\r\n\tCell viability is defined as the number of healthy cells in a sample and proliferation of cells is a vital indicator for understanding the mechanisms inaction of certain genes, proteins, and pathways involved in cell survival or death after exposure to toxic agents. The methods used to determine viability are also common for the detection of cell proliferation. A cell viability assay is performed based on the ratio of live and dead cells. This assay is based on an analysis of cell viability in cell culture for evaluating in vitro drug effects in cell-mediated cytotoxicity assays for monitoring cell proliferation. Various methods are involved in performing a cell viability assay, including the dilution method, surface viable count, roll tube technique, nalidixic acid method, fluorogenic dye assay, and the Trypan Blue Cell Viability Assay. The cell viability assays can determine the effect of drug candidates on cells and be used to optimize the cell culture conditions. The parameters that define cell viability can be as diverse as the redox potential of the cell population, the integrity of cell membranes, or the activity of cellular enzymes. \r\n\tCytotoxicity is the degree to which a substance can cause damage to a cell. Cytotoxicity assays measure the ability of cytotoxic compounds to cause cell damage or cell death. Cytotoxicity assays are widely used in fundamental research and drug discovery to screen libraries for toxic compounds. The cell cytotoxicity and proliferation assays are mainly used for drug screening to detect whether the test molecules have effects on cell proliferation or display direct cytotoxic effects. In a cell-based assay, it is important to know how many viable cells are remaining at the end of the experiment. There are a variety of assay methods based on various cell functions such as enzyme activity, cell membrane permeability, cell adherence, ATP production, co-enzyme production, and nucleotide uptake activity. These methods could be classified in to different categories: (I) dye exclusion methods such as trypan blue dye exclusion assay, (II) methods based on metabolic activity, (III) ATP assay, (IV) sulforhodamine B assay, (V) protease viability marker assay, (VI) clonogenic cell survival assay, (VII) DNA synthesis cell proliferation assays and (V) Raman micro-spectroscopy. \r\n\tMedical devices have been widely used in various clinical disciplines and these devices have direct contact with the tissues and cells of the body, they should have good physical and chemical properties as well as good biocompatibility. Biocompatibility testing assesses the compatibility of medical devices with a biological system. It studies the interaction between the device and the various types of living tissues and cells exposed to the device when it comes into contact with patients.
\r\n
\r\n\t \r\n\tThe book will cover original studies, reviews, all aspects of Cell Viability and Cytotoxicity assays, methods, Biocompatibility of studies of biomedical devices, and related topics.
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\n
1. Introduction
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Palliative care is a philosophy based approach in patient care not on physical facilities but on attitudes and skills [1] and is redefined by the World Health Organization (WHO) in 2002 and extended to include palliative care for children for the active total care of patients facing life-threatening illness through prevention and relief of sufferings by means of early identification and impeccable assessment and treatment of pain and other problems as physical, psychosocial and spiritual, with an aim to improve the quality of life of the patient and their families [2, 3]. Most of the developed and developing countries recognized palliative medicine for the improvement of the quality of life of patients with chronic disease such as malignancy [4]. The primary goal of palliative care is the achievement of the best possible quality of life for the patients and their families and role extends to support on bereavement, if necessary. The term ‘care’ underpinned by the concept of total pain, defined as including not only physical symptoms but also mental distress and social or spiritual problems [5]. This concept of palliative care points to the need of holistic approach including symptom control for the management of the patients with terminal illness. Based on the above definition by WHO, the primary aim of palliative medicine is to prevent, treat the symptoms of patients with non-curable diseases as total care and to improve the quality of life (QoL) of the patient and their families.
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The evaluation of QoL of patients in Palliative Care is an important procedure in the identification of a patient’s overall condition as well as in the evaluation of the quality of service provided [6]. In patient’s perspective, the following aspects such as physical abilities, personal autonomy, emotional state, socializing, spirituality, cognition, health care provision and preparation for death are important factors of quality of life in people with a life-limiting illness receiving palliative care [7] and to be considered during the assessment of quality of life in these patient cohort. The occurrence of incurable diseases can cause an enormous challenge to the patient, their family as well as medical professionals, affecting the QoL of patients in many ways [8]. With key components of systematic symptom assessment, pain control and other symptom relief, psychosocial support and family support, it is evident that early interdisciplinary palliative care and care givers’ support help the patient to achieve effective symptom control and better quality in life [9]. However, usual practice to seek palliative care service is still limited to the terminal phase of illness. A coherent and empathetic communication of health professionals with the patient and their family has a major role in adopting patients’ and their families’ readiness for palliative care at the time of or shortly after diagnosis of incurable life-threatening illness [10, 11, 12, 13, 14]. In this context, this chapter highlights the facts with the primary objectives of:
To explain definitions and the variables for the terms “quality of life”, and “Health Related Quality of Life (HRQoL)” in the concept of “Health”
To suggest appropriate research tools for the assessment of QoL and HRQoL in patients under palliative care
To describe the influence of palliative care medicine in the improvement of QoL in these patients.
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\n
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2. Definitions and the variables for the assessment of QoL of patients under early palliative care
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\n
2.1 Definitions
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Defining the QoL is challenging and many approaches based on human needs, subjective well-being, expectations and phenomenal viewpoints exists [15]. The available definitions of QoL that are useful in health care can be grouped into five categories:
As early as in 1949, Karnofsky outlined the necessity of assessment of patients’ subjective improvement in terms of mood and attitude, general well-being and activity, appetite and alleviation of distressing symptoms such as pain, weakness and dyspnea in addition to performance status, length of remission and prolongation of life during the evaluation of new drugs in cancer chemotherapy and high lightened the importance of psycho-social and QoL variables in molecule development. In contemporary terms, these subjective improvement criteria can be considered as QoL measurements and can be considered one of the first description on QoL in health care [17]. The alternative approach is with a view that individuals are the centre point to judge their own experiences and referred to as subjective QoL of subjective well-being (SWB) [18]. The subjective approach defines QoL as the congruence between aspirations and accomplishments, as perceived by the person and measures of life satisfaction, happiness, and positive and negative emotions falling in this category of subjective well-being [19]. These approaches direct to the necessity of a patient-centered approach for the evaluation of quality of life in the health care system. Since the introduction of the term “quality of life” in the medical literature in the 1960s, a number of researches have been happening, especially in patients with malignancy.
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Based on a review, Aaronson [20] suggested two common threads in the structure and content of measures that carry the quality of life label.
Such measures tend to reflect a multidimensional conceptual approach. The following health dimensions are frequently incorporated to a greater or lesser degree in assessment of QoL.
Physical health with variables such as somatic sensations, disease symptoms, and treatment related complications.
Mental health ranging from a positive sense of well-being to non-pathological forms of psychological distress to diagnosable psychiatric disorders.
Social health including qualitative and quantitative assessment of community contacts and interactions
Functional health which includes both physical functioning in terms of self-care, mobility and physical activity as well as social role functioning in relation to family and work
Beyond these dimensions, other variables specific to a given disease may be incorporated, for example, quality of life evaluations in breast cancer will often include measures of sexual activities and body image. Another example studies in rheumatoid arthritis may include expanded assessment of joint mobility and pain.
The patient focused approach is primarily reliance on the subjective judgment of the patient themselves, rather than on observations of physicians, nurses, family members or other third parties. Although this process adds complexity to the data collection, considering the manner in which this approach addresses the psychosocial factors surrounding disease and treatment, it is generally considered as the most appropriate.
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This concept on QoL is supported by Ware [21] who suggested that routine assessment of a fairly broad, comprehensive set of psychosocial variables may often be most appropriate given our limited knowledge of the impact of chronic disease on everyday functioning, and of the psychosocial tradeoff associated with alternative treatments. Marcel [17] highlighted the importance of having a definition of QoL that covers the topic of research. Alternatively, he suggested getting umbrella coverage for any aspect of living with illness or disability to the term ‘quality of life’ in a QoL article. He advised the reader to focus on the variables which are actually measured in the study rather than the terms used.
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In 1993, the WHO Quality of Life Group clarified the definition of the term Quality of Life as ‘an individual’s perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns. This broad concept on QoL is influenced by the individual’s physical health, psychological state, level of independence, social relationships and their relationships to salient features of their environment in a complex manner [22]. However, at this point, it is important to consider the fact that the term QoL does not have same meaning to every person [23] and it is suggested that there are some aspects of QoL that are universal, where as some of them would be important only to the individual [24]. The interaction between these aspects-general and individual- will also vary from individual to individuals and their correlation is not static and moreover, changes overtime in response to life circumstances such as life-threatening or severity of illness [25]. Based on the above concepts and hypothesis, a number of definitions for QoL exist and many of them focus on subjective judgments. In view of this, a number of researchers have argued for the importance of inclusion of objective factors in the assessment of QoL [15]. Including all these variables in to consideration, QoL has been defined as “an overall general well-being which includes the objective assessments and subjective measurements of physical, material, social and emotional well-being together with the extent of personal development and purposeful activity, all weighted by a personal set of values” [26].
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The term “Health- Related Quality of Life” appeared in published articles by the mid-1980s and it was defined as a subset of QoL, relating only to the health domain of that existence [15]. However, in 1994, Gill and Feinstein reviewed 75 articles titled with word quality of life and concluded that none of the article distinguished overall QoL from the HRQoL [27]. To reverse these situations, many theorists, researchers, organizations and the consensus groups have proposed definitions for QoL and HRQoL [17]. There are at least four definitions for HRQoL can be found in literature [15]. In 2010 Hays and Reeve defined HRQoL in terms of individual’s functioning life and perception of well-being based on physical, mental and social domains of health [28]. Here functioning life represents the individual’s ability to carry out some pre-defined activities, [28, 29] while wellbeing refers to an individual’s subjective feelings [28].
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In another article, Torrance WH, correlates QoL and HRQoL and quotes as “quality of life is an all-inclusive concept incorporating all factors that impact upon an individual’s life. The Health Related QoL includes only those factors that are part of an individual’s health”. Non-health aspects of QoL are not included in HRQoL, for example economic and political factors [30]. Focusing on aspects of QoL affected by disease factors, in 1995 Ebrahim S provided a definition of HRQoL as “those aspects of self-perceived wellbeing that are related to or affected by the presence of disease or treatment” [31]. In another definition of HRQoL, Gold MR et al. focuses on the value of health and refer HRQoL to “the values assigned to different health states” [32].
