture_1564224512145",biography:'Carlos Pedro Gonçalves (PhD) is an Associate Professor at Lusophone University of Humanities and Technologies and a researcher on Complexity Sciences, Quantum Technologies, Artificial Intelligence, Strategic Studies, Studies in Intelligence and Security, FinTech and Financial Risk Modeling. He is also a progammer with programming experience in:\n\nA) Quantum Computing using Qiskit Python module and IBM Quantum Experience Platform, with software developed on the simulation of Quantum Artificial Neural Networks and Quantum Cybersecurity;\n\nB) Artificial Intelligence and Machine learning programming in Python;\n\nC) Artificial Intelligence, Multiagent Systems Modeling and System Dynamics Modeling in Netlogo, with models developed in the areas of Chaos Theory, Econophysics, Artificial Intelligence, Classical and Quantum Complex Systems Science, with the Econophysics models having been cited worldwide and incorporated in PhD programs by different Universities.\n\nReceived an Arctic Code Vault Contributor status by GitHub, due to having developed open source software preserved in the \\"Arctic Code Vault\\" for future generations (https://archiveprogram.github.com/arctic-vault/), with the Strategy Analyzer A.I. module for decision making support (based on his PhD thesis, used in his Classes on Decision Making and in Strategic Intelligence Consulting Activities) and QNeural Python Quantum Neural Network simulator also preserved in the \\"Arctic Code Vault\\", for access to these software modules see: https://github.com/cpgoncalves. He is also a peer reviewer with outsanding review status from Elsevier journals, including Physica A, Neurocomputing and Engineering Applications of Artificial Intelligence. Science CV available at: https://www.cienciavitae.pt//pt/8E1C-A8B3-78C5 and ORCID: https://orcid.org/0000-0002-0298-3974',institutionString:"University of Lisbon",institution:{name:"Universidade Lusófona",country:{name:"Portugal"}}},{id:"241400",title:"Prof.",name:"Mohammed",middleName:null,surname:"Bsiss",slug:"mohammed-bsiss",fullName:"Mohammed Bsiss",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241400/images/8062_n.jpg",biography:null,institutionString:null,institution:null},{id:"276128",title:"Dr.",name:"Hira",middleName:null,surname:"Fatima",slug:"hira-fatima",fullName:"Hira Fatima",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/276128/images/14420_n.jpg",biography:"Dr. Hira Fatima\nAssistant Professor\nDepartment of Mathematics\nInstitute of Applied Science\nMangalayatan University, Aligarh\nMobile: no : 8532041179\nhirafatima2014@gmal.com\n\nDr. Hira Fatima has received his Ph.D. degree in pure Mathematics from Aligarh Muslim University, Aligarh India. Currently working as an Assistant Professor in the Department of Mathematics, Institute of Applied Science, Mangalayatan University, Aligarh. She taught so many courses of Mathematics of UG and PG level. Her research Area of Expertise is Functional Analysis & Sequence Spaces. She has been working on Ideal Convergence of double sequence. She has published 17 research papers in National and International Journals including Cogent Mathematics, Filomat, Journal of Intelligent and Fuzzy Systems, Advances in Difference Equations, Journal of Mathematical Analysis, Journal of Mathematical & Computer Science etc. She has also reviewed few research papers for the and international journals. She is a member of Indian Mathematical Society.",institutionString:null,institution:null},{id:"414880",title:"Dr.",name:"Maryam",middleName:null,surname:"Vatankhah",slug:"maryam-vatankhah",fullName:"Maryam Vatankhah",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Borough of Manhattan Community College",country:{name:"United States of America"}}},{id:"414879",title:"Prof.",name:"Mohammad-Reza",middleName:null,surname:"Akbarzadeh-Totonchi",slug:"mohammad-reza-akbarzadeh-totonchi",fullName:"Mohammad-Reza Akbarzadeh-Totonchi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Ferdowsi University of Mashhad",country:{name:"Iran"}}},{id:"414878",title:"Prof.",name:"Reza",middleName:null,surname:"Fazel-Rezai",slug:"reza-fazel-rezai",fullName:"Reza Fazel-Rezai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"American Public University System",country:{name:"United States of America"}}},{id:"302698",title:"Dr.",name:"Yao",middleName:null,surname:"Shan",slug:"yao-shan",fullName:"Yao Shan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Dalian University of Technology",country:{name:"China"}}},{id:"125911",title:"Prof.",name:"Jia-Ching",middleName:null,surname:"Wang",slug:"jia-ching-wang",fullName:"Jia-Ching Wang",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Central University",country:{name:"Taiwan"}}},{id:"357085",title:"Mr.",name:"P. Mohan",middleName:null,surname:"Anand",slug:"p.-mohan-anand",fullName:"P. Mohan Anand",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"356696",title:"Ph.D. Student",name:"P.V.",middleName:null,surname:"Sai Charan",slug:"p.v.-sai-charan",fullName:"P.V. Sai Charan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Indian Institute of Technology Kanpur",country:{name:"India"}}},{id:"357086",title:"Prof.",name:"Sandeep K.",middleName:null,surname:"Shukla",slug:"sandeep-k.-shukla",fullName:"Sandeep K. 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He obtained his Master’s degree in the Department of Information and Communications from Gwangju Institute of Science and Technology (GIST) in 2003. In 2010, he received his Ph.D. degree in the School of Information and Mechatronics from GIST. In the meantime, he was an executed team leader at Culture Technology Institute, GIST, 2010-2012. In 2011, he worked at Lancaster University, the UK as a visiting scholar. In September 2012, he joined Daegu University, where he is currently an associate professor in the School of ICT Conver, Daegu University. Also, he served as the Board of Directors of KSIIS since 2019, and HCI Korea since 2016. From 2017~2019, he worked as a center director of the Mixed Reality Convergence Research Center at Daegu University. From 2015-2017, He worked as a director in the Enterprise Supporting Office of LINC Project Group, Daegu University. 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