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2.2 Difference between the terms: Health, QoL and HRQoL
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It is acknowledged that “health is only one dimension of quality of life” [16]. Satisfaction with life is influenced by health, but health status only explains a small part of life satisfaction outcomes [33]. Therefore we can consider the Health and QoL as distinct concepts [15]. As some of definitions of HRQoL indicate to health status of person and others resembles QoL, differentiation between HRQoL and both health status and QoL is more problematic [15]. Especially when considering, the first two definitions of HRQoL given above do not seem to add much to the concept of health. If HRQoL is considered as functioning and wellbeing in physical, psychological, and social domains, then we need to take HRQoL as a particular type of description of health, in view of the WHO definition of health. HRQoL describes health using functioning and well-being rather than, for example, in terms of clinical symptoms or biological variables [29]. It is thus should be considered as a type of health measure, but not a type of QoL measure. Similarly, if HRQoL is the health aspect of QoL then HRQoL should be considered as same as health condition. Particularly, the first two definitions of HRQoL, which included here do not distinguish HRQoL from that of health [15]. The third definition of HRQoL highlights the aspects of QoL that are indirectly influenced by health (e.g., health affects income and hence housing, education and so forth) [34]. Perhaps more reasonable is the variant of this definition, where HRQoL is the aspects of QoL most affected by ill health [15]. Qualitative research has observed that existence of a wide variety of non-health factors those are important to participants for evaluating their health states [35]. If the research participant’s preferences are based on how health affects the QoL and if respondents estimate the effect of health status on QoL correctly then the utility of a health state could be referred to as health-related quality of life or more accurate term of ‘health-adjusted quality of life’ [15]. In summary, the above definitions of HRQoL reflect the values of definitions of both QoL and health in to its considerations.
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2.3 The importance of HRQoL questionnaires measure in palliative care
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As stated above, WHO defines palliative care as “an approach that improves the QoL of patients and their families facing the problems associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial, and spiritual” [36]. Since the patients under palliative care with chronic illness or non-curable disease, most of the measures in palliatives address for the symptom control and help the patients and their family to improve the quality of life physically, psycho-socially and spiritually. Based on the concept of above definition, the HRQoL questionnaire, such as the Personal Wellbeing Index (PWI) asks about satisfaction with: the standard of living, health, achievement, personal relationships, personal safety, community connectedness, and future security [37] in its assessment of variables. All these variables are more or less likely to be affected by ill health status of the individual. Because of this correlation between the domains and patient’s perception on health status, it is recommendable that the QoL questionnaires could therefore be to measure self-perceived health status, unless the connection between measuring functioning and well-being and QoL is justified [15]. The domains of the two most validated assessment tools such as SF-6D and the EQ-5D would fit to the WHO health definition, although the questions range across the WHO classification scheme of impairment, activity limitation, and participation restriction. Yet, there have not been many explicit justifications for differentiating HRQoL from health status [15]. However, neither the EQ-5D nor the SF-6D contains patient valuation. Measures of HRQoL describe health status in terms of functioning health and wellbeing of individual than clinical parameters, and with a broad description of health condition than the measures of QoL. It is therefore more justified to classify typical HRQoL measures as measures of self-perceived health status [15]. So the ideal questionnaire should cover the concept of WHO definition along with patient self-evaluation on all aspect of QoL measures in relation his or her present health condition.
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Spitzer et al. introduced a concise QL-index for measuring quality of life in cancer patients in 1981. This QoL instrument was based on the assessment of socio-personal variables and included physical, social, and emotional functions; attitude towards illness, personal features of patient’s daily lives, including family interactions and the cost of illness. The considered items measures activities, self-care, general health, social support and out-look on life [38].
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The findings in a systematic review by Nicola et al. [7] in 2016, with an objective to identify the aspects of QoL, which are important from the perspective of palliative care patients, suggests the following aspects as important for the quality of life in people with a life-limiting illness receiving palliative care on their own perspective: physical abilities, personal autonomy, emotional state, socializing, spirituality, cognition, health care provision and preparation for death. He also suggested a refinement of existing QoL measures in palliative care setting to improve the sensitivity and concluded with an opinion of generic preference based, HRQoL measures commonly used to inform public funding decisions do not include the domains such as cognition, emotional, physical, preparatory, social and the spirituality. Because of the existence of this mismatch between the domains available in assessment tools and the reality on the context of patient considerations, the assessment with the tools may fail to inform adequately on the money decisions about palliative care. Because of these mismatching facts, Carr and Higginson suggested for a patient-centered outcome measures (PCOMs), which capture the health status and well-being form the patient’s perspective and focus on concern important to patient [24]. This point supported by Etkind et al., in a systematic review on the impact of PCOMs on processes and outcomes of palliative care, concluding that these type of measures raise the awareness of unmet need, improve recognition of symptoms and communication about QoL and benefit patient’s emotional and psychological quality of life [39]. In short, during the selection of assessment tools for the evaluation of quality of life in patients under palliative care, it is recommendable for a patient centered outcome measuring questionnaire which correlate with definition of QoL.
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3. The improvement of QOL of patients and their families under early palliative care
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During early decades, palliative care services were initiated to provide a medical alternative to questionable medical practice regarding the end of life period: abandonment, euthanasia and inappropriate aggressive therapy and palliative care are usually offered late. Recently WHO recommends palliative care introduction as early as possible in the course of illness to increase the quality of life of patients and to positively influence the course of illness, in conjunction with other therapies, which are intended to prolong the life; such as chemotherapy or radiotherapy [40]. Palliative care is a multi-disciplinary approach that aims to improve the quality of life of all patients including both children and elderly and their families who are facing the challenges associated with life-threatening illness. These objectives of PC are achieved through the prevention and relief of sufferings, by means of early identification, assessment and treatment of pain and other physical, psychosocial and spiritual distress [40]. The WHO recommendations also support the use of necessary laboratory investigations for the better understanding and management of distressing clinical complications in these patient group.
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3.1 The evidences supporting the early introduction of palliative care
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The role of good doctor-patient communication is important in acceptance of illness, deciding the treatment options. With a focused intensified doctor-patient communication, early palliative care may lead to higher social support and increase the likelihood of the acceptance of the diagnosis and illness severity. This in turn improves the patient’s openness to symptom control and psycho-social interventions, and thereby to reduce the disease related distress. The reduced distress itself associated with improved quality of life and consistently promotes survival [41, 42, 43]. Early palliative care intends to outline realistic and attainable goals of treatment and to facilitate patient’s choices by providing adequate information and assessment of his or her values and preferences with regard to advance care planning [44, 45]. In a systematic review of a small number of trials, Haun MW et al. found that early palliative care interventions may have more beneficial effects on quality of life and symptom intensity among patients with advanced cancer than among those given usual/standard cancer care alone. Apart from small effect size of the studies, they observed the findings may be clinically relevant at an advanced disease stage with limited prognosis, at which time further decline in quality of life is very common [46].
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There are evidences that under early palliative care patient and family members are better informed on disease symptoms and severity and treatment directives and are provided with more time for end of life decisions, which promotes the experience of higher self-efficacy and sense of control in decisions with respect to the individual values [47]. It is proved that, the effective use of palliative care in linked with less aggressive cancer treatment, such as reduced use of questionable chemotherapeutic agents and treatments and this practice will de-escalate treatment intensity in final, irreversible health conditions [48]. The above observations is also supported by Temel et al. in 2010 [49] with their findings in a randomized trial with participation of 151 patients of newly diagnosed metastatic non-small cell carcinoma. The primary objective of this study was improvement in quality of life and overall survival as secondary objective. In their study, it has been observed that the patients in group of early palliative care service along with standard oncologic treatment showed significant improvement in quality of life and in mood, than the patients in the group of standard oncology treatment only. In addition, the patients with early palliative care led a significantly longer survival (p = 0.02), despite less aggressive end of life care. In view of the observations in this randomized controlled trail, American Society of Clinical Oncology supported the combined use standard oncology treatment along with palliative care in the course of illness for any patients with metastatic cancer.
\n
The early integration of palliative care service for the treatment of cancer patients especially with metastasis is also supported by, Pirl et al. [50] in 2012, with the observations in their trial. It claimed that early introduction of palliative care improved the result of medical comorbidity management, including depression and helps in the discontinuation of inappropriate and possibly detrimental cancer treatment at the end of life. Recently, Hutt et al. [51] conducted a phase III randomized trial in 2018, with an aim to test the hypothesis that the use of early palliative care provides greater clinical benefits than standard practice for a population of patients with metastatic upper gastro-intestinal cancers. The primary objective in this study was overall survival. The authors concluded with expectation of integration of earlier palliative care in oncologic care of patients with metastatic gastro-intestinal cancer.
\n
\n
\n
3.2 The factors should be addressed under palliative care for the betterment of quality of life in patients
\n
In 2011 Jacoba et al. [25] studied the effect of palliative care in a resource poor community in South Africa, with the themes of:
the factors that had a positive influence on quality of life,
factors that had a negative influence on quality of life
experience of quality of life.
\n
In their study, it is observed that: being able to work as a very important factor for all the participants involved in the study, as it keeping them busy and having no time to spend for unnecessary worries in addition to help in earnings. Support from friends and family as well as health care professionals was another major factor contributing for the improvement of quality of life. Spiritual activities such as going to church, participating church services, singing in choir and prayers made the participants to feel strong and comfort and gave them a feel of “alright”. Lastly, comes the symptom control. The poverty was the predominant negative factor on the quality of life of the study participants. Other negative factors were unemployment, separation from children, rejection and stigmatization and experiencing the symptoms with pain as mostly described symptom. It is observed that uplifting of education and economic status of the community will help for the improved psycho-social support extending to the terminally ill patients and there by their quality of life [52].
\n
\n
\n
\n
4. Conclusion
\n
The primary objective of palliative care is to improve the QoL of the patients facing life threatening illness by means of a multidisciplinary approach. The process of QoL assessment identifies the patient’s overall conditions including psycho-social, spiritual issues as well as the evaluation of the services provided to him. So the ideal assessment tool the measurement of QoL in patients under palliative care should be patient centered and contain both subjective and objective domains and be able to correlate with the definition of QoL. It is evident that early integration of palliative care improves the QoL of patients with terminally ill condition and Early adaptation of palliative care is advisable for the management of patients with chronic conditions such as cancer.
\n
\n
Conflict of interest
None.
\n',keywords:"quality of life, palliative care, early palliative care, QoL assessment, QoL tools, symptom management, psycho-social support",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/65999.pdf",chapterXML:"https://mts.intechopen.com/source/xml/65999.xml",downloadPdfUrl:"/chapter/pdf-download/65999",previewPdfUrl:"/chapter/pdf-preview/65999",totalDownloads:1148,totalViews:0,totalCrossrefCites:3,totalDimensionsCites:4,totalAltmetricsMentions:2,impactScore:4,impactScorePercentile:92,impactScoreQuartile:4,hasAltmetrics:1,dateSubmitted:"September 13th 2018",dateReviewed:"February 12th 2019",datePrePublished:"June 7th 2019",datePublished:"October 2nd 2019",dateFinished:"March 6th 2019",readingETA:"0",abstract:"Based on the WHO definition, the primary objective of palliative care (PC) is to improve the quality of life (QoL) of the patients facing life threatening illness by means of a multidisciplinary approach. The assessment of QoL in patients under PC is an important process for the identification of patient’s overall conditions including psycho-social, spiritual issues as well as the evaluation of the services provided to the patient. The ideal assessment tool the measurement of QoL in patients under PC should be patient centered and contain both subjective and objective domains and be able to correlate with the definition of QoL. The factors which positively influence the extend of the QoL include, good doctor-patient communication, economic status, education, socio-economic support and spirituality. The negative factors are social isolation, lack of employment, poverty, rejection and stigmatization and experience of symptoms, such as uncontrolled pain. Early Integration of PC leads to higher psycho-social support and acceptance of diagnosis, and severity of illness, which in turn helps for the better symptom management and reduces the disease related stress, which clearly associated with improved QoL. It provides more time for the end of life decision making, promotes self-efficacy and sense of control in decision with respect to individual values.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/65999",risUrl:"/chapter/ris/65999",book:{id:"7909",slug:"palliative-care"},signatures:"Thomas Antony Thaniyath",authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Definitions and the variables for the assessment of QoL of patients under early palliative care",level:"1"},{id:"sec_2_2",title:"2.1 Definitions",level:"2"},{id:"sec_3_2",title:"2.2 Difference between the terms: Health, QoL and HRQoL",level:"2"},{id:"sec_4_2",title:"2.3 The importance of HRQoL questionnaires measure in palliative care",level:"2"},{id:"sec_6",title:"3. The improvement of QOL of patients and their families under early palliative care",level:"1"},{id:"sec_6_2",title:"3.1 The evidences supporting the early introduction of palliative care",level:"2"},{id:"sec_7_2",title:"3.2 The factors should be addressed under palliative care for the betterment of quality of life in patients",level:"2"},{id:"sec_9",title:"4. Conclusion",level:"1"},{id:"sec_13",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Saunders C. The evolution of palliative care. Journal of the Royal Society of Medicine. 2001;94:430-432\n'},{id:"B2",body:'World Health Organization. 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DOI: 10.1200/JCO.2007.15.8253\n'},{id:"B49",body:'Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with metastatic non-small cell lung cancer. The New England Journal of Medicine. 2010;363:733-742\n'},{id:"B50",body:'Pirl WF, Greer JA, Traeger L, et al. Depression and survival in metastatic non-small cell lung cancer: Effects of early palliative care. Journal of Clinical Oncology. 2012;30:1310-1315\n'},{id:"B51",body:'Hutt E, Da Silva A, Bogart E, Sara Le LD, Pannier D, Stephane D, et al. Impact of early palliative care on overall survival of patients with metastatic upper gastrointestinal cancers treated with first-line chemotherapy: A randomised phase III trial. BMJ Open. 2018;88:e015904. DOI: 10.1136/bmjopen-2017-015904\n'},{id:"B52",body:'Antony T, Merghani TH. The influence of demographic factors on social affections among chronic patients under home based nursing care. AARJSH. 2015;2(7):166-175\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Thomas Antony Thaniyath",address:"thaniyan1@gmail.com",affiliation:'
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1. Introduction
Macrophages were historically considered as specialized immune cells that are resident in every tissue. They are professional phagocytic cells and are considered to be one of the most evolutionary conserved components of the innate immune system [1]. However, studies of the past two decades identified several additional functions of macrophages particularly those involved in maintaining tissue homeostasis such as wound healing and regeneration [2]. Macrophage populations within the tissue were originally assumed to be continuously replaced by the differentiation of monocytes derived from peripheral blood [3, 4]. However recent studies using methods such as lineage tracing and single cell transcriptomics have established that several macrophage populations resident in organs including brain, lung, intestine and liver, originate from yolk-sac (YS) myeloid precursor cells that were seeded within the tissues during early embryonic hematopoiesis [5]. These myeloid precursors differentiate into macrophages (microglia in case of brain) within their resident tissue site, and are self-maintained throughout the life course of the organism [5]. Tissue resident macrophages (TRMs) are functionally distinct from macrophages derived from the more accessible circulating blood monocytes but their yolk sac origin makes them difficult to study [5]. In order to successfully study these cells in vitro, researchers have develop methods that permit functional TRMs to be isolated [5]. In vitro strategies to replicate the tissue resident differentiation of macrophages in a way that mimics their tissue specific developmental and differentiation pathways have been developed using a variety of growth factors and cytokines [6]. However, cells produced using these methods do not completely recapitulate the properties of TRMs and it would be challenging to scale up and produce large numbers of cells.
The ground-breaking discovery that human somatic cells could be reprogramed into induced pluripotent stem cells (iPSCs) that are capable of differentiating into any cell type has revolutionized many areas of medical research including macrophage biology [7]. Several studies have shown that human iPSCs can be differentiated into macrophage populations that are phenotypically and functionally comparable to human macrophages. The major advantage of the iPSCs-derived macrophages is that they share some phenotypic and functional profiles with both tissue resident macrophages and monocyte derived macrophages (MDMs) [8]. Here, we review the potential of iPSCs derived macrophages in both classical immune function as well as their tissue repair and regeneration properties. We summarize the various protocols that have been used for macrophage production from iPSCs, discuss their disease modeling potential including hereditary and pathogen associated diseases and describe some of the pre-clinical trials lay the foundations for their use in cell therapies.
2. Human induced pluripotent stem cells for macrophage production in vitro
The generation of iPSCs from adult somatic cells by the introduction of four genes encoding the “Yamanaka” transcription factors, octamer-binding transcription factor 3/4 (OCT3/4), sex determining region Y-box 2 (SOX2), Kruppel-like factor 4 (KLF4), and myelocytomatosis viral oncogene homolog (MYC), was first reported in 2006 [9]. Resultant iPSCs were shown to be comparable to embryonic stem cells (ESCs), thus providing an ethical strategy for creating clonal PSC lines that did not involve the destruction of human embryos [10]. Initially reprogramming of somatic cells to iPSCs was successfully performed using genome integrating retroviral or lentiviral vectors such as retroviruses and lentiviruses [7]. Though viral integration was efficient, it was associated with risks of random mutational insertions into the genome. Alternate non-viral integration methods such as plasmids, synthetic mRNA, minicircle DNA molecules and small chemical molecules to generate iPSCs reduced random mutations but the efficiency of generating iPSCs was low [7, 8]. Sendai virus is now commonly used for iPSC generation as its replication is limited within the cytoplasm and it does not integrate into the genome. Initially skin fibroblasts were used for reprogramming iPSCs, but other easily accessible cells such as peripheral blood monocytes and renal epithelial cells from urine have been successfully used as the starting cells [11, 12]. iPSCs are able to be differentiated into the three embryonic germ layers namely ectoderm, endoderm and mesoderm and can differentiate into somatic cells associated with all cell lineages [13].
Following the generation of stable iPSCs, their pluripotent properties are maintained using specific growth factors [9]. Removal of these maintenance factors results in spontaneous differentiation and, under appropriate conditions the formation of 3-dimensional (3D) embryoid bodies (EBs) that are considered to mimic early embryogenesis [14]. Differentiation factors such as cytokines and small molecules have been used to stimulate specific differentiation pathways resulting in the production of cells displaying phenotypes and gene expression patterns of almost any cell type including cells of the blood and immune system [15].
Doetschman and colleagues were the first to report that hematopoietic cell types could be produced from mouse embryonic stem cells (ESCs) by demonstrating structures resembling blood islands in cystic embryoid bodies (EBs) that were comparable to the primitive wave of hematopoiesis in the yolk sac [16]. Differentiation protocols were subsequently developed and refined to include the use of feeder cells, extracellular matrices and specific growth factors [17, 18, 19, 20]. Many of these protocols failed to generate the long-term reconstituting hematopoietic stem cells (HSCs) associated with the definitive wave of hematopoietic development and a significant amount of research has gone into addressing this problem in both the mouse and human systems [21, 22, 23, 24]. The production of macrophages was reported even in the first, rather crude differentiation protocols with the ability to harvest on regular basis for several weeks represented a significant advance in the field [18, 25]. The fact that these differentiation protocols most likely mimic the primitive wave of hematopoiesis it is not surprising that resultant cells have some features that are comparable to TRMs.
The production of macrophages from human iPSCs is now well established and they are considered to have features associated with both YS-derived TRMs as well as MDMs [5]. As iPSCs can been maintained indefinitely in culture and can be readily genetically manipulated, they can therefore provide an inexhaustible source of macrophages carrying any desired genetic alteration. The first protocols that were developed involved the co-culture of iPSCs with OP9 mouse stromal cell monolayers to induce hematopoietic differentiation, followed by expansion of myeloid progenitors and selective differentiation into macrophages by using growth factors to differentiate dendritic cells and macrophages [26, 27]. These protocols were further modified to establish embryoid body (EB)-based protocols for IPSC-derived macrophage differentiation. We have used a modified serum-free protocol in which EB-based hematopoiesis is used to generate monocyte-like cells in suspension that can then be differentiated into mature macrophages [28]. Briefly, differentiation from human iPSCs is initiated by the removal of pluripotency factors and the addition of stem cell factor (SCF), bone morphogenetic protein (BMP)-4 and vascular endothelial growth factor (VEGF) to induce EB formation. The addition of interleukin (IL)-3 and macrophage colony stimulating factor (M-CSF) to EBs that are then plated down onto the culture plates results in the production of monocyte precursors that are released into suspension. Monocyte-like cells are then plated down and differentiated into mature macrophages by the addition of M-CSF [29]. iPSCs derived macrophages express macrophage-specific markers including cluster of differentiation (CD)11b, CD163, and CD169 [30]. Macrophages generated from iPSCs that carried the Zeiss Green reporter gene integrated into the adeno-associated virus integration site 1 (AAVS1) locus showed that neither expression of the reporter nor the targeting of the AAVS1 locus affected of macrophage phenotype confirming the idea that genetically manipulated macrophages can be generated using this strategy [30].
2.1 iPSCs-derived macrophages share features of MDM
Yeung and colleagues demonstrated that the iPSCs-derived macrophages exhibited gene expression profiles and responsiveness to external stimuli that were comparable to MDMs. Their data demonstrated that untreated iPSCs-derived macrophages and MDMs expressed 12,599 human genes overlapping and a further 93% of these genes were expressed to a similar level [31]. This pattern of gene expression iPSCs-derived macrophages and MDMs remained consistent even after stimulation, as upon Chlamydia trachomatis infection, the two cell types had more than 2000 differentially expressed genes in common [31].
iPSCs-derived macrophages secrete comparable levels of cytokines as MDMs upon stimulation with pattern recognition receptors such as toll-like receptor (TLR) agonist [32]. They are able to phagocytose live Salmonella typhi or fungal particles like zymosan [30, 33]. Most importantly, iPSCs-derived macrophages retain plasticity which is one of the key characteristic of macrophages [34]. Naive macrophages express an M0-like steady state phenotype, which can be switch to either an inflammatory (M1) or immunosuppressive (M2) function based on their microenvironment. It is proposed that due to the genetic and functional similarities between iPSCs-derived macrophages and primary macrophages, the former could be used as a tool to model macrophage polarization in inflammatory diseases and genetic diseases such as autosomal recessive disorders. A study from Matsuo et al modeling a disease fibro dysplasia ossificans progressiva using iPSCs derived macrophages showed the potential of 2D and 3D based differentiation of macrophages having a differential role in their polarization potential [35]. While the 2D iPSCs-derived macrophages could be polarized to either M1 or M2, the 3D differentiated macrophages showed a mixed M1 and M2 like functional features, highlighting the complexity of macrophage plasticity.
2.2 iPSCs derived macrophages model tissue resident macrophages
Although iPSCs-derived macrophages have demonstrated similar phenotypic, functional, and transcriptomic characteristics to MDMs as discussed above, they are also reported to have comparable characteristics to tissue resident macrophages (TRMs). This TRM like phenotype gives iPSCs-derived macrophages an advantage over other models such as MDMs or monocytic cell lines such as THP-1. It has been recognized that the standard hematopoietic differentiation protocols of iPSCs resemble the primitive rather than definitive wave of hematopoiesis in vivo [36]. To confirm this theory, Vanhee and colleagues used a reporter PSC line with myeloblastosis proto-oncogene with a green fluorescent protein (MYB-eGFP), a marker for definitive hematopoietic stem cell (HSC)-dependent hematopoiesis, and as expected the in vitro generation of EB-based iPSCs derived macrophages lacked MYB+ HSCs [37]. The results were further validated by demonstrating that clustered regularly interspaced short palindromic repeats and its associated protein 9 (CRISPR/Cas9) knockout of MYB in human iPSCs, did not impact macrophage differentiation [38]. The theory was further verified in experiments where two important transcription regulators of YS hematopoiesis transcription factor PU.1 encoding gene SPI1 and Runt-related transcription factor 1 gene RUNX1 were knocked out in iPSCs, they were unable to produce mature macrophages [37, 38]. Several studies have indicated the TRM nature of iPSCs-derived macrophages is based on in vitro microglia modeling. Indeed, several cytokine mediated iPSCs to microglia-like cell differentiation protocols were published in recent years using coculture with iPSCs-derived neurons and astrocytes or using conditioned media from those cell types to recapitulate organ-specific microenvironment [39]. Takata and colleagues further demonstrated by macrophages derived from iPSCs using a protocol that specifically resembles primitive hematopoiesis and yolk sac macrophages that they are very similar to TRMs [5]. They did this by engrafting iPSCs derived macrophages into the mouse brain which then underwent functional and morphological changes to become microglia, while the iPSCs derived macrophages engrafted to the lung of the Pulmonary Alveolar Proteinosis (PAP) mouse model matured into alveolar macrophages. This study showed that the iPSC-derived macrophages developed to microglia-like cells in vivo and showed genomic profile similar to that of both human adult and foetal microglia, while in the lung of the PAP mouse model they eliminated the surfactant protein that had accumulated as a result of the disease. Our lab recently used iPSCs-derived macrophages to model the erythroblastic Island (EBI) niche in vitro by genetic programming with the transcription factor, KLF1 [29].
2.3 iPSCs derived macrophages in disease modeling
Another important feature of human iPSCs derived macrophages is that iPSCs are amenable to genetic engineering and thus can be manipulated to be model genetic disease. Disease modeling can be achieved either through the production of iPSCs from patients carrying disease-causing mutations and/or specific genome-wide associations or by targeted gene edited using the (CRISPR)/Cas9 system. iPSCs-derived macrophages are increasingly being used to study genetic disease, including validation of known causative genes or identifying novel mutations associated with single nucleotide polymorphisms (SNPs) [40]. iPSCs-derived macrophages helped overcome the limitations of the poor availability of disease-specific primary macrophages in studying these rare genetic diseases. The ability to derive macrophages from iPSCs provided new opportunities to develop models relevant to human genetics, resulting in a progressive accumulation of studies describing macrophage functions in both tissue homeostasis and disease. For example, patient iPSCs-derived macrophages have been utilized to investigate several genetically inherited diseases including Blau Syndrome, Tangier disease and Gaucher disease. In additions there are studies where a diseased condition such as Dyskeratosis Congenita has been generated in iPSCs using genetic engineering technology and macrophages or myeloid cells derived from these used to understand the disease mechanism [41, 42, 43, 44]. Table 1 lists some of the genetic studies performed using patient iPSCs-derived macrophages, that would not have been possible using primary cells.
Studies utilizing iPSCs derived macrophages for disease modeling
Disease
Research findings
References
Tangier Disease (TD)
iPSC-derived macrophages from TD patients recapitulate the clinical defect of failed cholesterol efflux resulting in reverse cholesterol transport.
TD effect of reverse cholesterol transport in macrophages derived from CRISPR/Cas9 induced adenosine triphosphate binding cassette subfamily A member 1 gene (ABCA1) knockout iPSCs.
iPSCs-derived macrophages from GD patients exhibited delayed clearance of phagocytosed RBC which was reversed when treated with recombinant glucocerebrosidase enzyme.
iPSCs-derived macrophages from dihydronicotinamide-adenine dinucleotide phosphate (NADPH) oxidase defective patient showed normal phagocytic properties unlike patient MDMs, however showed a lack in reactive oxygen species production, correlating with clinical diagnosis.
iPSCs-derived macrophages from nucleotide-binding oligomerization domain-containing protein 2 (NOD2) mutated patient showed ligand-independent pro-inflammatory cytokine production in vitro upon Interferon (IFN)-γ treatment. The cytokine production was terminated upon NOD2 mutation correction by CRISPR/Cas9.
iPSCs-derived macrophages from Diabetic patient showed potential for antigen presentation to proinsulin-specific T cell receptors from donor-matched islet-infiltrating T cells.
Patient iPSCs-derived macrophages exhibited the disease characteristics including enhanced IL-1β secretion and hyperactivation of the pyrin inflammasome.
Mendelian Susceptibility to Mycobacterial Disease (MSMD)
iPSCs-derived macrophages from MSMD patients with autosomal recessive complete- and partial IFN-γR2 deficiency, partial IFN-γR1 deficiency and complete STAT1 deficiency demonstrated varying phenotypes including cytokine secretion for the partial and complete deficiencies.
Patient iPSCs-derived microglia to confirmed findings in patients brain tissue of having elevated IL1B, IL10 and NLRP3 expression after in vitro LPS stimulation. iPSCs-derived microglia showed high phagocytic capacity under basal conditions that was exacerbated upon stimulation with LPS.
Chronic infantile neurologic cutaneous and articular syndrome
iPSCs-derived macrophages from NLRP3 mutated patient showed the disease relevant phenotype of abnormal IL-1β secretion which were inhibited by anti-inflammatory compounds.
Summary of studies that have used iPSCs-derived monocytes and macrophages for in vitro modeling of genetic diseases.
As well as generating valuable disease models these studies also described the novel approach of immortalizing iPSCs-derived myeloid cells using transducing lentiviral vectors that encoded genes MYC, polycomb complex protein gene BMI1 and mouse double minute 2 homolog gene MDM2, creating a strategy to generate monocytic cell lines, with the diseased phenotype [53]. These iPSC-derived immortalized myeloid cell lines have the advantage that they can be stored and differentiated into terminally differentiated progenies and expanded from one experimental batch with reduced financial and labour costs, overcoming many of the hurdles associated with iPSCs.
2.4 iPSCs-derived macrophages in host-pathogen interactions
iPSCs-derived macrophages have also been used widely in studies relating to their classical role in infection biology. iPSCs-derived macrophages can polarized to a pro-inflammatory or anti-inflammatory phenotype by treating with lipopolysaccharide (LPS)/IFN-γ or IL-4/IL-10, respectively [30]. These features make them a powerful in vitro tool to study bacterial, viral, and parasitic infections and their resultant immune responses. Hale et al infected iPSC-derived macrophages with Salmonella enterica serovar Typhimurium (S. Typhimurium) and S. Typhi and reported comparable data to that observed using the commonly used human monocyte-like THP1 cell line thus opening the way for their application to other bacterial infections [33].
One such example was the study of the interaction between Staphylococcus aureus toxin leukocidins with macrophages, which are the initial targets during S. aureus lung infection [54]. iPSCs-derived macrophages were susceptible to the leukocidins and triggered NLPR3 inflammasome activation resulting in IL-1β secretion and eventual cell death. CRISPR/Cas9-mediated deletion of the leukocidin receptor, complement component 5a receptor 1 (C5aR1) also known as CD88 protected the macrophages from cytotoxicity [54]. Another bacterial study using the iPSCs-derived macrophages model was on C. trachomatis, which causes bacterial sexually transmitted infections and preventable blindness worldwide. Yeung and colleagues demonstrated that iPSC-derived macrophages supported the full infectious life cycle of C. trachomatis in vitro in a manner that resembled the infection of human blood in vivo [31]. Using transcriptomic and proteomic profiling of the macrophage they identified that the key players in response to chlamydial infection are type I interferon and interleukin 10. This was further confirmed by knocking-out IRF5 and IL-10RA in iPSCs, which resulted in limited chlamydial infection in genetically-deficient macrophages. Though the studies mentioned above showed that bacterial infection studies using iPSCs-derived macrophages are comparable with the data generated using MDMs, one recent study clearly highlights an additional advantage of using iPSCs-derived macrophages. Nenasheva et al reported that iPSCs-derived macrophages differed from MDMs by an low-activated/low- polarized naïve-like (HLA-DRlow CD14+CD16int) phenotype compared to the HLA-DRhigh CD14+CD16+ phenotype of mature macrophages shown by MDMs, where HLA-DR stands for human leukocyte antigen – DR isotype [8]. These naïve-like iPSCs-derived macrophages were transcriptionally similar to pulmonary macrophages and restricted Mycobacterium tuberculosis growth in vitro by >75% higher phagocytic potential than MDMs [8]. Similarly, a study from Hong et al also showed that iPSCs-derived macrophages perform the immunological functions in response to Bacillus Calmette-Guérin a vaccine against M. tuberculosis, similar to MDMs by undergoing apoptosis, increased production of nitric oxide and elevated expression of Tumor necrosis factor (TNF)-α, thus demonstrating their suitability as a potential drug target [55].
Viruses require a specific cellular host for replication and so the readily available supply of infectable cells is crucial in viral research. iPSCs are ideal for this purpose because they can be differentiated into the specific cell type associated with an infectious agent, including endothelial cells for cytomegalovirus, neurons for herpes simplex virus, hepatocytes for hepatitis viruses, CD4 T-cells for human immunodeficiency virus (HIV) [56]. The field of HIV research has used iPSCs-derived macrophages widely. Using various genetic editing techniques, Kambal et al and Ye et al introduced mutations into C-C chemokine receptor type 5 (CCR5), the major coreceptor required for macrophage trophic strains of HIV and demonstrated that monocytes and macrophages differentiated from CCR5-mutated iPSCs were resistant to HIV-1 challenge [57, 58]. Kang et al confirmed this study by demonstrating that CCR5-mutant iPSCs derived macrophages showed unique and enhanced resistance to CCR5-tropic HIV challenge but were susceptible to CCR4-tropic viruses [59]. One of the most elegant studies that utilized human PSCs-derived macrophages characterized the molecular and cellular basis involved in both Zika and Dengue viral infections [60]. Using macrophages derived from both human ESCs and iPSCs, Lang et al showed that though both these viruses are closely related, their mechanism of infection was different. Zika virus disrupts the nuclear factor κB (NF-κB)-migration inhibitory factor (MIF) positive feedback loop by inhibiting the NF-κB signaling pathway and thus the infected macrophages exhibit prolonged migration but expressed low levels of pro-inflammatory cytokines and chemokines. In contrast, Dengue virus strongly activates MIF secretion and results in decreased macrophage migration. In summary the characteristics of iPSCs-derived macrophages together with genetic editing tools such as CRISPR/Cas9 has significantly enhanced our ability to study host–pathogen interactions as well as the role of human genetic variations in influencing the susceptibility to specific pathogens and disease outcomes.
2.5 iPSCs-derived macrophages in cell and regenerative therapy
Several studies performed in the last decade identified macrophages to have a prominent role in tissue repair and regeneration by their injury response features including clearing cell debris by phagocytosis, activating and resolving inflammation and promoting fibrosis by providing growth factors [61, 62]. For example the transplantation of mouse bone marrow-derived macrophages into a CCL4 mediated advanced liver injury mice model resulted in the reduction of fibrosis by increased recruitment of host effector cells such as neutrophils and secretion of regenerative factors such as matrix metallopeptidase 9 (MMP9), insulin-like growth factor 1 (IGF-1), M-CSF, vascular endothelial growth factor (VEGF) and IL10 [63]. Similarly exogenous macrophage treatments were shown to promote injury resolution in a several murine models of inflammatory and degenerative diseases including pulmonary fibrosis and osteochondral defect [64, 65]. This successful demonstration of macrophage therapy in pre-clinical models led to the use of autologous macrophages in therapeutic interventions in clinical studies against chronic liver injury and neurodegenerative diseases [66, 67]. It is thought that these repair functions are performed by the anti-inflammatory or resolving M2-polarized macrophages and several studies identified iPSCs-derived macrophages to be able to be polarized into an M2-phenotype similar to MDMs [30]. The polarization potential together with their ability for unrestricted production makes the iPSCs-derived macrophages ideal candidates for future cell therapies. Some of the studies highlighting these in vivo studies using iPSCs-derived macrophages as exogenous interventions are summarized in Table 2.
Studies demonstrating iPSCs derived macrophages as therapeutic interventions
Disease
Research findings
References
Liver Fibrosis
Mouse ESC-derived macrophages showed repair capacity in CCL4 murine model.
Human iPSCs–derived macrophages transplanted into the lung of humanized PAP mice showed in situ differentiation to an alveolar macrophage-like phenotype and disease remission.
Human iPSCs-derived macrophages engrafted into the lung of the PAP mouse model differentiated into alveolar macrophages and eliminated disease associated surfactant proteins.
Very early onset of IBDs in patients leads to decreased bacterial killing ability in macrophages, which was reverted by the pharmacological inhibition of PGE2 synthesis and PGE2 receptor blockade.
Genetic correction of patient iPSCs-derived macrophages in vitro led to reinitiating of the anti-inflammatory response and reduction of IBD associated traits.
Summary of studies that have used iPSCs-derived macrophages as a source of therapeutic cells and/or to study mechanism of disease.
Studies from our lab demonstrated that in vitro generated macrophages from mouse ESCs had the capacity for repair in vivo in a murine model of liver fibrosis [68]. Using a chemokine (C-C motif) ligands 4 (CCL4)-mediated liver injury model, the effect of injecting ESCs-derived macrophages or bone marrow derived macrophages (BMDMs) were assessed. ESCs-derived macrophages had a higher capacity to repopulate the Kupffer cell compartment of injured liver compared to BMDMs, supporting the theory that PSC-derived macrophages have a phenotype more akin to tissue resident macrophages. In addition, markers of liver damage were significantly lowered in mice that received ESCs-derived macrophages compared to controls indicating their reparative capacity. Another study assessed the effects of human iPSCs-derived macrophages polarized to an M1 or M2 phenotype on CCL4-induced fibrosis of immunodeficient recombination activating gene knock-out (Rag2−/− γc−/−) mice [69]. These human iPSCs-M1 (in presence of IFN-γ and LPS) and M2 (in presence of IL-4 and IL-13) macrophage subtypes demonstrate distinct pro-inflammatory and anti-inflammatory phenotypes at both gene and protein level, which was confirmed by their RNA-seq analysis. Interestingly administration of both M1 and M2-polarized macrophages led to reduced liver fibrosis and inflammation. iPSCs-M2 as expected demonstrated a stronger downregulation of clinically relevant fibrotic markers. However, the profound antifibrogenic potential and resolution in the presence of iPSCs-M1 was unexpected based on currently thinking on the reparative phenotype of macrophages. The scenario of iPSCs-M1 showing a resolving phenotype could be corroborated by a previous study reporting the therapeutic potential of M1 polarized BM-derived macrophages to ameliorate fibrosis by the recruitment of endogenous macrophages as well as promote apoptosis through mediators of inflammation including MMPs, transforming growth factors (TGFs) and TNF related apoptosis inducing ligand (TRAIL) [73]. This could be the situation as the iPSCs-M1 macrophages in this study were shown to secrete MMP9 and TGF-β [69]. However more detailed study is required to understand the mechanisms underlying this resolving capacity of iPSCs-M1 macrophages. Nevertheless, the study clearly confirms the potential of iPSCs-derived M2 macrophages as a therapeutic option against liver fibrosis.
The therapeutic potential of iPSCs-derived macrophages has also been assessed in lung fibrosis particularly in the case of pulmonary alveolar proteinosis (PAP). Hereditary PAP is a disorder known to be originated by a defect in the CSF2RA gene coding for the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor alpha-chain (CD116). Happle et al demonstrated for the first time that transplantation of human iPSCs–derived macrophages into the lung of a humanized PAP mice model led to their pulmonary engraftment and their differentiation to an alveolar macrophage like phenotype in situ [70]. They also showed that this engraftment resulted in a reduction of alveolar proteinosis as measured by diminished protein content and surfactant protein D levels, decreased turbidity of the BAL fluid, and reduced surfactant deposition in the lungs of transplanted humanized PAP model mice. Similar results were observed using the aid of wild type murine iPSCs-derived macrophage in vivo transplantation to a CD116 (CSF2RA) deficient PAP mice model resulted in the former’s integration into the diseased lung, gaining an alveolar macrophage phenotype and improving alveolar protein deposition [34]. Kuhn et al gene-corrected patient-derived PAP-specific iPSCs carrying a defective CSF2RA gene using targeted insertion of a codon-optimized CSF2RA-cDNA into the AAVS1 locus [71]. This strategy resulted in robust expression of the CSF2RA gene in both undifferentiated iPSCs as well as in differentiated macrophages. The authors further demonstrated that these genetically-modified macrophages showed that the exogenous CSF2RA protein was functional by STAT5 phosphorylation and GM-CSF uptake studies, supporting the idea that these functionally restored iPSCs-derived macrophages could serve as a source for an autologous cell-based gene therapy for the treatment of PAP.
Inflammatory bowel disease (IBD) is another group of inflammatory syndromes where the potential role of iPSCs-derived macrophage mediated therapy has been evaluated. Studies have demonstrated that these macrophages can be used in disease modeling and to reduce the disease pathology in vitro. A recent study showed that macrophages derived from an infantile-onset IBD patient iPSCs were unable to phosphorylate signal transducer and activator of transcription 3 (STAT3), and failed to reduce LPS induced inflammatory cytokines even in the presence of exogenous IL-10 [72]. These macrophages exhibited a functional defect in their ability to kill S. Typhimurium, but were rescued by the introduction of a functional IL10RB gene. The study also showed that macrophages derived from patient iPSCs produced higher amounts of eicosanoid prostaglandin E2 (PGE2) after LPS stimulation and that pharmacological inhibition of PGE2 synthesis and PGE2 receptor blockade enhanced their bacterial killing ability. This study identified a regulatory interaction between IL-10 and PGE2 and that their dysregulation contributed to IBD pathogenesis. Gene correction in an independently-derived iPSC line from another IL10RB−deficient IBD patient led to reconstitution of the anti-inflammatory response - reinitiating the IL-10RB expression, IL-10-inducible phosphorylation of STAT3, and subsequent SOCS3 expression [76]. This second study also showed that LPS-mediated TNF-α secretion could be modulated by IL-10 stimulation in gene-edited iPSCs-derived macrophages. Taken together, these established iPSC-derived macrophages based IBD models provide the opportunity to identify and validate new curative molecular and cellular therapies against IBD and other inflammatory syndromes.
The iPSCs-derived macrophage strategy has also been applied to the exciting field of cancer immunotherapy. Chimera antigen receptor (CAR)-T cells and NK cells re shown to have potent cytotoxicity against tumor cells with CAR-T cell therapy having gained great success in the clinic [77]. Recently CAR-macrophages have been developed by engineering an adenoviral vector to express a CAR targeted against human epidermal growth factor receptor 2, (a biomarker in many solid tumors) and imparted a sustained pro-inflammatory (M1) phenotype [78]. The model showed great success by demonstrating antigen-specific phagocytosis and tumor clearance in vitro as well as decreasing tumor burden and prolonged overall survival in two solid tumor xenograft models [78]. These successful pre-clinical data have led to an Phase-1 clinical trial using HER2 re-targeted CAR-macrophages for the treatment of solid tumors [77]. Other examples of iPSC-derived CAR-macrophages with antigen-dependent anti-cancer functions include those expressing either CD19 and mesothelin-specific fusion receptors [74]. CAR-macrophages demonstrated functions including expression and secretion of cytokines, polarization toward the pro-inflammatory/anti-tumor state, enhanced phagocytosis of tumor cells, and in anti-cancer cell activity in vivo when stimulated by tumor antigens. These data demonstrate the technology platform of iPSC-derived CAR-macrophage to eliminate cancer cells. These CAR engineered iPSCs-derived macrophages is a ground breaking technology in cancer immunotherapy and when combined with novel methods of bioreactor based bulk macrophage differentiation from iPSCs will provide an unlimited source of therapeutic cells [79].
3. Conclusion
In summary, the phenotypic, functional, and transcriptomic characteristics of iPSCs-derived macrophages share many similarities with both tissue resident macrophages and MDMs. The unlimited replication potential of iPSCs and the ease of genetic manipulation thus provides a valuable platform for disease modeling, drug screening, and studying the mechanisms of infection biology in various genetic backgrounds. Their autologous nature and polarization potential could also make them ideal tools for cell and regeneration therapy. iPSCs-derived macrophages have enormous potential in advancing our understanding of diseases that involve human macrophages and to date have demonstrated proof of principle utility in the development of disease models and in novel cell therapies. The use of iPSCs-derived macrophages does not eliminate the need for other models such as MDMs or BM-derived macrophages, but rather provides a complementary or alternative approach to further ensure validity and reproducibility. Together with genetic manipulations techniques such as CRISPR/Cas9 they can facilitate clinical and therapeutic translation for diseases such as liver fibrosis or inflammatory lung diseases where macrophages play an important clinical modulatory role. This is well highlighted by a research article under peer-review where M2 polarized iPSCs-derived macrophages are studied in context with COVID19 therapy [80]. The clinical potential of the macrophage cell therapy is highlighted by several clinical trials approved for autologous macrophages as intervention in various diseases including chronic liver injury, spinal cord injury, non-acute stroke, chronic anal fissure and as an anti-fibrotic treatment following COVID-19 infection [clinicaltrials.gov]. The future of iPSCs-derived macrophage therapy could be focused toward increasing their universality or increasing their better storage and differentiation as demonstrated by the studies of developing iPSCs-derived myeloid lines, continuous differentiation or cryopreservation [53, 81, 82]. An overview of the iPSCs-derived macrophages features and applications covered in this review is summarized as Figure 1.
Figure 1.
Summary of iPSCs-derived macrophages attributes and applications.
Acknowledgments
This work was funded by the UK Medical Research Council (MR/T013923/1) and Figure 1 was created using BioRender.com
Conflict of interest
The authors declare no conflict of interest.
\n',keywords:"iPSCs, macrophages, polarization, inflammation, regeneration, cell therapy",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/81477.pdf",chapterXML:"https://mts.intechopen.com/source/xml/81477.xml",downloadPdfUrl:"/chapter/pdf-download/81477",previewPdfUrl:"/chapter/pdf-preview/81477",totalDownloads:14,totalViews:0,totalCrossrefCites:0,dateSubmitted:"February 17th 2022",dateReviewed:"March 15th 2022",datePrePublished:"April 27th 2022",datePublished:null,dateFinished:"April 23rd 2022",readingETA:"0",abstract:"The ability to derive macrophages from human-induced pluripotent stem cells (iPSCs) provides an unlimited source of genotype-specific cells with the potential to play a role in advancing our understanding of macrophage biology in both homeostasis and disease. While sharing many of the functional characteristics of monocyte-derived macrophages, iPSC-derived macrophages have also been shown to have phenotypical and functional features associated with tissue resident macrophages. These features present new opportunities to develop models of human disease and to understand the role of developmental or tissue context in innate immune cell function. iPSCs-derived macrophages have also been identified as a highly attractive source for cell and gene therapy in the treatment of diverse degenerative diseases based on their anti-inflammatory activity, their ability to clear scarred cells by phagocytosis, and providing extracellular matrices. We review and present a concise discussion on macrophage differentiation from stem cells highlighting their advantages over classical monocyte-derived macrophages in modelling organ specific macrophages. We summarize the various disease models utilizing iPSCs-derived macrophages including hereditary syndromes and host-pathogen interactions in tissue repair and the strategies used to mimic pathological phenotypes. Finally, we describe the pre-clinical studies that have addressed the application of iPSCs-derived macrophages as a therapeutic intervention.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/81477",risUrl:"/chapter/ris/81477",signatures:"Shyam Sushama Jose and Lesley M. Forrester",book:{id:"11277",type:"book",title:"Macrophages -140 Years of Their Discovery",subtitle:null,fullTitle:"Macrophages -140 Years of Their Discovery",slug:null,publishedDate:null,bookSignature:"Dr. Vijay Kumar",coverURL:"https://cdn.intechopen.com/books/images_new/11277.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80355-625-3",printIsbn:"978-1-80355-624-6",pdfIsbn:"978-1-80355-626-0",isAvailableForWebshopOrdering:!0,editors:[{id:"63844",title:"Dr.",name:"Vijay",middleName:null,surname:"Kumar",slug:"vijay-kumar",fullName:"Vijay Kumar"}],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. Human induced pluripotent stem cells for macrophage production in vitro",level:"1"},{id:"sec_2_2",title:"2.1 iPSCs-derived macrophages share features of MDM",level:"2"},{id:"sec_3_2",title:"2.2 iPSCs derived macrophages model tissue resident macrophages",level:"2"},{id:"sec_4_2",title:"2.3 iPSCs derived macrophages in disease modeling",level:"2"},{id:"sec_5_2",title:"2.4 iPSCs-derived macrophages in host-pathogen interactions",level:"2"},{id:"sec_6_2",title:"2.5 iPSCs-derived macrophages in cell and regenerative therapy",level:"2"},{id:"sec_8",title:"3. Conclusion",level:"1"},{id:"sec_9",title:"Acknowledgments",level:"1"},{id:"sec_12",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Murray PJ. Macrophage polarization. Annual Review of Physiology. 2017;79(1):541-566. DOI: 10.1146/annurev-physiol-022516-034339'},{id:"B2",body:'Wynn TA, Vannella KM. Macrophages in tissue repair, regeneration, and fibrosis. 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Clinical Immunology. 2010;137(1):89-101'},{id:"B66",body:'Brennan PN, MacMillan M, Manship T, Moroni F, Glover A, Graham C, et al. Study protocol: A multicentre, open-label, parallel-group, phase 2, randomised controlled trial of autologous macrophage therapy for liver cirrhosis (MATCH). BMJ Open. 2021;11(11):e053190'},{id:"B67",body:'Chernykh ER, Shevela EY, Starostina NM, Morozov SA, Davydova MN, Menyaeva EV, et al. Safety and therapeutic potential of M2 macrophages in stroke treatment. Cell Transplantation. 2016;25(8):1461-1471. DOI: 10.3727/096368915X690279'},{id:"B68",body:'Haideri SS, McKinnon AC, Taylor AH, Kirkwood P, Starkey Lewis PJ, O’Duibhir E, et al. Injection of embryonic stem cell derived macrophages ameliorates fibrosis in a murine model of liver injury. npj. Regenerative Medicine. 2017;2(1):14. DOI: 10.1038/s41536-017-0017-0'},{id:"B69",body:'Pouyanfard S, Meshgin N, Cruz LS, Diggle K, Hashemi H, Pham TV, et al. Human induced pluripotent stem cell-derived macrophages ameliorate liver fibrosis. Stem Cells. 2021;39(12):1701-1717. DOI: 10.1002/stem.3449'},{id:"B70",body:'Happle C, Lachmann N, Ackermann M, Mirenska A, Göhring G, Thomay K, et al. Pulmonary transplantation of human induced pluripotent stem cell–derived macrophages ameliorates pulmonary alveolar proteinosis. American Journal of Respiratory and Critical Care Medicine. 2018;198(3):350-360. DOI: 10.1164/rccm.201708-1562OC'},{id:"B71",body:'Kuhn A, Ackermann M, Mussolino C, Cathomen T, Lachmann N, Moritz T. TALEN-mediated functional correction of human iPSC-derived macrophages in context of hereditary pulmonary alveolar proteinosis. Scientific Reports. 2017;7(1):15195. DOI: 10.1038/s41598-017-14566-8'},{id:"B72",body:'Mukhopadhyay S, Heinz E, Porreca I, Alasoo K, Yeung A, Yang H-T, et al. Loss of IL-10 signaling in macrophages limits bacterial killing driven by prostaglandin E2. The Journal of Experimental Medicine. 2019;217(2):e20180649. DOI: 10.1084/jem.20180649'},{id:"B73",body:'Ma P-F, Gao C-C, Yi J, Zhao J-L, Liang S-Q , Zhao Y, et al. Cytotherapy with M1-polarized macrophages ameliorates liver fibrosis by modulating immune microenvironment in mice. Journal of Hepatology. 2017;67(4):770-779'},{id:"B74",body:'Zhang L, Tian L, Dai X, Yu H, Wang J, Lei A, et al. Pluripotent stem cell-derived CAR-macrophage cells with antigen-dependent anti-cancer cell functions. Journal of Hematology & Oncology. 2020;13(1):153. DOI: 10.1186/s13045-020-00983-2'},{id:"B75",body:'Senju S, Koba C, Haruta M, Matsunaga Y, Matsumura K, Haga E, et al. Application of iPS cell-derived macrophages to cancer therapy. Oncoimmunology. 2014;3(3):e27927. DOI: 10.4161/onci.27927'},{id:"B76",body:'Hoffmann D, Sens J, Brennig S, Brand D, Philipp F, Vollmer Barbosa P, et al. Genetic correction of IL-10RB deficiency reconstitutes anti-inflammatory regulation in iPSC-derived macrophages. Journal of Personalized Medicine. 2021;11:221'},{id:"B77",body:'Mazza R, Maher J. Prospects for development of induced pluripotent stem cell-derived CAR-targeted immunotherapies. Archivum Immunologiae et Therapiae Experimentalis (Warsz). 2021;70(1):2. DOI: 10.1007/s00005-021-00640-7'},{id:"B78",body:'Klichinsky M, Ruella M, Shestova O, Lu XM, Best A, Zeeman M, et al. Human chimeric antigen receptor macrophages for cancer immunotherapy. Nature Biotechnology. 2020;38(8):947-953. DOI: 10.1038/s41587-020-0462-y'},{id:"B79",body:'Ackermann M, Kempf H, Hetzel M, Hesse C, Hashtchin AR, Brinkert K, et al. Bioreactor-based mass production of human iPSC-derived macrophages enables immunotherapies against bacterial airway infections. Nature Communications. 2018;9(1):5088. DOI: 10.1038/s41467-018-07570-7'},{id:"B80",body:'Duan F, Guo L, Yang L, Han Y, Thakur A, Nilsson-Payant BE, et al. Modeling COVID-19 with human pluripotent stem cell-derived cells reveals synergistic effects of anti-inflammatory macrophages with ACE2 inhibition against SARS-CoV-2. Res Sq. 2020:rs.3.rs-rs62758 [Preprint repository article ahead of peer-review]'},{id:"B81",body:'Ackermann M, Rafiei Hashtchin A, Manstein F, Carvalho Oliveira M, Kempf H, Zweigerdt R, et al. Continuous human iPSC-macrophage mass production by suspension culture in stirred tank bioreactors. Nature Protocols. 2022;17(2):513-539. DOI: 10.1038/s41596-021-00654-7'},{id:"B82",body:'Munn C, Burton S, Dickerson S, Bakshy K, Strouse A, Rajesh D. Generation of cryopreserved macrophages from normal and genetically engineered human pluripotent stem cells for disease modelling. PLoS One. 2021;16(4):e0250107. DOI: 10.1371/journal.pone.0250107'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Shyam Sushama Jose",address:null,affiliation:'
Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, Scotland
'},{corresp:"yes",contributorFullName:"Lesley M. Forrester",address:"l.forrester@ed.ac.uk",affiliation:'
Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, Scotland
'}],corrections:null},book:{id:"11277",type:"book",title:"Macrophages -140 Years of Their Discovery",subtitle:null,fullTitle:"Macrophages -140 Years of Their Discovery",slug:null,publishedDate:null,bookSignature:"Dr. Vijay Kumar",coverURL:"https://cdn.intechopen.com/books/images_new/11277.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80355-625-3",printIsbn:"978-1-80355-624-6",pdfIsbn:"978-1-80355-626-0",isAvailableForWebshopOrdering:!0,editors:[{id:"63844",title:"Dr.",name:"Vijay",middleName:null,surname:"Kumar",slug:"vijay-kumar",fullName:"Vijay Kumar"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},profile:{item:{id:"193947",title:"Dr.",name:"Mohammad",middleName:null,surname:"Mojtahedi",email:"m.mojtahedi@unsw.edu.au",fullName:"Mohammad Mojtahedi",slug:"mohammad-mojtahedi",position:null,biography:null,institutionString:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",totalCites:0,totalChapterViews:"0",outsideEditionCount:0,totalAuthoredChapters:"2",totalEditedBooks:"0",personalWebsiteURL:null,twitterURL:null,linkedinURL:null,institution:{name:"UNSW Sydney",institutionURL:null,country:{name:"Australia"}}},booksEdited:[],chaptersAuthored:[{id:"56346",title:"An Additive Statistical Modeling Approach to the Analysis of Transport Infrastructure Flood Risk-Based Resilience",slug:"an-additive-statistical-modeling-approach-to-the-analysis-of-transport-infrastructure-flood-risk-bas",abstract:"Australia is a very vulnerable region to flood events, and the frequency of flood events and damage has increased dramatically over the past decades. Although flood has impacted diverse types of buildings and built infrastructure, there has been limited research investigating flood risk management specific to transport infrastructure in Australia and the factors that might influence the resilience of the transport infrastructure to flooding. To develop an appropriate design management system for roads and bridges specific to risk assessment from flooding requires a multitude of factors to be identified and analyzed. In this study, we review the range of critical factors necessary to represent the resilience of bridges to extreme flood events and demonstrate a novel mathematical approach to evaluate the relationship between the bridge resilience and flood risk. We use additive statistical approach in arriving at a framework to evaluate the resilience of bridges. The findings confirm that metrological characteristics such as annual exceedance probability and probable maximum precipitation and structural integrity of the bridge represented by the structural age of the bridge and mechanical properties of the soils have a substantial impact on the resilience of the Australian transport infrastructure, particularly bridges located on main roads.",signatures:"Mohammad Mojtahedi, Sidney Newton and Faham Tahmasebinia",authors:[{id:"193947",title:"Dr.",name:"Mohammad",surname:"Mojtahedi",fullName:"Mohammad Mojtahedi",slug:"mohammad-mojtahedi",email:"m.mojtahedi@unsw.edu.au"},{id:"200222",title:"Dr.",name:"Sidney",surname:"Newton",fullName:"Sidney Newton",slug:"sidney-newton",email:"s.newton@unsw.edu.au"},{id:"200223",title:"Dr.",name:"Faham",surname:"Tahmasebinia",fullName:"Faham Tahmasebinia",slug:"faham-tahmasebinia",email:"f.tahmasebinia@unsw.edu.au"}],book:{id:"6018",title:"Flood Risk Management",slug:"flood-risk-management",productType:{id:"1",title:"Edited Volume"}}},{id:"70039",title:"A GIS-Based Risk and Safety Analysis of Entrance Areas in Educational Buildings Based on Students’ Experience",slug:"a-gis-based-risk-and-safety-analysis-of-entrance-areas-in-educational-buildings-based-on-students-ex",abstract:"The architecture of educational buildings is required to meet the contemporary needs and follow regulations concerning safety issues in an intelligent, resilient, and systematic manner. However, the current literature generally neglects to identify geo-referenced risks within GIS environment based on the users’ perceptions of educational environments. This research aims to present a newly formulated risk evaluation criteria for assessing the spaces within and outside educational buildings. This chapter investigates students’ experience of using different micro-spaces, architects’ predesign assumptions and expectations of the spaces, and post-design assessment of the spaces. Two case studies of educational spaces within University of New South Wales campus in Kensington, Sydney was selected, and the questionnaire method was employed to collect data from students, who routinely use the selected areas. By comparing the results of the two buildings and mapping them in GIS, it is suggested that feelings of safety and security can be increased via improving the building features and enhancing the building control and security control, for example, installing CCTV and other security infrastructure. Data-driven findings mapped into GIS create a prototype for the identification of problematic areas on a map. The results help decision-makers to understand risks and strengthen risk reduction strategies. This work is also a step towards smarter buildings and enhanced preparedness for an effective response to a security threat, both minimal and extreme.",signatures:"Sara Shirowzhan, Laurence Kimmel, Mohammad Mojtahedi, Samad Sepasgozar and Jack Peacock",authors:[{id:"193947",title:"Dr.",name:"Mohammad",surname:"Mojtahedi",fullName:"Mohammad Mojtahedi",slug:"mohammad-mojtahedi",email:"m.mojtahedi@unsw.edu.au"},{id:"221172",title:"Dr.",name:"Samad M.E.",surname:"Sepasgozar",fullName:"Samad M.E. Sepasgozar",slug:"samad-m.e.-sepasgozar",email:"samad.sepasgozar@gmail.com"},{id:"273838",title:"Dr.",name:"Sara",surname:"Shirowzhan",fullName:"Sara Shirowzhan",slug:"sara-shirowzhan",email:"s.shirowzhan@unsw.edu.au"},{id:"306365",title:"Dr.",name:"Laurence",surname:"Kimmel",fullName:"Laurence Kimmel",slug:"laurence-kimmel",email:"laurence.kimmel@unsw.edu.au"},{id:"306367",title:"Mr.",name:"Jack",surname:"Peacock",fullName:"Jack Peacock",slug:"jack-peacock",email:"j.peacock@unsw.edu.au"}],book:{id:"9431",title:"Smart Cities and Construction Technologies",slug:"smart-cities-and-construction-technologies",productType:{id:"1",title:"Edited Volume"}}}],collaborators:[{id:"11196",title:"Dr.",name:"Khiruddin",surname:"Abdullah",slug:"khiruddin-abdullah",fullName:"Khiruddin Abdullah",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"50312",title:"Prof.",name:"Ali",surname:"Assani",slug:"ali-assani",fullName:"Ali Assani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"151303",title:"Prof.",name:"Nik Norulaini",surname:"Ab Rahman",slug:"nik-norulaini-ab-rahman",fullName:"Nik Norulaini Ab Rahman",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universiti Sains Malaysia",institutionURL:null,country:{name:"Malaysia"}}},{id:"151344",title:"Prof.",name:"Mohd Omar",surname:"Ab Kadir",slug:"mohd-omar-ab-kadir",fullName:"Mohd Omar Ab Kadir",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"202188",title:"Dr.",name:"Sebastian",surname:"Goers",slug:"sebastian-goers",fullName:"Sebastian Goers",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Johannes Kepler University of Linz",institutionURL:null,country:{name:"Austria"}}},{id:"202772",title:"Ph.D.",name:"Elżbieta",surname:"Jarosińska",slug:"elzbieta-jarosinska",fullName:"Elżbieta Jarosińska",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Cracow University of Technology",institutionURL:null,country:{name:"Poland"}}},{id:"202833",title:"MSc.",name:"Katarzyna",surname:"Pierzga",slug:"katarzyna-pierzga",fullName:"Katarzyna Pierzga",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"206477",title:"Prof.",name:"Friedrich",surname:"Schneider",slug:"friedrich-schneider",fullName:"Friedrich Schneider",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"206478",title:"Dr.",name:"Horst",surname:"Steinmüller",slug:"horst-steinmuller",fullName:"Horst Steinmüller",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"206479",title:"MSc.",name:"Andreas",surname:"Zauner",slug:"andreas-zauner",fullName:"Andreas Zauner",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null}]},generic:{page:{slug:"prior-publication-policy",title:"Prior Publication Policy",intro:"
The Internet has irrevocably changed the dynamics of scholarly communication and publishing. Consequently, we find it necessary to indicate, unambiguously, our definition of what we consider to be a published scientific work.
A significant number of working papers, early drafts, and similar work in progress are openly shared online between members of the scientific community. It has become common to announce one’s own research on a personal website or a blog to gather comments and suggestions from other researchers. Such works and online postings are, indeed, published in the sense that they are made publicly available. However, this does not mean that if submitted for publication by IntechOpen they are not original works. We differentiate between reviewed and non-reviewed works when determining whether a work is original and has been published in a scholarly sense or not.
\\n\\n
The significance of Peer Review cannot be overstated when it comes to defining, in our terms, what constitutes a published scientific work. Peer Review is widely considered to be the cornerstone of modern publishing processes and the key value-adding contribution to a scholarly manuscript that a publisher can make.
\\n\\n
Other than the issue of originality, research misconduct is another major issue that all publishers have to address. IntechOpen’s Retraction & Correction Policy and various publication ethics guidelines identify both redundant publication and (self)plagiarism to fall within the definition of research misconduct, thus constituting grounds for rejection or the issue of a Retraction if the work has already been published.
\\n\\n
In order to facilitate the tracking of a manuscript’s publishing history and its development from its earliest draft to the manuscript submitted, we encourage Authors to disclose any instances of a manuscript’s prior publication, whether it be through a conference presentation, a newspaper article, a working paper publicly available in a repository or a blog post.
\\n\\n
A note to the Academic Editor containing detailed information about a submitted manuscript’s previous public availability is the preferred means of reporting prior publication. This helps us determine if there are any earlier versions of a manuscript that should be disclosed to our readers or if any of those earlier versions should be cited and listed in a manuscript’s references.
\\n\\n
Some basic information about the editorial treatment of different varieties of prior publication is laid out below:
\\n\\n
1. CONFERENCE PAPERS & PRESENTATIONS
\\n\\n
Given that conference papers and presentations generally pass through some sort of peer or editorial review, we consider them to be published in the accepted scholarly sense, particularly if they are published as a part of conference proceedings.
\\n\\n
All submitted manuscripts originating from a previously published conference paper must contain at least 50% of new original content to be accepted for review and considered for publication.
\\n\\n
Authors are required to report any links their manuscript might have with their earlier conference papers and presentations in a note to the Academic Editor, as well as in the manuscript itself. Additionally, Authors should obtain any necessary permissions from the publisher of their conference paper if copyright transfer occurred during the publishing process. Failure to do so may prevent Us from publishing an otherwise worthy work.
\\n\\n
2. NEWSPAPER & MAGAZINE ARTICLES
\\n\\n
Newspaper and magazine articles usually do not pass through any extensive peer or editorial review and we do not consider them to be published in the scholarly sense. Articles appearing in newspapers and magazines rarely possess the depth and structure characteristic of scholarly articles.
\\n\\n
Submitted manuscripts stemming from a previous newspaper or magazine article will be accepted for review and considered for publication. However, Authors are strongly advised to report any such publication in an accompanying note to the External Editor.
\\n\\n
As with the conference papers and presentations, Authors should obtain any necessary permissions from the newspaper or magazine that published the work, and indicate that they have done so in a note to the External Editor.
\\n\\n
3. GREY LITERATURE
\\n\\n
White papers, working papers, technical reports and all other forms of papers which fall within the scope of the ‘Luxembourg definition’ of grey literature do not pass through any extensive peer or editorial review and we do not consider them to be published in the scholarly sense.
\\n\\n
Although such papers are regularly made publicly available via personal websites and institutional repositories, their general purpose is to gather comments and feedback from Authors’ colleagues in order to further improve a manuscript intended for future publication.
\\n\\n
When submitting their work, Authors are required to disclose the existence of any publicly available earlier drafts in a note to the Academic Editor. In cases where earlier drafts of the submitted version of the manuscript are publicly available, any overlap between the versions will generally not be considered an instance of self-plagiarism.
\\n\\n
4. SOCIAL MEDIA, BLOG & MESSAGE BOARD POSTINGS
\\n\\n
We feel that social media, blogs and message boards are generally used with the same intention as grey literature, to formulate ideas for a manuscript and gather early feedback from like-minded researchers in order to improve a particular piece of work before submitting it for publication. Therefore, we do not consider such internet postings to be publication in the scholarly sense.
\\n\\n
Nevertheless, Authors are encouraged to disclose the existence of any internet postings in which they outline and describe their research or posted passages of their manuscripts in a note to the Academic Editor. Please note that we will not strictly enforce this request in the same way that we would instructions we consider to be part of our conditions of acceptance for publication. We understand that it may be difficult to keep track of all one’s internet postings in which the researcher´s current work might be mentioned.
\\n\\n
In cases where there is any overlap between the Author´s submitted manuscript and related internet postings, we will generally not consider it to be an instance of self-plagiarism. This also holds true for any co-Author as well.
A significant number of working papers, early drafts, and similar work in progress are openly shared online between members of the scientific community. It has become common to announce one’s own research on a personal website or a blog to gather comments and suggestions from other researchers. Such works and online postings are, indeed, published in the sense that they are made publicly available. However, this does not mean that if submitted for publication by IntechOpen they are not original works. We differentiate between reviewed and non-reviewed works when determining whether a work is original and has been published in a scholarly sense or not.
\n\n
The significance of Peer Review cannot be overstated when it comes to defining, in our terms, what constitutes a published scientific work. Peer Review is widely considered to be the cornerstone of modern publishing processes and the key value-adding contribution to a scholarly manuscript that a publisher can make.
\n\n
Other than the issue of originality, research misconduct is another major issue that all publishers have to address. IntechOpen’s Retraction & Correction Policy and various publication ethics guidelines identify both redundant publication and (self)plagiarism to fall within the definition of research misconduct, thus constituting grounds for rejection or the issue of a Retraction if the work has already been published.
\n\n
In order to facilitate the tracking of a manuscript’s publishing history and its development from its earliest draft to the manuscript submitted, we encourage Authors to disclose any instances of a manuscript’s prior publication, whether it be through a conference presentation, a newspaper article, a working paper publicly available in a repository or a blog post.
\n\n
A note to the Academic Editor containing detailed information about a submitted manuscript’s previous public availability is the preferred means of reporting prior publication. This helps us determine if there are any earlier versions of a manuscript that should be disclosed to our readers or if any of those earlier versions should be cited and listed in a manuscript’s references.
\n\n
Some basic information about the editorial treatment of different varieties of prior publication is laid out below:
\n\n
1. CONFERENCE PAPERS & PRESENTATIONS
\n\n
Given that conference papers and presentations generally pass through some sort of peer or editorial review, we consider them to be published in the accepted scholarly sense, particularly if they are published as a part of conference proceedings.
\n\n
All submitted manuscripts originating from a previously published conference paper must contain at least 50% of new original content to be accepted for review and considered for publication.
\n\n
Authors are required to report any links their manuscript might have with their earlier conference papers and presentations in a note to the Academic Editor, as well as in the manuscript itself. Additionally, Authors should obtain any necessary permissions from the publisher of their conference paper if copyright transfer occurred during the publishing process. Failure to do so may prevent Us from publishing an otherwise worthy work.
\n\n
2. NEWSPAPER & MAGAZINE ARTICLES
\n\n
Newspaper and magazine articles usually do not pass through any extensive peer or editorial review and we do not consider them to be published in the scholarly sense. Articles appearing in newspapers and magazines rarely possess the depth and structure characteristic of scholarly articles.
\n\n
Submitted manuscripts stemming from a previous newspaper or magazine article will be accepted for review and considered for publication. However, Authors are strongly advised to report any such publication in an accompanying note to the External Editor.
\n\n
As with the conference papers and presentations, Authors should obtain any necessary permissions from the newspaper or magazine that published the work, and indicate that they have done so in a note to the External Editor.
\n\n
3. GREY LITERATURE
\n\n
White papers, working papers, technical reports and all other forms of papers which fall within the scope of the ‘Luxembourg definition’ of grey literature do not pass through any extensive peer or editorial review and we do not consider them to be published in the scholarly sense.
\n\n
Although such papers are regularly made publicly available via personal websites and institutional repositories, their general purpose is to gather comments and feedback from Authors’ colleagues in order to further improve a manuscript intended for future publication.
\n\n
When submitting their work, Authors are required to disclose the existence of any publicly available earlier drafts in a note to the Academic Editor. In cases where earlier drafts of the submitted version of the manuscript are publicly available, any overlap between the versions will generally not be considered an instance of self-plagiarism.
\n\n
4. SOCIAL MEDIA, BLOG & MESSAGE BOARD POSTINGS
\n\n
We feel that social media, blogs and message boards are generally used with the same intention as grey literature, to formulate ideas for a manuscript and gather early feedback from like-minded researchers in order to improve a particular piece of work before submitting it for publication. Therefore, we do not consider such internet postings to be publication in the scholarly sense.
\n\n
Nevertheless, Authors are encouraged to disclose the existence of any internet postings in which they outline and describe their research or posted passages of their manuscripts in a note to the Academic Editor. Please note that we will not strictly enforce this request in the same way that we would instructions we consider to be part of our conditions of acceptance for publication. We understand that it may be difficult to keep track of all one’s internet postings in which the researcher´s current work might be mentioned.
\n\n
In cases where there is any overlap between the Author´s submitted manuscript and related internet postings, we will generally not consider it to be an instance of self-plagiarism. This also holds true for any co-Author as well.
\n'}]},successStories:{items:[]},authorsAndEditors:{filterParams:{},profiles:[{id:"396",title:"Dr.",name:"Vedran",middleName:null,surname:"Kordic",slug:"vedran-kordic",fullName:"Vedran Kordic",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/396/images/7281_n.png",biography:"After obtaining his Master's degree in Mechanical Engineering he continued his education at the Vienna University of Technology where he obtained his PhD degree in 2004. He worked as a researcher at the Automation and Control Institute, Faculty of Electrical Engineering, Vienna University of Technology until 2008. 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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. Shukla",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:"356823",title:"MSc.",name:"Seonghee",middleName:null,surname:"Min",slug:"seonghee-min",fullName:"Seonghee Min",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Daegu University",country:{name:"Korea, South"}}},{id:"353307",title:"Prof.",name:"Yoosoo",middleName:null,surname:"Oh",slug:"yoosoo-oh",fullName:"Yoosoo Oh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:"Yoosoo Oh received his Bachelor's degree in the Department of Electronics and Engineering from Kyungpook National University in 2002. 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. His research interests include Activity Fusion & Reasoning, Machine Learning, Context-aware Middleware, Human-Computer Interaction, etc.",institutionString:null,institution:{name:"Daegu Gyeongbuk Institute of Science and Technology",country:{name:"Korea, South"}}},{id:"262719",title:"Dr.",name:"Esma",middleName:null,surname:"Ergüner Özkoç",slug:"esma-erguner-ozkoc",fullName:"Esma Ergüner Özkoç",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Başkent University",country:{name:"Turkey"}}},{id:"346530",title:"Dr.",name:"Ibrahim",middleName:null,surname:"Kaya",slug:"ibrahim-kaya",fullName:"Ibrahim Kaya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"419199",title:"Dr.",name:"Qun",middleName:null,surname:"Yang",slug:"qun-yang",fullName:"Qun Yang",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Auckland",country:{name:"New Zealand"}}},{id:"351158",title:"Prof.",name:"David W.",middleName:null,surname:"Anderson",slug:"david-w.-anderson",fullName:"David W. Anderson",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Calgary",country:{name:"Canada"}}}]}},subseries:{item:{id:"86",type:"subseries",title:"Business and Management",keywords:"Demographic shifts, Innovation, Technology, Next-gen leaders, Worldwide environmental issues and clean technology, Uncertainty and political risks, Radical adjacency, Emergence of new business ecosystem type, Emergence of different leader and leader values types, Universal connector, Elastic enterprise, Business platform, Supply chain complexity",scope:"
\r\n\tThe Business and Management series topic focuses on the most pressing issues confronting organizations today and in the future. Businesses are trying to figure out how to lead in a time of global uncertainty. In emerging markets, issues such as ill-defined or unstable policies, as well as corrupt practices, can be hugely problematic. Changes in governments can result in new policy, regulations, and interest rates, all of which can be detrimental to foreign businesses and investments. A growing trend towards economic nationalism also makes the current global political landscape potentially hostile towards international businesses.
\r\n
\r\n\tThe demographic shifts are creating interesting challenges. People are living longer, resulting to an aging demographic. We have a large population of older workers and retirees who are living longer lives, combined with a declining birthrate in most parts of the world. Businesses of all types are looking at how technology is affecting their operations. Several questions arise, such as: How is technology changing what we do? How is it transforming us internally, how is it influencing our clients and our business strategy? It is about leveraging technology to improve efficiency, connect with customers more effectively, and drive innovation. The majority of innovative companies are technology-driven businesses. Realizing digital transformation is today’s top issue and will remain so for the next five years. Improving organizational agility, expanding portfolios of products and services, creating, and maintaining a culture of innovation, and developing next -generation leaders were also identified as top challenges in terms of both current and future issues.
\r\n
\r\n\tThe most sustained profitable growth occurs when a company expands its core business into an adjacent space. This has significant implications for management because innovation in business ecosystems differs from traditional, vertically integrated firms. Every organization in the ecosystem must be aware of the bigger picture. Innovation in ecosystems necessitates collaborative action to invent and appraise, efficient, cross-organizational knowledge flows, modular architectures, and good stewardship of legacy systems. It is built on multiple, interconnected platforms. Environmental factors have already had a significant impact in the West and will continue to have an impact globally. Businesses must take into account the environmental impact of their daily operations. The advantage of this market is that it is expected to grow more rapidly than the overall economy. Another significant challenge is preparing the next generation of leaders to elevate this to the number one priority within the next five years. There can be no culture of innovation unless there is diverse leadership or development of the next generation of leaders; and these diverse, next-generation leaders are the ones who will truly understand the digital strategies that will drive digital transformation.
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